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  1. 1. AIDS
  2. 2. AIDS <ul><li>Retroviral disease characterized by profound inmunosupression, primarily affecting cell-mediated inmunity, that leads to neurologic manifestations, opportunistic infections, and neoplasms </li></ul>
  3. 3. AIDS epidemiology <ul><li>AIDS has been reported from more than 190 countries worldwide </li></ul><ul><li>In U.S. several high risk groups of adult have been identified: </li></ul><ul><li>1.-Homosexual or bisexual men </li></ul><ul><li>2.-Intravenous drug users </li></ul><ul><li>3.-Hemophiliacs, especially who received factor VIII concentates before 1985. </li></ul><ul><li>4.-Recipients of blood and blood components. </li></ul><ul><li>5.-Heterosexual contacts with other high-risk individual(s) </li></ul>
  4. 4. AIDS epidemiology <ul><li>About 75% of AIDS transmission are by sexual transmission. </li></ul><ul><li>Heterosexual transmission is the dominant mode if infection in Africa and Asia. </li></ul>
  5. 5. AIDS epidemiology <ul><li>Pediatric population consist 2% </li></ul><ul><li>of all AIDS cases in U.S. and more than 90% of these cases are secondary to mother-to-child transmission. </li></ul><ul><li>Infected mother can transmit by: </li></ul><ul><li>Transplacental spread in utero </li></ul><ul><li>Infected birth canal during delivery </li></ul><ul><li>Ingestion of virus infected milk after birth </li></ul><ul><li>Higher risk of transmission is associated with high maternal viral load and low CD4+ cell count as well as chorioamnionitis </li></ul>
  6. 6. AIDS epidemiology <ul><li>All forms of sexual transmission of HIV are facilitated by coexisting sexually transmitted diseases. </li></ul><ul><li>Greater concentration of virus in seminal fluid is seen in genital inflammatory states that cause increased numbers of inflammatory cells in the semen. </li></ul>
  7. 7. AIDS epidemiology <ul><li>HIV is NOT transmitted by casual personal contact in the household, workplace or school </li></ul>
  8. 8. AIDS etiology <ul><li>HIV: a human retrovirus belonging to the lentivirus family </li></ul><ul><li>Two genetically different but related forms of virus have been isolated. </li></ul><ul><li>HIV-1: Most common type seen in U.S., Europe and central Africa </li></ul><ul><li>HIV-2 : Primarily seen in West Africa. </li></ul>
  9. 9. HIV-1 <ul><li>Core: electron dense, cone-shaped containing </li></ul><ul><li>(1) p24 capsid protein </li></ul><ul><li>(2) p7/p9 capsid protein </li></ul><ul><li>(3) genomic RNA (2 copies) </li></ul><ul><li>(4) viral enzymes </li></ul><ul><ul><ul><li>(i) protease </li></ul></ul></ul><ul><ul><ul><li>(ii) reverse transcriptase </li></ul></ul></ul><ul><ul><ul><li>(iii) Integrase </li></ul></ul></ul><ul><ul><ul><li>(2) p17 matrix protein </li></ul></ul></ul><ul><ul><ul><li>(3) Lipid bilayer envelope-derived from host cell memb. Containing viral glycoprotein </li></ul></ul></ul><ul><ul><ul><li>Gp 120 </li></ul></ul></ul><ul><ul><ul><li>gp 41 </li></ul></ul></ul>
  10. 10. HIV-1 <ul><li>There are considerable genomic variations, most of which are clustered in the areas for envelope glycoproteins </li></ul><ul><li>(difficult to make “universal vaccine”) </li></ul><ul><li>Genetical subgroups </li></ul><ul><li>group M (major)-subtypes A through J </li></ul><ul><li>Group O (outlier) </li></ul>
  11. 11. AIDS PATHOLOGY <ul><li>Immune system and CNS are two major targets of HIV infection. </li></ul><ul><li>Infection and loss of CD4+ T cells. </li></ul><ul><li>Macrophages and dendritic cells are also targeted by HIV </li></ul>
  12. 12. AIDS <ul><li>CD4+ T cells play a pivotal role, as a “master cell” in regulating immune system. </li></ul><ul><li>CD4+ T cells produce cytokines (IL-2, IL-4, IL-5, IFN-?), macrophage chemotactic factors (GM-CSF) </li></ul><ul><li>Loss of this “master cell” has ripple effects on virtually every other cell in immune system </li></ul>
  13. 13. AIDS PATHOLOGY <ul><li>CD4 molecule is a high-affinity receptor for HIV </li></ul><ul><li>However, binding of CD4 alone is not sufficient for infection </li></ul><ul><li>HIV gp 120 must also bind to cell surface core receptors (CCR5 and/or CXCR4) for viral core to enter the cell </li></ul>
