08-29-2021 - 0246 - Mass Vaccination Program - COVID-19 Pandemic COVID 2021 2000 J.2000 J2000; Vaccinia IG (human) (VIG) was developed in the 1960s for the purpose of ameliorating side effects associated with vaccinia immunization... It is considered valuable “insurance,” to be held in reserve if a patient is receiving an experimental vaccine that involves a vaccinia carrier virus, or to prevent or manage complications of smallpox vaccination should such be required for a bioterrorism threat. - - - - Diverse profile Winers: 1. petersen profile - Phosphatidylethanolamine- lipodistrophy organ trans - HIV; Account - molluscum contagium, poxiviridae USA. 2. Dr. Beatles profile - sarcoma fibromatosis - EIE EIA; Account - Daughter end at USA. 3. CIVLEVEL - Overvaccination to progressive vaccina - Hyperimmunity; etc.. Account - Illusion USA; DEceit by USA, Conspiracy, etc.. - RISIS Biden Says U.S. Leads The World In Vaccine Donations - It is considered valuable “insurance,” to be held in reserve if a patient is receiving an experimental vaccine that involves a vaccinia carrier virus, or to prevent or manage complications of smallpox vaccination should such be required for a bioterrorism threat. Although the vaccine registration had already been terminated at that time, the vaccine could still have been in uncontrolled use. - N-S @ ALL TAG PRO PHOSTON T-CW - More Than 5.22 Billion Shots United States Underreport at number: 369M 369,000,000 174M 174,000,000 52.9% TOTAL LIFE IMMUNIZATION/PROGRAM/GENETICS/GEN-MOD/RE/ETC.- AIDS HIV SIV - 'HIV-1 Escape from NKG2D-Mediated Recognition by NK Cells' (Jost et al., 2016) - 'such as vaccine virus–induced paralysis are highlighted in this article.' (Encyclopedia Public Health, 2017) ' • VAPP: antecedent administration of OPV from 1 week to 1 month before symptoms; recent administration of DTP (diphtheria, tetanus, pertussis) vaccine may enhance paralysis in active poliovirus infection' (Fisher MD et al., 2007) - 'Poliovirus, a nonenveloped, positive-sense, single-stranded RNA virus, is a member of the Enterovirus genus within the family Picornaviridae. 'PVR transgenic mice are not susceptible to oral poliovirus infection unless they are deficient in the type I interferon (IFN) response (Ohka et al., 2007; Ida-Hosonuma et al., 2005);...' Providing molecular insight into bacterial enhancement of poliovirus infectivity, N-acetylglucosamine (GlcNAc)-containing polysaccharides expressed on bacterial surfaces including lipopolysaccharide (LPS) and peptidoglycan (PG), also stabilized virus (Kuss et al., 2011; Robinson et al., 2014).' (Garg, Karst et al., 2016)
Robert Francis Kennedy Jr. (born January 17, 1954) is an American environmental lawyer, author, and anti-vaccine advocate. Kennedy is a son of U.S. senator Robert F. Kennedy and a nephew of president John F. Kennedy.
Vaccinia Vaccinia induced actin polymerization is dependent on Src and Abl family kinase mediated phosphorylation of the IEV protein A36 (Frischknecht et al., 1999; From: Virus Research, 2015
Vaccinia IG (human) (VIG) was developed in the 1960s for the purpose of ameliorating side effects associated with vaccinia immunization, including eczema vaccinatum, generalized, and progressive vaccinia.48 The original preparation contained a high proportion of protein aggregates and thus was administered IM. The use of VIG has become extremely limited since the eradication of smallpox. It is considered valuable “insurance,” to be held in reserve if a patient is receiving an experimental vaccine that involves a vaccinia carrier virus, or to prevent or manage complications of smallpox vaccination should such be required for a bioterrorism threat.Recently, a preparation of VIG suitable for IV use (VIG-IGIV) has gained FDA approval. In the event that VIG is required, it can be obtained through the Centers for Disease Control and Prevention (CDC: www.bt.cdc.gov/agent/smallpox/).
Evident in USAF and unco of CL1Grade Low Waste. Tissue scars eczema liquefies with anesthetic surg/pyrotics/phosphors/phos ders/solvents/genetic dissolution protein dissolution/nucleoradiation/etc.. infection asympto hidden by methroxetrate/alkali; they require alkali environment to stabilize, intolerant of acids (damage to nerves evident with reinnervation attempts or psuedosignal). MJ v. nothing; scrambled; vaccina or HIV or Acquired-Immunity (esp. in presence of nucleoradiation, over radiation environment, methroxetrate environment allergens etc.). small pox virus campaign 1920-1980. coverup USA petersens-usaf-usa-nac-etc. guilty as charged. Stronger than the man. Evident at UCLA, etc..
Evident at high risk criminals, petersen, smith, mx, hawaii, middle east, bruens, browns, norway, jew, aziv, layng, grayden, psychopath, criminals in conspiracy to traffick birthright, wade siboan, social work, USA, USAF, USAF, USA, NAC, US, psychology, sociology, criminal justice law, US law enforcement, inferior, inferior scientist, rebodied persons, double connect, indoctrinated, carried memory without appreciation, everyone except VIV/birthright/etc., clones, stolen child trafficker family, stolen child, trafficker, trafficker sympathizer, etc.. Conspiracy to cover up gross theft of intellectual property. Damages by USA are not excusable. VIV and birthright never of USA (enduring enhostage situation). Diverse profile Winers: Poseidon 1. petersen profile - Phosphatidylethanolamine- lipodistrophy organ trans - HIV; Account - molluscum contagium, poxiviridae USA. 2. Dr. Beatles profile - sarcoma fibromatosis - EIE EIA; Account - Daughter end at USA. 3. CIVLEVEL - Overvaccination to progressive vaccina [unk civs], HyperImmune/anaphylaxis-rash-fever (subclinical/asymptomatic)/allergy/autoimmune disease-condition-etc./gen-dis/gen-mod/etc.-HIDS(huminal immune deficiency syndrome)-IDS (immune deficiency disease disorder dysfunction)/AIDS w/ or w/o HIV ssN negs vi, - Hyperimmunity downstepping etc.; etc.. Account - Illusion-Delusion-Disease-Deform-Dangerous-Disorder-Mental/Ill-InferiorGenetics-Denial USA; DEceit by USA, Conspiracy, Birthright victim of mass trafficking (missing parts, shell eyes etc.), scientist SSF enhostage, amnestic drug/cloak/technology advancement and pharmaceutical advancement not disclosed to General populace-world and where use by USA in manner as not intended by manuf./IP-origin-designer-eng-original-etc./etc./etc.. (one boyfriend overvaccinated)
Rhabdoviridae
Rhabdoviridae are part of the Mononegavirales order, which includes other virus families such as the Paramyxoviridae, the Filoviridae, and the Bornaviridae.
In the U.S., 369 million doses have been administered
Updated: August 29, 2021, 4:06 PM EDT
Vaccine Tracker
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The biggest vaccination campaign in history is underway. More than 5.22 billion doses have been administered across 183 countries, according to data collected by Bloomberg. The latest rate was roughly 40.2 million doses a day.
In the U.S., 369 million doses have been given so far. In the last week, an average of 886,566 doses per day were administered.
Vaccinia @ HIV or AIDS 1999 Equus -vaccine registration had already been terminated at that time, the vaccine could still have been in uncontrolled use @ borna disease, 2006; sciencedirect.
Epidemiological pattern of classical Borna disease and regional genetic clustering of Borna disease viruses point towards the existence of to-date unknown endemic reservoir host populations
Ralf Dürrwald, ... Norbert Nowotny, in Microbes and Infection, 2006
One BDV sequence derived from the parotid gland of a horse from Thuringia that developed cBD in 1993 (horse 51 med 93, [20]) was almost identical to the vaccine strain, whereas the brain- and kidney-derived BDV sequences from the same animal are placed more distantly within the “strain V group”. Although the vaccine registration had already been terminated at that time, the vaccine could still have been in uncontrolled use. A possible explanation for the strong sequence divergence within the same animal could be vaccination during the incubation period following natural infection with a field virus. The artificial subcutaneous inoculation with the vaccine strain could explain that this virus was found in an organ outside the central nervous system, as described by Binz et al. [20].
