Human Immunodeficiency Viruses PDF

Medical Virology Chapter 13: Human Immunodeficiency Viruses  HIV… Classification & Biology: Family: Retroviridae, Genus: Lentivirus, there are two distinct types of human AIDS viruses: HIV-1 and HIV-2. AIDS was first described in the United States...

Medical Virology Chapter 13: Human Immunodeficiency Viruses  HIV… Classification & Biology: Family: Retroviridae, Genus: Lentivirus, there are two distinct types of human AIDS viruses: HIV-1 and HIV-2. AIDS was first described in the United States in 1981 as a new disease entity in homosexual men. Twenty years later, AIDS was recognized as a worldwide epidemic that continues to expand. It is estimated that more than 35 million people worldwide are living with HIV/AIDS, the majority having been infected by heterosexual contact.  …HIV… Both HIV-1 and HIV-2 show considerable sequence variability, allowing their classification into a number of subtypes with marked differences in geographical distribution and association with risk groups. HIV-1 variants are classified into three genetic groups: major (M), outlier (O) and non-M, non-O (N). Group M viruses which dominate the pandemic are further classified into subtypes A, B, C, D, F, G, H, J and K and several ‘circulating recombinant forms’ (CRF) that comprise more than one subtype, e.g. CRF01-A/E.  …HIV… Subtype B is most frequently found in western countries, whereas other genotypes such as C (Africa, parts of Asia), E (Thailand) and F (South America) are the main subtypes responsible for the recent epidemic spread. HIV-1 diversity is greatest in sub-Saharan African countries such as the Congo, where there is wide co-circulation of most of the current subtypes. A total of seven subtypes of HIV-2, two of which are epidemic (A and B) and 5 nonepidemic (C to G), have been defined, resulting from as many different simian-to-human transmissions.  …HIV… All retroviruses have an outer envelope of lipid and viral proteins; the envelope encloses the core, consisting of other viral proteins, within which lie two molecules of viral RNA (positive single-stranded) and the enzyme reverse transcriptase, an RNA-dependent DNA polymerase. Genome and gene coding assignment: genomes contain in the same order the genes gag, pol and env coding for three groups of structural and enzymatic proteins.  …HIV… The long terminal repeat sequences (LTR) at both ends of the genome contain promoter and enhancer sequences. 1) gag gene: coded six protein all found in the virion. 2) pol gene: produce protease, reverse transcriptase and integrase enzymes; all required during replication. 3) env gene: codes for a large protein that is glycosylated and cleaved to gp41, the transmembrane protein and gp120, present on the envelope as a trimer with many glycosylation sites.  …HIV… Replication: Retroviruses replicate and produce viral RNA from a DNA copy of the virion RNA (hence their name). Initial attachment of HIV to target cells is by the interaction of the external envelope glycoprotein gp120 with part of the CD4 molecule of T helper lymphocytes and other cells. The HIV envelope then interacts with a second (co-) receptor. These include the chemokine receptors, CCR5 and CXCR4 expressed on a wide range of lymphoid and non-lymphoid cells  …HIV… After the second binding step, entry of the virus occurs by fusion of the viral envelope with the cellular membrane, which requires exposure of a hydrophobic domain in gp41. Once the RNA is released into the cytoplasm, the reverse transcriptase acts to form the double-stranded DNA copy, which is transported to the nucleus and is spliced into the host cell DNA in which state it is referred to as the provirus. Once inserted into the host DNA, infection with HIV is permanent.  …HIV… Transcription of mRNA from the provirus is by the host RNA polymerase II to produce viral mRNA and RNA. Proteins are synthesized and processed to form the virion components. Virions are assembled at the cell membrane where envelope and core proteins have located. The internal structure of the virion matures as it buds from the cell; at least 10¹⁰ HIV particles are produced newly every day, a single viral replication cycle lasts 1 to 2 days on average and the half-life of virus in plasma is in the order of one hour.  …HIV… The HIV infected person has accumulation of virus variants due to: 1. Retroviral RTs do not possess a proofreading activity and thus have a high misincorporation rate. 2. Genomic recombination, which may occur after coinfection of a cell with two different viruses and encapsidation of both viral RNAs in the same particle. Virus source in blood: 1. Productively infected CD4+ T lymphocytes; 93 to 99% of the virus in the blood, infected, produce virus, and die with a half-life of only 0.7 ± 0.2 days.  …HIV… 2. 1 to 7% of the virus in plasma originates from longer-lived cells (monocytes or macrophages, release of surface-bound virus from dendritic cells) that have a half-life of 14 ± 7.5 days. 3. Less than 1% of the virus in plasma is produced by latently infected CD4+ T-cells, which become activated and then start producing virus. This last compartment has a very slow decay rate with a half-life estimated at 6 to 44 months, or it may even not decay at all.  …HIV… Epidemiology: According to UNAIDS, between 33 and 37 million people were living with HIV in 2013. The global prevalence among individuals aged > 15 years was estimated at 0.7 to 0.8%. New infections in 2013 amounted to 1.9 million in adults and to 240,000 in children. The highest in epidemic is sub-Saharan Africa with overall prevalence among adults in 2013 was 4.7%. 