Hiv vrus
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Hiv vrus

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Of Iran. Damghan. P.h.d.Dorostkar

Of Iran. Damghan. P.h.d.Dorostkar

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Hiv vrus Hiv vrus Presentation Transcript

  • Retroviridae
  • • The Retroviridae are a family of enveloped (+) sense ssRNA viruses that have been intensely studied because of their association with cancers, leukemias and the AIDS syndrome
  • HumanImmunodeficiency Virus
  • Transfer of SIV to Humans• “Natural transfer” theory (Science 2000) – SIV was transferred to humans through hunting and handling of chimpanzees – The epidemic required urbanization and increased population mobility – Most scientific-based theory4
  • Transfer of SIV to Humans (2)• “Human error” theory (Edward Hooper,“The River” 2000) – Oral polio vaccine used in West Africa during the late 1950s may have been contaminated with SIV – SIV has not been recovered from this vaccine5 in subsequent studies
  • Classification of HIV• HIV class: Lentivirus – Retrovirus: single stranded RNA transcribed to double stranded DNA by reverse transcriptase – Integrates into host genome – High potential for genetic diversity – Can lie dormant within a cell for many years, especially in resting (memory) CD4+ T4 lymphocytes6
  • • HIV type (distinguished genetically) – HIV-1 -> worldwide pandemic (current ~ 40 M people) – HIV-2 -> isolated in West Africa; causes AIDS much more slowly than HIV-1 but otherwise clinically similar05:21
  • HIV Structure surface transmembrane matrix protein capsid protein nucleocapsid protein RT Integrase protease
  • 9
  • Retroviral Proteins• gag, pol, and env – Gag protein proteolytically processed into • MA (matrix) • CA (capsid) • NC (nucleocapsid) – Pol protein encodes enzymes • PR (protease) • RT (Reverse Transcriptase which has both DNA polymerase and RNase H activities) • IN (Integrase) – Env protein encodes • SU surface glycoprotein • TM transmembrane protein• “Accessory” genes (in Complex Retroviruses) - regulate and coordinate virus expression; function in immune escape
  • HIV genome organization
  • Env Proteins: Surface (SU)• Glycoprotein (gp, followed by apparent molecular weight)• Attaches to a specific receptor on cell surface• Major neutralizing antigen on retrovirus, also often highly variable (EIAV, HIV). Hard to make vaccines. SU (gp120) Lipid Bilayer (derived from cell) TM (gp 41)
  • CXCr4 is the major coreceptor for T-cell-tropic strainsCCr5 is the major coreceptor for macrophage-tropic strains
  • 14
  • Retroviruslife cycle:
  • HIV integration:
  • HIV at Surface of CD4 Lymphocyte17 Courtesy of CDC
  • Viral-host Dynamics 10• About 10 (10 billion) virions are produced daily• Average life-span of an HIV virion in plasma is ~6 hours• Average life-span of an HIV-infected CD4 lymphocytes is ~1.6 days• HIV can lie dormant within a cell for many years, especially in resting (memory) CD4 cells, unlike other retroviruses18
  • HIV Evasion Methods• Makes 10 billion copies/day -> rapid mutation of HIV antigens• Integrates into host DNA• Depletes CD4 lymphocytes• Down-regulation of MHC-I process• Impairs Th1 response of CD4 helper T lymphocyte• Infects cells in regions of the body where antibodies penetrate poorly, e.g., the19 central nervous system
  • Pathogenesis of HIV
  • Primary HIV Infection• The period immediately after infection characterized by high level of viremia (>1 million) for a duration of a few weeks• Associated with a transient fall in CD4• Nearly half of patients experience some mononucleosis-like symptoms (fever, rash, swollen lymph glands) Patient 21 enters “clinical latency”
  • Cells Infected by HIV• Numerous organ systems are infected by HIV: – Brain: macrophages and glial cells – Lymph nodes and thymus: lymphocytes and dendritic cells – Blood, semen, vaginal fluids: macrophages – Bone marrow: lymphocytes – Skin: langerhans cells – Colon, duodenum, rectum: chromaffin cells22 – Lung: alveolar macriphages
  • General Mechanisms of HIV Pathogenesis• Direct injury – Nervous (encephalopathy and peripheral neuropathy) – Kidney (HIVAN = HIV-associated nephropathy) – Cardiac (HIV cardiomyopathy) – Endocrine (hypogonadism in both sexes) – GI tract (dysmotility and malabsorption)• Indirect injury – Opportunistic infections and tumors as a23 consequence of immunosuppression
  • General Principles of Immune Dysfunction in HIV• All elements of immune system are affected• Advanced stages of HIV are associated with substantial disruption of lymphoid tissue – Impaired ability to mount immune response to new antigen – Impaired ability to maintain memory responses – Loss of containment of HIV replication – Susceptibility to opportunistic infections24
  • Consequence of Cell-mediated Immune Dysfunction• Inability to respond to intracellular infections and malignancy – Mycobacteria, Salmonella, Legionella – Leishmania, Toxoplama, Cryptosporidium, Mi crosporidium – Histoplamosis – HSV, VZV, JC virus, pox viruses – EBV-related lymphomas25
  • Transmission• Modes of infection – Sexual transmission at genital or colonic mucosa – Blood transfusion – Mother to infant – Accidental occupational exposure26
  • Laboratory Markers of HIV• Viral load Infection – Marker of HIV replication rate – Number of HIV RNA copies/mm3 plasma• CD4 count – Marker of immunologic damage – Number of CD4 T-lymphocytes cells/mm3 plasma – Median CD4 count in HIV negative Ethiopians is significantly lower than that seen in Dutch controls • Female 762 cells/mm3 (IQR 604-908)27 • Male 684 cells/mm3 (IQR 588-832)
  • HIV RNA Set Point Predicts Progression to AIDS• HIV RNA viral loads after infection can be used in the following ways: – To assess the viral set point – To predict the likelihood of progression to AIDS in the next 5 years• The higher the viral set point: – The more rapid the CD4 count fall – The more rapid the disease progression to AIDS28
  • CD4 T-cell Count and Progression to AIDS• In contrast to VL, baseline CD4 is not a good predictor of time to progression to AIDS – Unless CD4<321 cells/ml• However, as the CD4 count declines over time, patients will develop opportunistic infections – Develop in a sequence predictable according to CD4 count29 – WHO Staging system
  • THE END R.DOROST@yahoo.com05:21