08-29-2021 - 0246 - Mass Vaccination Program - COVID-19 Pandemic COVID 2021 2000 J.2000 J2000; Vaccinia IG (human) (VIG) was developed in the 1960s for the purpose of ameliorating side effects associated with vaccinia immunization... It is considered valuable “insurance,” to be held in reserve if a patient is receiving an experimental vaccine that involves a vaccinia carrier virus, or to prevent or manage complications of smallpox vaccination should such be required for a bioterrorism threat. - - - - Diverse profile Winers: 1. petersen profile - Phosphatidylethanolamine- lipodistrophy organ trans - HIV; Account - molluscum contagium, poxiviridae USA. 2. Dr. Beatles profile - sarcoma fibromatosis - EIE EIA; Account - Daughter end at USA. 3. CIVLEVEL - Overvaccination to progressive vaccina - Hyperimmunity; etc.. Account - Illusion USA; DEceit by USA, Conspiracy, etc.. - RISIS Biden Says U.S. Leads The World In Vaccine Donations - It is considered valuable “insurance,” to be held in reserve if a patient is receiving an experimental vaccine that involves a vaccinia carrier virus, or to prevent or manage complications of smallpox vaccination should such be required for a bioterrorism threat. Although the vaccine registration had already been terminated at that time, the vaccine could still have been in uncontrolled use. - N-S @ ALL TAG PRO PHOSTON T-CW - More Than 5.22 Billion Shots United States Underreport at number: 369M 369,000,000 174M 174,000,000 52.9% TOTAL LIFE IMMUNIZATION/PROGRAM/GENETICS/GEN-MOD/RE/ETC.- NASTY - ENV AIR USA NAC DOM, F-CR-AR-Methroxetrates-bacillus and derivatives of rodular negative virus - etc.; Water, Rates constrained by infrastructure/building/concrete/cheap materials/reused copper/etc..
Vaccinia IG (human) (VIG) was developed in the 1960s for the purpose of ameliorating side effects associated with vaccinia immunization, including eczema vaccinatum, generalized, and progressive vaccinia.48 The original preparation contained a high proportion of protein aggregates and thus was administered IM. The use of VIG has become extremely limited since the eradication of smallpox. It is considered valuable “insurance,” to be held in reserve if a patient is receiving an experimental vaccine that involves a vaccinia carrier virus, or to prevent or manage complications of smallpox vaccination should such be required for a bioterrorism threat.Recently, a preparation of VIG suitable for IV use (VIG-IGIV) has gained FDA approval. In the event that VIG is required, it can be obtained through the Centers for Disease Control and Prevention (CDC: www.bt.cdc.gov/agent/smallpox/).
Diverse profile Winers: 1. petersen profile - Phosphatidylethanolamine- lipodistrophy organ trans - HIV; Account - molluscum contagium, poxiviridae USA. 2. Dr. Beatles profile - sarcoma fibromatosis - EIE EIA; Account - Daughter end at USA. 3. CIVLEVEL - Overvaccination to progressive vaccina, HI-HIDS-IDS/AIDS w/ or w/o HIV ssN negs vi, - Hyperimmunity; etc.. Account - Illusion USA; DEceit by USA, Conspiracy, etc..
-NLAB
Evident in USAF and unco of CL1Grade Low Waste. Tissue scars eczema liquefies with anesthetic surg/pyrotics/phosphors/phos ders/solvents/genetic dissolution protein dissolution/nucleoradiation/etc.. infection asympto hidden by methroxetrate/alkali; they require alkali environment to stabilize, intolerant of acids (damage to nerves evident with reinnervation attempts or psuedosignal). MJ v. nothing; scrambled; vaccina or HIV or Acquired-Immunity (esp. in presence of nucleoradiation, over radiation environment, methroxetrate environment allergens etc.). small pox virus campaign 1920-1980. coverup USA petersens-usaf-usa-nac-etc. guilty as charged. Stronger than the man. Evident at UCLA, etc.. Wade petersen smith USA HIV or AIDS STV or Vaccina prefer alkali environment, evidence phosphate pain/dysfunctional cell system-cycle-metabolism-etc.; MJSth.
Statistics and Research Coronavirus (COVID-19) Vaccinations HomeCoronavirusVaccinations 39.7% of the world population has received at least one dose of a COVID-19 vaccine. 5.24 billion doses have been administered globally, and 38.46 million are now administered each day. Only 1.6% of people in low-income countries have received at least one dose. https://ourworldindata.org/covid-vaccinations?country=OWID_WRL
RISIS Biden Says U.S. Leads The World In Vaccine Donations — And Promises More Updated August 3, 20215:00 PM ET Heard on Morning Edition https://www.npr.org/sections/goatsandsoda/2021/08/03/1023822839/biden-is-sending-110-million-vaccines-to-nations-in-need-thats-just-a-first-step
Saroja Adusumilli MD, Evan S. Siegelman MD, in Body MRI, 2005
AIDS CHOLANGIOPATHY
Acquired immunodeficiency syndrome (AIDS) can affect the biliary tree in one of two ways: infectious cholangiopathy or biliary obstruction secondary to extrinsic compression by periportal lymph nodes from AIDS-related lymphoma.116 AIDS cholangiopathy is usually the result of bile infection by either Cytomegalovirus or Cryptosporidium. The imaging features of AIDS cholangiopathy include moderate biliary duct dilatation with irregular mural thickening and nodules, ampullary stenosis, and gallbladder sludge.116 Intrahepatic duct findings such as focal stenoses with segmental dilatation (“beaded” appearance) simulate primary sclerosing cholangitis. The extrahepatic duct abnormalities present in PSC such as saccules and high-grade strictures are not present in AIDS cholangiopathy.116
Acquired immunodeficiency syndrome (AIDS) was first reported in hemophiliacs in early 1982, and it was suspected that blood products were the source because of similarities to infection caused by blood-borne hepatitis viruses in the 1970s. In addition to those with AIDS, other apparently healthy hemophilic men and boys, especially those using concentrates, had decreases in their CD4 T cells. Because it was unclear if the disorder was more serious than hepatitis, the National Hemophilia Foundation encouraged hemophiliacs to continue infusing concentrates but advised manufacturers to exclude persons at high risk for AIDS from the pool of concentrate donors. However, as the number of people with AIDS increased, hemophiliacs attempted to obtain alternative blood products, such as cryoprecipitate. These efforts were mostly unsuccessful because blood banks considered cryoprecipitate inconvenient to prepare and store. At a meeting in 1983, the consensus of blood bankers and the Food and Drug Administration (FDA) was that there should be no mandatory recall of concentrate even if it had been prepared with plasma from a donor subsequently found to have AIDS.
Before the availability of effective treatments, a person with an AIDS diagnosis had an 8–10-month life expectancy. Once immunosuppression has occurred, people with AIDS (PWAs) become susceptible to “opportunistic” infections, cancers and metabolic illness.
Already, serious complications such as liver and kidney failure, heart disease and bone disease are on the increase in individuals using the AIDS treatments for long periods.
Antiretrovirals, particularly nucleosidereverse transcriptase inhibitors (NRTIs), changed HIV/AIDS from a fatal disease to a chronic illness. Cardiomyopathy (CM) is a bona fide HIV/AIDS comorbidity. It may result from individual or combined effects of the HIV per se, immune reactions to it, or from toxicities of NRTIs.
Acquired immunodeficiency syndrome (AIDS) and its antecedent infection human immunodeficiency virus (HIV) do occur in elderly patients. Most often HIV infection in this population is a result of having received a blood transfusion or blood products that contained the virus before proper screening measures were developed.
Acquired immunodeficiency syndrome – a severe disease of the human immune system caused by the human immunodeficiency virus (HIV).
Antiretroviral drugs (ARVs)
Drugs used to treat HIV.
Treatment with combinations of several drugs against HIV.
Body mass index (BMI)
Calculated as weight in kg per height in meters squared; often used as an indicator of overall nutritional status.
CD4 cells
A subgroup of lymphocytes which are targets of HIV infection. Destruction of CD4 cells is both a cause and a marker of HIV/AIDSdisease progression; therefore blood CD4 count is often used to measure the degree of immunodeficiency.
Acquired immunodeficiency syndrome (AIDS) is a disease caused by the human immunodeficiency virus (HIV). This virus probably arose from similar viruses in African primates (see Box 17.1). The first known case of HIV infection was found in a man from the Democratic Republic of Congo in 1959.
(etc. including contaminant at need/trust (food, water, vaccine, prescription, etc.), medical induced infection, dust/sewer, travel, veteran of foreign wars, biological treatment of water/crop (minimum standard too low), mass very inhuman human experimentation, mass vaccination campaign, programs/institutions/etc., food supply chain, import-export, immigrancy third world, waste disposal/hazardous waste disposal, adventuring-expansion-exploration of undersea/outerspace, etc.)
Acquired Immune Deficiency Syndrome
Acquired immune deficiency syndrome (AIDS) occurs when an HIV-positive person's immune system is weakened, specifically when the T cell count drops below 200.
What Is Polio? Definitions, Description of the Disease, and Surveillance
Polio is the abbreviation for the disease poliomyelitis, caused by poliovirus. It typically causes a mild enteric or febrile infection, but it can spread systemically and affect the nervous system. The early twentieth-century technical term was acute anterior poliomyelitis or paralytic poliomyelitis, and its diagnosis was clinical without laboratory support. The site of pathology in typical paralytic poliomyelitis is the anterior hornmotor neurons in the gray (polios) matter of the spinal cord (myelos). When motor neuron death and local inflammation reaches a threshold, limb paralysis occurs. In 20–30% of subjects, recovery from paralysis occurs, but in the majority, paralysis is permanent, leading to muscle atrophy and joint deformities. Other infections (such as other enteroviruses or West Nile virus) may cause limb muscle paralysis known as acute flaccid paralysis (AFP) syndrome, but only that caused by polioviruses(antigenic types 1, 2, or 3, one species of the genus Enterovirus, family Picornaviridae) is poliomyelitis; hence laboratory confirmation test has become essential to the diagnosis of polio.