2/3 of the global total of HIV infection. Other world regions with a high prevalence include the Caribbean (1.1%) and Eastern Europe/Central Asia (0.6%), while the prevalence in other world regions is between 0.1 and 0.4%.  …HIV… HIV is transmitted predominantly by sexual intercourse, connatally from mother to child, postnatally by breast feeding or by parenteral inoculation, most importantly intravenous drug injection. Globally, the most frequent route of transmission is by sexual intercourse. In general, the risk is proportional to the viral load, as determined by RT-PCR for HIV-1 RNA.  …HIV… Sexual transmission is mediated by infectious HIV-1 particles and/or virus-infected cells in the semen or mucosal secretions. The risk of transmitting or acquiring infection varies greatly. Epidemiologic studies indicate that transmission is linked to viral shedding, i.e., the amount of infectious virus in genital fluids. This in turn is linked to the disease stage and is highest during acute infection and late-stage AIDS.  …HIV… Clinical Significance: The duration between primary infection and progression to clinical disease averages about 10 years. In untreated cases, death usually occurs within 2 years after the onset of clinical symptoms. Following primary infection, there is a 4- to 11-day period between mucosal infection and initial viremia; the viremia is detectable for about 8–12 weeks. Virus is widely disseminated throughout the body during this time, and the lymphoid organs become seeded.  …HIV… The clinical course of HIV infection is characterized by several phases, culminating in immune deficiency 1. Acute HIV syndrome: patients may experience a mild acute illness with fever and malaise, correlating with the initial viremia. 2. Latency: progressive loss of CD4+ T cells in lymphoid tissues and destruction of the architecture of these tissues. Eventually, the blood CD4+ T cell count begins to decline, and when the count falls below 200 cells per mm3 (normal level about 1500 cells/mm3), patients become susceptible to infections. 3. Clinical AIDS : increased susceptibility to infections and some cancers, as a consequence of immune deficiency.  …HIV… Laboratory Diagnosis: HIV infection can be diagnosed through detection of antibodies to the virus (anti-HIV), or of the virus itself (e.g. HIV p24 antigen, RNA or proviral DNA) in a peripheral blood sample. All current tests use HIV antigens derived from cloned recombinant HIV gag, pol and env genes expressed in E. coli, or synthetic peptides. Western or immunoblotting has been used extensively as a confirmatory assay.  …HIV… Most current assays can detect antibody to both HIV-1 and HIV-2 antigens. A first positive result must be confirmed by at least two other different assays with different viral antigens and a second serum sample checked to confirm that the original sample was identified correctly. Combination assays: Reliable and highly sensitive methods to detect anti- HIV and p24 antigen in a single EIA are now available (so-called 4th generation assays); these allow improved diagnostic sensitivity of diagnosis of primary HIV infections by approximately 1 week.  …HIV… PCR: Direct detection methods are required when serological tests are inappropriate, such as during the early acute stage and in infants who still carry maternal anti-HIV, and for monitoring progression. RNA sequences are found in extracellular virus particles in plasma, and the RNA can be accurately quantified as the number of RNA copies to indicate the extent of virus replication in the patient. Measurement of plasma virus load is now essential for monitoring disease progression and the response to antiretroviral therapy.  …HIV… HIV proviral DNA is present in infected cells and can be detected in peripheral blood mononuclear cells. This method is used principally to diagnose infection in infants born to HIV infected mothers. The standard procedure involves analysis of serial blood samples collected at birth, 6 weeks and 3 months. The absence of proviral DNA at 3 months of age (or any time later) excludes HIV infection in babies who are not being breastfed.  …HIV… Rapid Tests and Use of Alternative Specimens: Rapid tests can be performed with minimal or no laboratory equipment; they yield results within 30 minutes. Such tests may be useful in certain situations, e.g., in assessing the risk of HIV transmission in needle stick injuries and similar exposures to possibly HIV-contaminated materials, organ donations, or whenever a laboratory test result may not be available quickly. Test formats: DAGS, indirect binding, Ig capture, agglutination, or chromatographic assay.  …HIV… Treatment and Prevention: The primary goals of therapy in HIV-infected patients are to reduce HIV-related morbidity and mortality, to improve quality of life, to restore and preserve immunologic function, and to maximally and durably suppress virus replication as measured by the viral load. Due to the high variability of HIV and the generation of drug- resistant mutants, antiretroviral agents are administered in combinations of different drug classes termed combined antiretroviral therapy (cART) to maximize efficacy and to minimize the induction of drug resistance.  …HIV E.g.; Abacavir (ABC) + lamivudine (3TC) - Epzicom (GSK). Prevention: Any measure that effectively reduces exposure to the viral inoculum present in genital secretions will contribute to reducing the extent of sexual transmission of HIV. 1. Condom use: reduces the incidence of new HIV infections by 80 to 95%. 2. Early identification, counseling, and treatment of infected individuals. 3. Change sexual behavior and Male circumcision 60% risk reduction. Questions? Thank you