Hiv vrus


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

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Hiv vrus

  1. 1. Retroviridae
  2. 2. • 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
  3. 3. HumanImmunodeficiency Virus
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. • 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
  8. 8. HIV Structure surface transmembrane matrix protein capsid protein nucleocapsid protein RT Integrase protease
  9. 9. 9
  10. 10. 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
  11. 11. HIV genome organization
  12. 12. 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)
  13. 13. CXCr4 is the major coreceptor for T-cell-tropic strainsCCr5 is the major coreceptor for macrophage-tropic strains
  14. 14. 14
  15. 15. Retroviruslife cycle:
  16. 16. HIV integration:
  17. 17. HIV at Surface of CD4 Lymphocyte17 Courtesy of CDC
  18. 18. 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
  19. 19. 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
  20. 20. Pathogenesis of HIV
  21. 21. 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”
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. Transmission• Modes of infection – Sexual transmission at genital or colonic mucosa – Blood transfusion – Mother to infant – Accidental occupational exposure26
  27. 27. 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)
  28. 28. 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
  29. 29. 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
  30. 30. THE END R.DOROST@yahoo.com05:21