Poliovirus attaches to cell surfaces via the poliovirus receptor (PVR), a membrane protein (CD155) of the immunoglobulin superfamily. Only polioviruses bind to PVR, which is expressed mainly on the nasopharyngeal mucosa, Peyer's patchM cells of small intestines, and the anterior horn motor neurons of the spinal cord and medulla oblongata. These are the main anatomic sites where polioviruses multiply inside the host. Almost all cultured human and primate cells express PVR, support growth of polioviruses and develop cytopathology(CPE), and have become the standard cells for virus isolation, detection, and cultivation for clinical and research purposes. The human PVR gene has been introduced into transgenic mice, and a fibroblastic cell line from them (L20B cells) has become very useful in primary isolation of polioviruses from clinical specimens.
Poliomyelitis, an acute communicable disease affecting primarily children with the major manifestation of muscle paralysis, is caused by an enterovirus – poliovirus – with previously worldwide distribution. The development of first inactivated, and then attenuated, live poliovirus vaccines in the 1950s was an historic public health achievement of the twentieth century. Although polio has been eliminated from most of the world, as of June 2014, it remains endemic in three countries (Afghanistan, Pakistan, and Nigeria); and exportations of poliovirus into previously polio-free countries occur frequently, causing large outbreaks if the virus reaches areas with low population immunity.
Lessons about research ethics, the selection of appropriate vaccine types for different populations, and the importance of reducing unintended side effectssuch as vaccine virus–induced paralysis are highlighted in this article.
The human PVR gene has been introduced into transgenic mice, and a fibroblastic cell line from them (L20B cells) has become very useful in primary isolation of polioviruses from clinical specimens.
Infection with poliovirus was essentially universal until the advent of vaccination. Polio was first clinically recognized in 1840 and an 1887 Swedish polio epidemic was described in 1891. No country was able to control or interrupt polio transmission solely by sanitation, clean water supply, personal hygiene, or very high living standards. Although dogma is that transmission was primarily through contaminated water and food (fecal–oral) there is compelling evidence to show that direct person-to-person transmission during ordinary social contact is a critical factor during outbreaks. Polio is highly contagious and can be transmitted via the respiratory route by inhalation of droplets or aerosols containing virus expelled through saliva or nasal secretions.
Polio has now been eliminated from most of the world through vaccination, and this article will focus on the development of the polio vaccineand eradication efforts.
Polio is an acute viral infection of the brainstem and spinal cord that leads to irreversible motor neuron damage and paralysis. Endemic wild‐type viral illness has been eradicated in North America as a result of vaccination.
Polio is an acute viral infection of the brainstem and spinal cord that leads to irreversible motor neuron damage and paralysis. Endemic wild‐type viral illness has been eradicated in North America as a result of vaccination.
Synonyms
Infantile paralysis
Paralytic polio
Poliomyelitis
ICD‐9‐CM Codes
045.9 Polio
V04.0 Polio immunization
Epidemiology & Demographics
•
Before widespread immunization, outbreaks of polio occurred in the late summer and fall, with the largest epidemic (more than 57,000 cases) occurring in the United States in 1952.
•
1955: inactivated (Salk) vaccine (IPV) was introduced.
•
1964: trivalent oral (Sabin) vaccine (OPV) was introduced.
•
1978: enhanced‐potency inactivated vaccine (E‐IPV) was developed.
•
1979: last case of wild‐type poliomyelitis was reported in the United States.
•
1999: ACIP voted to change the recommendation for childhood polio vaccination beginning in 2000 to a schedule using only the E‐IPV to eliminate the occurrence of vacane associated paralytic poliomyelitis (VAPP). VAPP has been eliminated in the United States as of 2000.
•
Outbreaks of polio are still occurring in Nigeria, India, Pakistan, Niger, Afghanistan, and Egypt.
Clinical Presentation
History
•
VAPP: antecedent administration of OPV from 1 week to 1 month before symptoms; recent administration of DTP (diphtheria, tetanus, pertussis) vaccine may enhance paralysis in active poliovirus infection
•
Immunocompromise or exposure to a person recently vaccinated with OPV
•
Abortive or aseptic meningitis: nonspecific signs and symptoms of a febrile illness, diarrhea, headache, meningismus, vomiting, and photophobia
•
Paralytic poliomyelitis (spinal type): ascending paralysis, may occur without antecedent prodrome, especially in young infants; weakness and paralysis progress through the febrile period of the illness
•
Respiratory difficulties occur with paralysis of the intercostal muscles and with bulbar polioencephalitis affecting the brainstem medullary respiratory center.
○
Symptoms include shallow or spasmodic breathing, other cranial nerve involvement, and paralysis of pharyngeal or laryngeal muscles
•
Constipation and voiding abnormalities (urinary retention, overflow incontinence)
Poliomyelitis is an old disease in humans but it only became a major health problem at the beginning of the twentieth century. It is caused by poliovirus, a member of the genus Enterovirus of the family Picornaviridae which normally produces an asymptomatic infection of the human gut. Killed and live vaccines were developed in the mid-twentieth century, and the live-attenuated strains given by mouth (oral polio vaccine, or OPV) have been employed in massive campaigns as part of the World Health Organization program on the eradication of poliomyelitis with the result that there are only four countries in the world from which poliomyelitis has never been eradicated, although reintroductions are a problem. The molecular basis of the attenuation of the OPV strains is well understood and the strains can revert to cause disease in recipients, or to circulate in the community or be excreted for prolonged periods by patients deficient in humoral immunity. The strategies to be used to allow vaccination to stop safely in view of these properties of the vaccine virus are in development.
Clinically, poliovirus infection can be divided into four types: subclinical infection, abortive poliomyelitis, nonparalytic poliomyelitis with aseptic meningitis, and paralytic poliomyelitis (Table 69-1). The incubation period after ingestionof the virus typically is 1 to 2 weeks but may range from 4 days to 5 weeks. Dissemination and viremia cause no symptoms in 90% of cases (subclinical infection). Malaise, fever, headaches, sore throat, cough, diarrhea, nausea, and vomiting are prominent in the remaining 10%.
Epidemics of paralytic poliomyelitis occurred regularly before the introduction of the polio vaccination. Such epidemics were most problematic in the developed world. In undeveloped countries, cases were generally sporadic with few epidemics. This difference was largely the result of public health practices in the developed world. In undeveloped countries, polio was transmitted via contaminated drinking water and typically infected infants at a young age. In this young age group, few subjects developed the paralytic form of the disease and most recovered without sequelae but with lifelong immunity. In the developed world with a protected water supply, inoculationoccurred later in life when the probability of the paralytic form of the disease was higher. In addition, without the continuous exposure, conditions were favorable for epidemics.
About half of the patients do not develop paralytic manifestations. In the remaining, a biphasic course evolves. As the initial enteritis subsides, the paralysis begins. Severe back and limb pain, headache, and meningismus develop,
Paralysis tends to occur in a patchy, multifocal distribution.
Recovery depends on collateral sprouting and reinnervation of muscles by surviving motor axons. The paralysis improves over many months to years.
In greater than 90% of patients, the virus remains in the oropharynx and gut, and the infection is asymptomatic.
Abortive poliomyelitis, which occurs in about 5% of cases, results in a minor febrile illness characterized by headache, neck pain, and nausea. The most serious complications of poliovirus infection occur when the virus spreads from the intestinal mucosa into the central nervous system. Occurring in about 1% of cases, it can result in minor back pain or muscle spasms, to flaccid paralysis without sensory loss Murray et al (2002). The most severe cases of poliomyelitis, bulbar poliomyelitis, can result in respiratory paralysis and death.
A phenomenon known as post-polio syndrome has emerged as polio victims from the mid 1900's have aged. This syndrome, which may occur 30 to 40 years after the original illness, is marked by muscle weakness, joint pain, fatigue, and dyspneaChasens and Umlauf (2000). Although many of the muscles affected are those that were involved in the initial infection, the virus itself is no longer present. Rather, the symptoms are believed to result from degradation of neurons and axons that innervate the muscle. This phenomenon, then, is thought due to a decreased number of functional neurons compounded by the aging process.
PV virions bind to a cell protein called the poliovirus receptor (PVR). The PVR is an integral membrane protein and member of the immunoglobulin superfamily of proteins. The PVR molecule has three immunoglobulin-like domains that extend from the cell surface. (The receptors for other picornavirusesinclude a wide variety of cell surface molecules including CD55of the complement cascade, ICAM-1 (a cellular adhesion molecule), integrins, and heparin sulfate.) Binding of PV to the PVR triggers a rearrangement of capsid proteins. The capsid protein, VP1, is inserted into the plasma membrane (PM) to form a protein channel through which the RNA genome enters the cell (Fig. 3.4). PV appears to enter cells at the PM although other picornaviruses are taken up by endocytosis (these viruses presumably use low pH to trigger capsid rearrangements).
The virus spreads quickly from the alimentary tract to regional lymph nodes. After several days, a minor viremiaensues, and a number of sites, such as muscle, fat, liver, spleen, and bone marrow, become infected. If virus is contained at this point, subclinical infection occurs.
Poliovirus replicates in the intestinal tract and occasionally spreads to motor neurons of the spinal cord or brain stem. Most infections with poliovirus are asymptomatic. Poliovirus can also cause a minor illness characterized by fever, malaise, drowsiness, headache, and vomiting. About 4% of people infected with polio develop aseptic meningitis (nonparalytic polio), and less than 1% develop paralysis. Three serotypes of poliovirus (types 1, 2, and 3) cause disease.
Paralytic polio occurs when poliovirus destroys anterior horn cells that innervate muscles of the arms and legs (i.e., spinal polio) or cells of the brain stem that innervate muscles of respiration (i.e., bulbar polio).
Polioviruses can be grown in a wide range of human and simian cells (see http://www.atcc.org/),123 but two cell lines are routinely used in combination by the GPLN for virus isolation124: (a) RD cells (a continuous line from human rhabdomyosarcoma125), which are highly sensitive to poliovirus infection and yield virus at high titers,59 and (b) L20B cells (a derivative of the mouse L cell line engineered to express the human PVR, CD155), which are highly selective for growth of poliovirus.124,126 RD cells have the advantage of being very sensitive to poliovirus infection and yielding high poliovirus titers in culture. RD cells will support the replication of other human enteroviruses, but not Coxsackie B viruses. L20B cells will support the replication of polioviruses, but, like their parenteral mouse L cells, are resistant to infection by most nonpolio enteroviruses. Thus L20B cells are used for the selective cultivation of polioviruses.
Poliovirus is an RNA virus that in 90% of individuals is entirely asymptomatic. In fewer than 1% of cases, however, the virus enters the central nervous system, preferentially infecting and destroying motor neurons, leading to muscle weakness and acute flaccid paralysis.90 Poliovirus enters susceptible cells through a specific poliovirus receptor but can also be taken up by FcγR,91 and FcγRs have been found to be expressed on both microglia and perivascular macrophages.92 IgG3 is the main antibody subtype produced in response to poliovirus in humans,93 and, although FcγRI is the receptor with the highest affinity for IgG3, of the low-affinity FcγRs FcγRIIIa-V/V158 predominates. A Norwegian study of patients who contracted poliomyelitis in the 1950–1954 epidemic found the FcγRIIA-V/V158 genotype was under-represented in patients with a history of acute poliomyelitis, suggesting that V/V homozygous individuals might have increased binding and clearance of antibody-opsonized poliovirus and therefore be protected against disease.94
'PVR transgenic mice are not susceptible to oral poliovirus infection unless they are deficient in the type I interferon (IFN) response (Ohka et al., 2007; Ida-Hosonuma et al., 2005);...'
Providing molecular insight into bacterial enhancement of poliovirus infectivity, N-acetylglucosamine (GlcNAc)-containing polysaccharides expressed on bacterial surfaces including lipopolysaccharide (LPS) and peptidoglycan (PG), also stabilized virus (Kuss et al., 2011; Robinson et al., 2014).
LT became a viable option once hepatitis B immune globulin (HBIg) had been shown to reduce recurrence rates to below 10%, and subsequently the combination of HBIg with an antiviral drug (lamivudine) further reduced recurrence to <5% at 5 years.
From: Encyclopedia of Microbiology (Fourth Edition), 2019
Related terms:
Graft-Versus-Host DiseaseRegulatory T CellHematopoietic Stem CellT CellsBone MarrowStem Cell
Currently CTTT is performed at Duke University. Of 88 subjects with complete DiGeorge anomaly transplanted with thymus tissue, the one-year survival is 65/86 (76%). (Two subjects were transplanted in the past year and are not included). Four subjects died after 1 year. Overall survival to date is 72% (63 of 88, of which 2 subjects are less than 1 year from CTTT) (Fig. 59.1). The surviving subjects are 1 month to 25.5 years after CTTT. The median age of survivors with complete DiGeorge anomaly is 11.9 years. Both subjects with FOXN1deficiency survive at 12 and 14 years after CTTT.
Transplantation is the only resort in the case of acute organ failure, burns, and when no other therapy is available. With the increasing need for organs, despite the available live donors and cadaveric donors (Fig. 1), the list is not sufficient to meet the demands of the people in need of organ transplantation.
While the demands on vital organ for saving lives is far more than that what is available has led to the development of possible xenotransplantation that involves transplantation, implantation, or infusion into a human recipient (i) live cells, tissues, organs from a nonhuman animal, or (ii) human body fluids, cells, tissues, or organs that have had ex vivo contact with live nonhuman animal cells. This also finds importance in therapy for certain diseases including neurodegenerative disorders and diabetes, with a dearth of available human replacements.
The transplantation of fecal material from a healthy individual into the GI tract of a patient recipient has been used to treat several intestinal as well as extraintestinal diseases with varying success. Donors are usually healthy relatives without a recent history of taking antimicrobial drugs.
Transplantation of gene corrected autologous stem cells has offered the potential for curative therapy to patients with no or poorly matched donors and also excludes the risk of graft versus host disease. In the initial clinical trials using gamma retrovirus vectors, correction of CYBB (introduction of normal CYBB into a subset of CD34 cells) in patients with X-linked CGD showed low levels of gene-marked neutrophils. Subsequent trials using gamma retroviruses showed improved response with higher numbers of gene corrected cells but several subjects developed hematologic malignancies.152,153 As detailed in the X-linked carrier section above, carriers in whom less than 20% of circulating neutrophils are oxidase normal are at significantly higher risk of infections, and those >20% oxidase normal circulating neutrophils are at less risk of infections. These data suggest that restoration of even 20% normal oxidase activity would achieve clinical benefit. There is no known survival advantage for gene-corrected CGD cells in the bone marrow or other tissues, further complicating low rates of reconstitution of treated cells. Development of hematologic malignancies has also complicated gene therapy in CGD.152,153
Renal transplants in cats are becoming increasingly more common at veterinary institutions across the country. Ultrasound is primarily used to evaluate renal size and to detect hydronephrosis or perinephric fluid collections.
Liver transplantation is the treatment of choice for patients who present with fulminant hepatic failure (grades II–IV encephalopathy) unresponsive to steroids, or who progress to end-stage liver disease despite immunosuppression (~10%–20% of patients) (Liberal et al., 2013). Recurrence of AIH, characterized by high transaminase levels, positive autoantibodies, interface hepatitis, and/or steroid dependence, occurs in ~20% of transplanted patients (Milkiewicz et al., 1999; Duclos-Vallee et al., 2003; Liberal et al., 2016) and can happen even years after transplantation. Prednisolone treatment long term and at a dose higher than that generally used after liver transplantation for other conditions is recommended to avoid recurrence
Renal transplants in cats are becoming increasingly more common at veterinary institutions across the country. Ultrasound is primarily used to evaluate renal size and to detect hydronephrosis or perinephric fluid collections.
Also, a mean increase of 30% in cross-sectional area between preoperative values and a 2-week postoperative period following transplantation was found in a study of feline allografts with immunosuppressive therapy (cyclosporine and prednisolone).173
The variability of results in these studies could reflect a combination of factors, such as use of autografts versus allografts, transplant procedures, kidney ischemia time, fluid therapy, immunosuppressive therapy, or other medications.16,172,173
Graft enlargement in the immediate postoperative period likely results from transient ischemia, acute tubular necrosis, interstitial edema, or other changes associated with the transplant procedure.16,172,173Acute tubular necrosis in the early posttransplant period is the result of ischemia before revascularization. Compensatory hypertrophy or redistribution of blood flow may also play a role in renal enlargement if the transplanted kidney is essentially the sole functioning kidney. If the kidney fails to enlarge, this may indicate an impaired vascular supply. Kidney size may decline slightly as the initial acute effects of the transplantation procedure resolve.16
As mentioned previously, acute renal failure in renal transplants may occur secondary to acute tubular necrosis, acute rejection, cyclosporine nephrotoxicity, or vascular thrombosis.
In humans, perinephric fluid collections consisting of hematomas, lymphoceles, urinomas, or abscesses are seen occasionally with renal transplants and must be differentiated by clinical signs, ultrasonographic appearance, and fine-needle aspiration.191,192 Hematomas, abscesses, and urinomas tend to occur early in the postsurgical period, whereas lymphoceles are usually discovered as an incidental finding 2 weeks to 6 months after transplantation. Urine leakage may also occur in the early postoperative period, most commonly at the site of ureterovesical anastomosis.
The first transplants were performed using HLA-matched sibling donors. Even using these donors there is a risk of developing GvHD, particularly if patients have received chemotherapy preconditioning beforehand. Many centers do not give chemotherapy preconditioning when a matched sibling donor is available.18,19 Results using matched sibling donors are good, and have improved over time174–177; in the last results reported for 25 European patients with all variants of SCID transplanted between 2000 and 2005 there was a 90% 5-year survival. In the most recent analysis of 662 SCID patients from North America by the Primary Immune Deficiency Treatment Consortium, there was a 95% 10 year survival for the 91
Despite recent successes, current gene therapy clinical trials rely on the replacement and integration of an additional wild-type copy of the mutated gene. Gene-editing technologies including zinc-finger nucleases and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system may facilitate editing and repair of the mutated gene directly, thereby negating the need for replacement with a wild-type gene.155,156
Each transplant procedure involves a team of three surgeons. The donor cat is brought into the surgical suite approximately 30 to 45 minutes before the recipient. During this time, the donor kidney will be prepared for the nephrectomy. When the abdominal incision is made, the donor is given a dose of mannitol (0.25 g/kg IV over 15 minutes) to help prevent renal arterial spasms, improve renal blood flow, and protect against injury that can occur during the warm ischemia period. The renal artery and vein are cleared of as much fat and adventitia as possible, and the ureter is dissected free to the point where it joins the bladder. The left kidney is preferred because it has a longer vein. It is essential, however, to harvest a donor kidney with a single renal artery at the point where the artery joins the aorta. A minimal length of 0.5 cm of single renal artery is necessary for the arterial anastomosis.1 The nephrectomy will be performed when the recipient is prepared to receive the kidney. Fifteen minutes before nephrectomy, an additional dose of mannitol (1 g/kg IV) is given to the donor cat.
Fecal bacteria have been found to survive more in benthic sediments, and there is a positive relationship with total suspended solids, suggesting that wind-driven resuspension may influence their densities in shallow waters (Howell et al., 1996).
Breastfeeding: The fecal microbiota of breastfed infants are less diverse and dominated by Bifidobacterium, followed by Streptococcus, Staphylococcus, Lactobacillus, Enterococcus, and Enterobacteria. Breast milk contains lactose as its main carbohydrate source and different oligosaccharides that are believed to favor the growth of certain bacterial species, particularly Bifidobacterium. Other bacteria that reportedly were found in breast milk are Streptococcus, Staphylococcus, and Lactobacillus. Breast milk also contains antimicrobial factors (e.g., lysozyme, lactoferrin), which explained the lower growth of facultative anaerobes in breastfed infants.
The more diverse fecal microbiota of formula-fed infants includes Enterobacteriaceae and a higher abundance and prevalence of facultative anaerobes such as Bacteroides and Clostridium as compared with breastfed infants. Bifidobacteriumalso was present in gut microbiota of formula-fed infants but in lower abundance and frequency.
Human immunodeficiency viruses 1 and 2 are retroviruses that exhibit tropism for cells of the immune system with subsequent immune disturbance, especially immunodeficiency.
From: Oh's Intensive Care Manual (Seventh Edition), 2014
HIV-1 is a retrovirus, belonging to a group of heterogeneous, lipid-enveloped RNA viruses. Another retrovirus, HIV-2, is relatively rare and causes a less severe AIDS-like syndrome. HIV-1 has two major viral envelope proteins—the external glycoprotein gp120 and the transmembrane glycoprotein gp41.
The primary target cell of HIV-1 is the human CD4+lymphocyte. The HIV-1 gp120 envelope protein binds to the CD4+ molecule on the host cell membrane with high affinity. This binding allows the virus to enter the T cell and to integrate its genome into the host DNA. HIV-1 also infects monocytesand macrophages but with less marked cytopathic effects. Infected monocytes serve as a reservoir for HIV-1, allowing further spread of the virus throughout the body.5 Infection with HIV-1 results in progressive depletion of the CD4+ helper lymphocytes. This depletion serves as a marker of the severity of HIV-1 infection because the incidence of opportunistic infections and other complications correlates with the number and percentage of CD4+ lymphocytes, particularly in children older than 1 year.6
HIV-2 can be classified into eight genetic groups, A–H, with only groups A and B circulating widely (Takebe, Uenishi, & Li, 2008). Group A viruses have been found in western Africa, including Guinea-Bissau, Senegal, Gambia, and Mali, whereas group B viruses are present in Côte d’Ivoire, Ghana, and Nigeria (Takebe, et al., 2008). A recombinant HIV-2 virus (HIV-2 CRF_01AB) has been identified in West Africa and in Japan (Ibe, et al., 2010). The modes of transmission of HIV-2 are similar to those of HIV-1; however, transmission efficiency is lower. Individuals infected with HIV-2 have higher CD4+ lymphocyte counts, lower plasma viral loads, and a longer asymptomatic period with slower disease progression.
HIV-1 infected individuals were passively treated with a neutralizing mouse monoclonal antibody to HIV-1 gp 120. Anti-idiotypic (anti-Id) antibodies to the Mab developed which could be demonstrated to react with the most strongly antigen-binding region of the Mab, CDR-H3. We describe the development of anti-Id antibodies to the variable heavy and light chain regions of the monoclonal antibody used in a passive immunotherapy study in HIV-1 infected individuals and the capacity of the complementarity determining regions (CDRs) from this antibody to function as Id molecules. The CDR-H3 region could be mimicked by a synthetic cyclic peptide, which in turn neutralized several HIV-1 primary isolates.
HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in vitro. Genotypic analysis of these resistant isolates showed mutations that resulted in amino acid substitutions at the enfuvirtide binding HR1 domain positions 36–38 of the HIV-1 envelope glycoproteingp41. In clinical trials, HIV-1 isolates with reduced susceptibility to enfuvirtide have been recovered from subjects failing enfuvirtide-containing regimen. Most of the isolates with decreased in susceptibility to enfuvirtide of greater than fourfold exhibited genotypic changes in the codons encoding gp41 HR1 domain amino acids 36–45.
HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors, and protease inhibitors are susceptible to enfuvirtide in cell culture.
The HIV-1/HIV-2 differentiation immunoassay is a rapid laboratory based test that is typically performed to confirm a positive fourth generation combined antibody antigen test and to distinguish between HIV-1 and HIV-2 infection.
The Western blot test has a much slower turnaround time. The HIV-1 Western blot cannot detect the O subtype virus. For detection of HIV-2 a separate HIV-2 Western blot needs to be performed. Thus, the preferred method of confirmation is the HIV-1/HIV-2 differentiation assay.
HIV-1 Escape from NKG2D-Mediated Recognition by NK Cells
HIV-1 infection does not only affect HLA class I expression, thereby impacting recognition by KIRs, but can also trigger the upregulation of ligands for less polymorphic receptors, such as NKG2D. Expression of these stress-induced ligands, and particularly that of UL16-binding proteins (ULBPs), results in increased recognition and killing of both HIV-1-infected and uninfected bystander CD4+ T cells by NK cells (Fogli et al., 2008; Norman et al., 2011; Richard et al., 2013; Ward et al., 2007). Given the high capacity of NKG2D ligands to activate NK cells, HIV-1, like other viruses, has evolved elaborate mechanisms to evade NKG2D-mediated recognition. For instance, the HIV-1 Nef protein appears to not only downregulate HLA-A and HLA-B molecules, but also to limit the expression of NKG2D ligands by triggering the degradation of ULBP-1 and -2, and to a lesser extent, that of MICA (Cerboni et al., 2007). An alternative way for HIV-1 to impair NKG2D-mediated NK cell activation might consist in promoting enzymatic cleavage of MICA and MICB from the surface of HIV-1-infected cells. Engagement of NKG2D by the soluble forms of MICA/B would lead to its downregulation, and to the generation of anergic NK cells. This hypothesis is supported by studies describing elevated plasma levels of soluble MICA and compromised NKG2D-mediated NK cell responses in chronic HIV-1 infection (Nolting et al., 2010), and would explain why MICA has been repeatedly reported to be barely detectable at the surface of CD4+ T cells following HIV-1 infection (Fogli et al., 2008; Ward et al., 2007). Overall, those strategies evolved by HIV-1 to escape from NKG2D recognition suggest that this pathway might play a significant role in the recognition of HIV-1-infected cells by NK cells.
Human Immunodeficiency Virus (HIV) infects cells by engaging the cognate receptor (CD4) and coreceptors (CCR5 and/or CXCR4) at the cells surface and fusing the viral envelope to the cell membrane.
From: Current Topics in Membranes, 2011
Related terms:
AntibodyProteinHepatitis C VirusAcquired Immune Deficiency SyndromeAntiretroviral TherapyHuman Immunodeficiency Virus Infection
Human immunodeficiency virus (HIV) is a human retrovirusbelonging to the lentivirus family. It is responsible for the progressive immune dysfunction that leads to acquired immunodeficiency syndrome; and has resulted in over 20 million deaths. Many of these are due to respiratory disease with pathogens such as bacteria (pneumococcus and Gram-negative organisms), the fungus Pneumocystis jirovecii, and Mycobacterium tuberculosis. The immune dysregulation induced by HIV also leads to a variety of noninfectious pulmonary complications. Highly active antiretroviral therapy has transformed HIV care: the rates of severe opportunist disease have plummeted in countries where the drugs are widely available.
AIDS was first recognized in the United States in 1981 following a sudden outbreak of opportunistic infections, including Pneumocystis carinii pneumonia and Kaposi’s sarcoma (KS) among homosexual men (Durack, 1981; Gottlieb et al., 1981; Masur et al., 1981). Subsequent epidemiologic studies implicated an infectious agent that was transmitted during sexual intercourse, through intravenous drug abuse, by therapies utilizing blood and blood products, and vertically from mother to child (Broder et al., 1994).
In 1983, Barre-Sinoussi, Chermann, and Montagier at the Pasteur Institute in Paris isolated a retrovirus from lymph node cells of a patient with lymphadenopathy; accordingly, this virus was designated lymphadenopathy-associated virus (LAV) (Wain-Hobson et al., 1991; Barre-Sinoussi et al., 1983). Several other laboratories were also searching for the agent responsible for AIDS. In 1984, Gallo and associates reported the characterization of another human retrovirus distinct from human T-lymphotropic virus (HTLV) that they called HTLV-III(Gallo et al., 1984; Popovic et al., 1984; Sarngadharan et al., 1984; Schupbach et al., 1984). Levy et al. (1984) simultaneously reported the identification of retroviruses that they named the AIDS-associated retroviruses (ARVs). Within a short time, the three prototype viruses (LAV, HTLV-III, and ARV) were recognized as members of the same group of retroviruses, and their properties identified them as lentiviruses. Their proteins were all distinct from those of HTLV (Rabson and Martin, 1985). The AIDS viruses had many properties distinguishing them from HTLV. For all these reasons, in 1986, the International Committee on Taxonomy of Viruses recommended giving the AIDS virus a separate name, human immunodeficiency virus (Coffin et al., 1986).
HIV isolates were subsequently recovered from the blood of many patients with AIDS, AIDS-related complex, and neurologic syndromes, as well as from the peripheral blood mononuclear cells (PBMCs) of several clinically healthy individuals (Salahuddin et al., 1985; Levy and Shimabukuro, 1985; Levy et al., 1985). The widespread transmission of this agent was appreciated and its close association with AIDS and related illnesses strongly supported its role in these diseases. Soon after the discovery of HIV-1, a separate epidemic caused by a related human retrovirus, HIV-2, was identified in West Africa (Clavel et al., 1987). Both HIV subtypes can lead to AIDS, although disease progression due to HIV-2 infection appears to be slower (Reeves and Doms, 2002; Whittle et al., 1994; Kanki et al., 1992).
HIV-positive patients may present with lower white blood cell counts than their HIV-uninfected counterparts. Tubo-ovarian abscess formation has been reported to occur in as many as 25% of HIV-infected women with PID versus 12% of HIV-uninfected controls with PID. Therefore, more surgical intervention may be required, especially in patients with more advanced HIV disease. Standard antibiotic regimens that include anaerobic coverage (such as metronidazole plus a fluoroquinolone) can be used initially in the less complicated patient. Most clinicians maintain a low threshold to hospitalize, and treat with i.v. antibiotics if the HIV disease is advanced.59
Mukund W Uplekar, ... Diana E.C. Weil, in Tuberculosis, 2009
Implement TB/HIV collaborative activities
HIV promotes the progression of recent and latent infection due to Mycobacterium tuberculosis to active TB. It also increases the rate of TB recurrences. The HIV epidemic has caused a substantial increase in the number of TB cases in high-HIV-prevalence settings, and in the percentage of TB cases that have smear-negative pulmonary and extrapulmonary TB disease. HIV-infected, smear-negative pulmonary TB patients have inferior treatment outcomes and higher early mortality compared with HIV-infected smear-positive pulmonary TB patients. Interventions to reduce HIV-related TB morbidity and mortality as well as additional care for HIV-infected TB patients need to be implemented in line with the Universal Access principle.18
HIV infection causes chronic immune activation and oxidative stress that may be reduced by the use of genistein
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Success HIV infection of human CD4 T cells and macrophages requires CXCR4/CCR5 signaling that promotes actin dynamics necessary for HIV nuclear migration.
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Genestein is a tyrosine kinase inhibitor that can block chemotactic signaling, and reduce HIV-initiated actin activity. Genistein inhibits HIV infection of blood CD4 T cells and macrophages and blocks viral DNA accumulation in T cells.
HIV does not appear to modify the risk of bacterial endocarditis, and rates in HIV-infected patients are similar to those in cohorts with similar risk profiles. The diagnosis and management of bacterial endocarditis in HIV patients do not differ from that of uninfected patients.154 Cardiac malignancies, including Kaposi sarcoma and malignant lymphoma, are quite rare in HIV patients.106 Finally, it has been reported that many HIV-positive patients have prolonged QTc intervals, a finding that may be associated with myocarditis, cardiomyopathy, autonomic neuropathy, and use of PIs.106
HIV and malaria each negatively affect the outcome and course of the other. HIV-related immune suppression compromises innate host malaria clearance mechanisms, including formation of opsonizing antibodies to Plasmodium. In regions where malaria transmission is low or unstable, HIV-positive adults with malaria are two- to fivefold, which are more likely to have a complicated or severe course. Similarly, HIV coinfection has been demonstrated to be a significant risk factor for severe malaria in areas of stable malaria transmission (Chalwe et al., 2009). HIV-positive children with severe malaria have a threefold higher mortality rate compared with those who are HIV-negative (Hendriksen et al., 2012). HIV has also been shown to impair the response to antimalarial therapy with higher rates of treatment failure among those who are coinfected, in particular, those with low CD4 counts. Malaria upregulates HIV transcription, with coinfected patients demonstrating a transient two- to sevenfold increase in HIV viral load during acute malaria infection. Although this could impact HIV transmission, whether this acute rise in viremia is clinically significant is debatable. However, at least one study in Uganda has shown a significant decline in CD4 counts in HIV-positive patients following episodes of malaria.
Simian immunodeficiency viruses (SIV) are members of the Lentivirus genus of Retroviruses that infect nonhuman primates such as monkeys, chimpanzees, and gorillas.
From: The Role of Animals in Emerging Viral Diseases, 2014
Simian immunodeficiency virus (SIV) was first isolated in 1984 from captive rhesus macaques (Macaca mulatta) at the New England Primate Research Center (NEPRC). This virus was originally called STLV-III because it displayed similar morphology, growth characteristics, and antigenic properties to the newly described immunosuppressive virus HTLV-III of humans. When HTLV-III was renamed human immunodeficiency virus (HIV), the name STLV-III was also changed to SIV. Retrospective studies have shown that SIV was introduced to the NEPRC when a group of rhesus macaques with immuosuppressive disease was delivered from another primate center 15years prior to the initial SIV isolation. The original cohort of rhesus monkeys was most likely accidentally infected with SIV from wild-caught sooty mangabey monkeys at the same institution. SIV has been subsequently isolated from other captive macaque species (M. fascicularis, M. nemestrina, and M. arctoides) that were dying of immunosuppression-associated diseases, and from many species of feral asymptomatic African nonhuman primates (Table 1).
Simian immunodeficiency viruses (SIVs) are members of the genus Lentivirus and the family Retroviridae. SIVmac was the first member of the group to be identified following isolation of a retrovirus from a captive rhesus macaque housed at a US primate center. The virus was introduced into captive macaque populations in the US during transfer of tissue from SIV-infected African monkeys to Asian macaques. Lentivirus genomes contain long terminal repeats at each end and genes encoding three virion structural proteins: core, polymerase, and envelope. In addition, all SIV genomes also contain five accessory genes, vif, vpr, rev, tat, and nef, and a subset of SIVshas one of two unique genes: vpr or vpu. SIV infects CD4+ cells of the immune system including T-cell, macrophages, and dendritic cells. While the CD4 molecule is the primary cellular receptor for SIV, a number of chemokine receptors are required co-receptors for SIV infection. While the endemic SIV infections of African monkeys and apes seem to be minimally pathogenic, SIV infections of Asian macaques cause simian acquired immune deficiency syndrome (AIDS). This disease results from the profound destruction of CD4+ T cells in lymphoid organs throughout the body. SIV infection of macaques closely mimics the pathogenesis, virology, immunology, and pathology of HIV infection in people and it has been used as a model to test strategies to prevent ot treat AIDS.
Soon after the recognition of clinical AIDS in people, several clinical reports described outbreaks of severe infections, wasting disease, and death in several colonies of Asian macaque monkeys housed at primate centers in the United States (Letvin et al., 1983; Henrickson et al., 1983). Due to their similarity to the human syndrome, these diseases were designated simian AIDS or SAIDS. As in the case of human AIDS, many possible causes were considered. Following the recognition that SAIDS appeared to be of infectious origin, cytomegalovirus of monkeys was also considered as a possible etiologic agent.
However, seroepidemiological screening revealed that a proportion of the SAIDS monkeys had antibodies that cross-reacted with HIV (Kanki et al., 1985a,b) while healthy monkeys had no such antibodies.
Human T-lymphotropic viruses (HTLVs) and STLVs are collectively called primate T-lymphotrophic viruses. In contrast to HIV, the majority of HTLV infections remain asymptomatic, but approximately 5% of them are associated with severe diseases such as adult T-cell leukaemia/lymphoma or an inflammatory disease of the central nervous system called HTLV-1-associated myelopathy/tropical spastic paraparesis [44, 45]. Simian counterparts, STLV-1 to STLV-3, have been described for HTLV-1 to HTLV-3 in humans [46]. No simian analogue of the recently discovered HTLV-4 has been identified yet, and no human analogue has been reported to date for the tentatively identified STLV-5 in a macaque species from Asia [47]. STLV has been documented in more than 30 non-human primate (NHP) species from sub-Saharan Africa and Asia, but few data are available on STLV infection in wild apes [43]. Phylogenetic analysis shows that primate T-lymphotrophic viruss cluster by geography, rather than by host species, suggesting multiple cross-species transmission events between NHPs, and also from NHPs to humans [47–49].
STLV-1 belonging to the African subtype B has been documented in captive but wild-caught chimpanzees (P. t. elliotiand P. t. troglodytes) and gorillas from west Central Africa [50]. Approximately 70% of wild chimpanzees in Ivory Coast are infected with STLV-1, and, in addition to subtype B, a variant closely related to STLVs observed in the western red colobuswas identified, suggesting cross-species transmission by predation [51]. STLV-2 has only been documented in bonobos, an ape species endemic to DRC [52]. The initial strains were isolated in captive animals, and STLV-2 DNA was also recently identified in a faecal sample from a wild bonobo in DRC [53]. No data are currently available on STLV pathogenicity in wild apes; however, STLV-1 has occasionally been associated with lymphoma or chronic fatal disease in captive gorillas [54, 55].
Because many other monkey species are also infected with STLV strains closely related to those that circulate among chimpanzees and gorillas, it is not easy to determine which primate species is at the origin of today's HTLV-1 B subtypes in humans.
HBZ regulates several different pathways in infected cells, enable immune escape, trigger inflammation through the induction of IFNg expression, and enable the infection to overcome immune suppressive effects.
HTLV-1 bZIP factor (HBZ) is also encoded in the X region but is transcribed in the opposite direction to all other transcripts. The promoter for HBZ transcription is the 3′ LTR. HBZ is a Basic Leucine Zipper Domain (bZIP) protein that interacts with many cellular proteins including several important transcription factors. HBZ activities are complex: (1) HBZ is required for efficient viral infectivity and persistence in a rabbit model; (2) HBZ is dispensable for HTLV-1-mediated cellular transformation in cultured cells but (3) HBZ by itself promotes proliferation of T-cell lines; (4) HBZ suppresses TAX-mediated viral gene transcription.
Human T-lymphotropic virus type-1 (HTLV-1) is the first human retrovirus ever associated with a human cancer called ‘adult T-cell leukemia (ATL)’. HTLV-1 is also a causative agent for an inflammatory neurological disorder called ‘HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)’. Only a minority of infected individuals develops HTLV-1-associated diseases, whereas the vast majority of infected individuals remains asymptomatic carriers of the virus in a lifetime. HTLV-1 infection into host immune cells and subsequent dysregulation of the host immune system appear to regulate in the development of HTLV-1-associated diseases.
For HTLV-1, transmission through breast-feeding is more efficient than in utero or perinatal transmission. On average, 20% of infants breast-fed by HTLV-1–positive mothers seroconvert to HTLV-1, whereas only 1 to 2% of bottle-fed infants of HTLV-1–positive mothers become infected. In contrast, in utero and perinatal transmission accounts for virtually all HIV-1 transmission in the West, and breast-feeding accounts for an additional 15 to 20% of infant HIV infection in Africa. This difference may reflect the fact that maternal antibody to HTLV-1 transmitted across the placenta appears to neutralize perinatal HTLV-1 but not the highly mutable HIV-1. HTLV-2 is detectable in breast milk and, similar to HTLV-1, accounts for many childhood infections.
Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukaemia/lymphoma (ATLL) in ∼5% of HTLV-1-infected people. ATLL cells frequently express several molecules that are characteristic of regulatory T cells (Tregs), notably CD4, CD25and the transcription factor FoxP3. It has therefore recently been suggested that HTLV-1 selectively infects and transforms Tregs. We show that HTLV-1 induces and maintains a high frequency of FoxP3+ T cells by inducing expression of the chemokineCCL22; the frequency is especially high in patients with chronic ATLL. In turn, the FoxP3+ T cells exert both potentially beneficial and harmful effects: they suppress the growth of autologous ATLL clones and may also suppress the host's cytotoxic T lymphocyte response, which normally limits HTLV-1 replication and reduces the risk of HTLV-1-associated diseases. Although ATLL cells may exert immune suppressive effects, we conclude that ATLL is not necessarily a tumour of classical FoxP3+ Tregs.
HTLV-1 also induces a slowly progressive myelopathy known in tropical zones as tropical spastic paraparesis (TSP) and, in endemic areas of Japan, as HTLV-1-associated myelopathy (HAM). The unique phenotypes of HAM/TSP are chronic, symmetrical, bilateral involvement of the pyramidal tracts, at mainly the thoracic level of the spinal cord, and include progressive spastic paresis with spastic bladder and minimal sensory deficits. HTLV-1-infected T cells infiltrate into the spinal fluid and cord.
Most patients with HAM/TSP have much higher titers of HTLV-1 antibodies than those of asymptomatic carriers or ATL patients. This might be associated with particular types of human leukocyte antigens (HLAs). Despite their strong immunological responses to HTLV-1 infection, most HAM/TSP patients have larger populations of infected cells than do HTLV-1 carriers.
HTLV-1 and HTLV-2, unlike HIV-1 and HIV-2, are cell associated and therefore predominantly transmissible only with blood component transfusions.34 Screening for both types is done with a single test. The rate of transmission of HTLV-1 decreased almost 10-fold (from 1 per 8,500 to 1 per 69,000) after introduction of the screening test.35 Transplantation of solid organs from an HTLV-1–infected donor resulted in rapid progression to subacute myelopathy in three recipients; this phenomenon has not been described in transfusion recipients.36
HTLV-1 was found to be associated with a slowly progressive myelopathy known in tropical zones as tropical spastic paraparesis (TSP) and, in endemic areas of Japan, as HTLV-1-associated myelopathy (HAM). The unique phenotypes of HAM/TSP are chronic, symmetrical, bilateral involvement of the pyramidal tracts, at mainly the thoracic level of the spinal cord, and include progressive spastic paresis with spastic bladder and minimal sensory deficits. Patients with HAM/TSP are mostly adults; thus, the disease has a long latency after HTLV-1 infection. However, transfusion of seropositive blood can lead to HAM/TSP after an average interval of two years. This feature is different from ATL. However, screening for seropositive blood has greatly reduced the risk of acquiring HAM/TSP through transfusion.
HTLV-1 is a retrovirus (family Retroviridae; genus Deltavirus) which, like HIV, infects CD4 T cells; after reverse transcription, its DNA becomes incorporated into the DNA of the host cell thus making a provirus. However, whereas HIV eventually destroys the cells it infects, HTLV-1 causes them to proliferate, hence leading to leukaemia in some patients.
Interestingly, HTLV-1 associated myelopathy is more likely when HTLV1 is acquired via blood transfusion, whereas HTLV1 acquired through breast feeding is more likely to be associated with adult T-cell leukaemia-lymphoma. Low levels of viral DNA in peripheral blood mononuclear cells occur in asymptomatic infection while higher levels correlate with symptomatic disease. The host response includes antibody production and development of cytotoxic T cells. These cells, plus CD4 T cells are part of the perivascular inflammatory infiltrate contributing to the myelitis. Neuronal damage is caused by release of inflammatory cytokines, rather than direct viral invasion of neurones.190 Risk factors for development of myelopathyinclude high proviral load and certain polymorphisms in the interleukin (IL)-10 promoter and in the IL28B gene.
HTLV-1 was found to be associated with a slowly progressive myelopathy known in tropical zones as tropical spastic paraparesis (TSP) and, in endemic areas of Japan, as HTLV-1-associated myelopathy (HAM). The unique phenotypes of HAM/TSP are chronic, symmetrical, bilateral involvement of the pyramidal tracts, at mainly the thoracic level of the spinal cord, and include progressive spastic paresis with spastic bladder and minimal sensory deficits. Patients with HAM/TSP are mostly adults; thus, the disease has a long latency after HTLV-1 infection. However, transfusion of seropositive blood can lead to HAM/TSP after an average interval of two years. This feature is different from ATL. However, screening for seropositive blood has greatly reduced the risk of acquiring HAM/TSP through transfusion.
Most patients with HAM/TSP have much higher (frequently one order higher) titers of antibodies against HTLV-1 antigens than asymptomatic carriers and ATL patients. These patients and their family members were reported to have particular types of human leukocyte antigens (HLA). The greater immunological response to HTLV-1 infection may be thus explained.
Despite their strong immunological responses to HTLV-1 infection, most HAM/TSP patients have much larger populations of infected T cells than do HTLV-1 carriers. Some of these infected T cells infiltrate the spinal cord particularly at the site of lesions and also the cerebrospinal fluid. Some of these virus-positive cells produce cytokines including cytotoxic tumor necrosis factor (TNF)-α in the spinal cord. The frequent or infrequent expression of cytotoxic cytokines is proposed to cause accumulation of damage in neuronal tissues as the mechanism of HAM/TSP.
HTLV-1 infection is also proposed to be associated with other diseases such as uveitis, chronic lung diseases, monoclonal gammopathy, and rheumatoid arthritis. The association of uveitis with HTLV-1 infection has been established; however, further studies are required to elucidate the exact relationship of these diseases with HTLV-1 infection.
HTLV-1 is a retrovirus, endemic in many areas worldwide, particularly southwestern Japan, Central Africa, and the Caribbean. HTLV-1 has been linked to the development of a specific clinicopathologic syndrome known as ATLL. Although the link is well established, epidemiologic studies from high-prevalence regions indicate a long latency period for HTLV-1, with a lifetime ATLL risk of approximately 2.5% in infected individuals.
Human T-Lymphotropic Virus 1–Associated Adult T-Cell Leukemia–Lymphoma—Fact Sheet
Clinical Features
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Often divided into four clinical subtypes: acute, chronic, smoldering, and lymphomatous
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Long latency period between HTLV-1 infection and development of ATLL
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Low overall lifetime risk of ATLL in chronically HTLV-1–infected individuals
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Virally encoded p40 Tax and HBZoncoproteins are important in leukemogenesis
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May show substantial clinical overlap with MF-SS
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Confirmation of HTLV-1 infection (by serology or otherwise) required for diagnosis
Peripheral Blood Morphology
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Bizarre flower-like lymphocytes
Immunophenotype
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Usually T-helper phenotype, CD3+, CD4+, CD8−; cells generally CD7−, CD25+
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FOXP3, a feature of T-regulatory cells, is often expressed
Genetics
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Clonal cytogenetic abnormalities may be seen, but no single abnormality is linked to this disease
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Clonal integration of HTLV-1 genome can be demonstrated
ATLL occurs in adults (median age, 56 years; range, 27 to 82 years) and has four major clinical presentations: acute, lymphomatous, chronic, and smoldering. The acute subtype (55% to 60% of cases) is marked by severe peripheral blood lymphocytosis (often greater than 100 × 109/L), numerous “flower” cells in the peripheral blood (Fig. 13.5), hypercalcemia, hepatosplenomegaly, elevated serum lactate dehydrogenase, and a rapidly progressive course with a median survival of 6 months despite multiagent chemotherapy. The acute variant may also present with lytic bone lesions, likely because of a release of cytokines that accelerate bone resorption—the same process that results in hypercalcemia at presentation. The chronic subtype (15% to 20% of cases) can manifest with a peripheral blood absolute lymphocytosis and circulating flower cells, but generally the lymphocyte count is much lower than that seen in the acute variant. Exfoliative skin rashes may be seen in chronic ATLL, but hypercalcemia is generally absent. The median survival for chronic ATLL is more than 2 years, but most patients die within 5 years because of progression to acute or lymphomatous ATLL. Smoldering ATLL (approximately 5% of cases) is marked by a normal peripheral blood leukocyte count, with circulating neoplastic cells constituting less than 5% of total leukocytes. Although skin rashes can develop in this variant, patients with smoldering ATLL do not have hepatosplenomegaly, hypercalcemia, or lymphadenopathy. The median survival for smoldering ATLL is also more than 2 years but less than 10 years because of the progression to acute ATLL or to infectious complications. Finally, presentation as lymphoma without leukemia occurs in approximately 20% to 25% of patients and has an aggressive clinical course with a median survival of approximately 1 year. These patients have generalized lymphadenopathy but generally do not have hepatosplenomegaly, skin involvement, or hypercalcemia; some patients may develop leukemia during the course of disease.
Lymphomagenesis in HTLV-1 infection is a complex, multiple-step process. This concept is manifest in the long latency period between HTLV-1 infection and onset of ATLL, and in the low lifetime risk of ATLL in HTLV-1–infected individuals. HTLV-1 randomly integrates into the genome of infected cells; in other words, the pattern of HTLV-1 integration is distinct in every infected cell, except in cells that are clonally related. The virus encodes for two oncoproteins, p40 Tax protein and HTLV-1 basic leucine zipper factor (HBZ), which are thought to have a key role in the development of ATLL in chronically infected individuals. Tax activates the viral promoter and the cyclic AMP and nuclear factor κB pathways. Anti-apoptotic proteins are upregulated and p53 is suppressed. HBZ, which is consistently expressed in all cases of ATLL, is thought to contribute to cellular proliferation and survival of the clone. Epigenetic alterations are also involved in the development of ATLL, and hypermethylation is associated with disease progression.
Epstein–Barr virus (EBV)-transformed B cell lines have been successfully infected with both HTLV-1 and -2, and HTLV-2 infection results in syncytia formation in the human B cell BJAB lymphoblastoid cell line.
HIV-1 is a retrovirus, belonging to a group of heterogeneous, lipid-enveloped RNA viruses. Another retrovirus, HIV-2, is relatively rare and causes a less severe AIDS-like syndrome. HIV-1 has two major viral envelope proteins—the external glycoprotein gp120 and the transmembrane glycoprotein gp41.
The primary target cell of HIV-1 is the human CD4+lymphocyte. The HIV-1 gp120 envelope protein binds to the CD4+ molecule on the host cell membrane with high affinity. This binding allows the virus to enter the T cell and to integrate its genome into the host DNA. HIV-1 also infects monocytesand macrophages but with less marked cytopathic effects. Infected monocytes serve as a reservoir for HIV-1, allowing further spread of the virus throughout the body.5 Infection with HIV-1 results in progressive depletion of the CD4+ helper lymphocytes. This depletion serves as a marker of the severity of HIV-1 infection because the incidence of opportunistic infections and other complications correlates with the number and percentage of CD4+ lymphocytes, particularly in children older than 1 year.6 The ability to produce cytokines, such as interleukin-2 and interferon-γ, is progressively lost in HIV-1-infected children. Natural killer cell–mediated cytotoxicity also is reduced in HIV-1-infected children. In addition, B cell dysfunction with defective humoral immunity further predisposes to severe infection.7
HIV-1 infected individuals were passively treated with a neutralizing mouse monoclonal antibody to HIV-1 gp 120. Anti-idiotypic (anti-Id) antibodies to the Mab developed which could be demonstrated to react with the most strongly antigen-binding region of the Mab, CDR-H3. We describe the development of anti-Id antibodies to the variable heavy and light chain regions of the monoclonal antibody used in a passive immunotherapy study in HIV-1 infected individuals and the capacity of the complementarity determining regions (CDRs) from this antibody to function as Id molecules. The CDR-H3 region could be mimicked by a synthetic cyclic peptide, which in turn neutralized several HIV-1 primary isolates.
HIV-associated polymyositis was first described in 1983, and many reports in the past several years confirm this association [2, 37]. Dermatomyositis is also seen in HIV infection [38]. The clinical course, laboratory and electromyography findings are similar to the idiopathic form [2]. Polymyositis in 64 HIV/AIDSpatients referred for the presence of elevated creatine kinase (CK) levels or muscle weakness was evaluated. Patients underwent neurologic and rheumatologic evaluation, electromyography, and muscle biopsy after exclusion for recreational drug or alcohol use, metabolic/endocrine disorders, zidovudine therapy, and other infections. Thirteen patients (20%) had biopsy-proven myositis. The median duration of HIV infection prior to diagnosis of myositis was 4.3 years. Six patients had concomitant diffuse infiltrative lymphocytosis syndrome. There was no correlation of severity of weakness, stage of HIV infection, or retroviral treatment with the CK level at diagnosis. Eight patients received prednisone(60 mg/day) with 5 attaining complete resolution of myositis. The remaining 3 patients received immunosuppressive therapy(azathioprine or methotrexate and intravenous immunoglobulin) and had normalization of strength and CK. Four patients had spontaneous resolution of their myositis without treatment. In this study, HIV-associated myositis occurred at any stage of HIV infection, had a relatively good prognosis, and responded well to immunosuppressive therapy [39].
HIV-1 Escape from NKG2D-Mediated Recognition by NK Cells
HIV-1 infection does not only affect HLA class I expression, thereby impacting recognition by KIRs, but can also trigger the upregulation of ligands for less polymorphic receptors, such as NKG2D. Expression of these stress-induced ligands, and particularly that of UL16-binding proteins (ULBPs), results in increased recognition and killing of both HIV-1-infected and uninfected bystander CD4+ T cells by NK cells (Fogli et al., 2008; Norman et al., 2011; Richard et al., 2013; Ward et al., 2007). Given the high capacity of NKG2D ligands to activate NK cells, HIV-1, like other viruses, has evolved elaborate mechanisms to evade NKG2D-mediated recognition.
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