  14. 14. CCR5 vs CXCR4 <ul><li>M-Tropic(macrophage-tropic) strains of HIV use CCR5 for their entry </li></ul><ul><li>(CCR5 is expressed on both macrophage and T-cell) </li></ul><ul><li>T-tropic (T-cell tropic) strains use CXCR4 for their entry </li></ul><ul><li>(CXCR4 is expressed on T-cells, but not on macrophages/monocytes) </li></ul><ul><ul><li>In 90% of cases HIV is transmitted by M-tropic strains, then, T-tropic strains gradually accumulate </li></ul></ul>
  15. 15. AIDS pathology <ul><li>Once internalized, HIV genome undergoes reverse transcription that results HIV cDNA proviral DNA) </li></ul><ul><li>Viral cDNA may remain silent for various length of time, or it may be, with activation by antigens or cytokines, trnascribed to form complete viral particles, that eventually bud from the cell membrane and cause death of infected cells </li></ul>
  16. 16. <ul><li>Physiologic stimuli that promote activation and growth of normal T-cells lead to the death of HIV-infected T-cells </li></ul>
  17. 17. AIDS PATHOLOGY <ul><li>Infection of monocytes and macrophages is also important in the pathogenesis of HIV infection </li></ul><ul><li>Early stage </li></ul><ul><ul><li>Monocytes and macrophages act as a virus factory and reservoir </li></ul></ul><ul><ul><li>“ safe vehicle” for virus to be transported to various body parts </li></ul></ul><ul><ul><li>Late Stage </li></ul></ul><ul><ul><li>Site of continued viral replication </li></ul></ul>
  18. 18. AIDS pathology <ul><li>Unexplainable monocyte defect </li></ul><ul><ul><li>Impaired microbicidal activity </li></ul></ul><ul><ul><li>Decreased chemotaxis </li></ul></ul><ul><ul><li>Decreased IL-1 secretion </li></ul></ul><ul><ul><li>Inappropiate TNF-a secretion </li></ul></ul><ul><ul><li>Poor capacity to present antigens to T-cells </li></ul></ul>
  19. 19. AIDS pathology <ul><li>Two types of dendritic cells are also infected by HIV </li></ul><ul><ul><li>Langerhans cells </li></ul></ul><ul><ul><ul><li>Capturing virus and transporting HIV to regional lymph nodes where CD4+ </li></ul></ul></ul><ul><ul><ul><li>T cells are infected. </li></ul></ul></ul><ul><ul><ul><li>Follicular dendritic cells </li></ul></ul></ul><ul><ul><ul><li>act as HIV reservoirs </li></ul></ul></ul><ul><ul><ul><li>-most virus particles are on the surface of the dendritic processes </li></ul></ul></ul><ul><ul><ul><li>Having receptors for Fc portion </li></ul></ul></ul><ul><ul><ul><li>Trap antibody-coated HIV virons </li></ul></ul></ul>
  20. 20. AIDS activation of latent infection <ul><li>How T-cell activation activates latent HIV infection </li></ul><ul><li>T-cell activation (by TNF-a, IL-1, IL-2) </li></ul><ul><li>Induction of cytoplasmic kinase </li></ul><ul><li>Release of NK-KB from I-KB </li></ul><ul><li>NF-KB into nucleus </li></ul><ul><li>NF-KB binds to enhancer sequences (KB sites) within promotor regions of several genes (including cytokines) </li></ul>
  21. 21. AIDS activation of latent infection <ul><li>The long terminal repeat (LTR) sequences that flank the HIV genome also contain similar KB sites. </li></ul><ul><li>Therefore, activation of cytokine genes also activates HIV genome. </li></ul>
  22. 22. AIDS B-cell function abnormalities <ul><li>Patients with AIDS also display profound abnormalities of B-cell function </li></ul><ul><ul><li>Hypergammaglobulinemia </li></ul></ul><ul><ul><li>Circulating immune complexes (due to polyclonal B-cell activation) </li></ul></ul><ul><ul><li>Unable to mount antibody response to a new antigen (probably due to lack of T-cell help) </li></ul></ul><ul><ul><li>Impaired humoral immunity </li></ul></ul><ul><ul><li>Disseminated infections caused by encapsulated bacteria </li></ul></ul><ul><ul><ul><li>S. Pneumonie </li></ul></ul></ul><ul><ul><ul><li>H. influenzae </li></ul></ul></ul>
  23. 23. AIDS CNS involvement <ul><li>90% of pts. Show some form of neurologic involvement </li></ul><ul><li>40-60% have clinically manifesting neurologic dysfunction </li></ul>
  24. 24. AIDS CNS involvement <ul><li>HIV is carried to brain by infected monocytes. </li></ul><ul><li>Neurologic deficit is probably caused directly by soluble HIV gp 120, and indirectly by viral products and soluble factors (IL-1, TNF-a, IL-6) produced by macrophages/microglia </li></ul><ul><li>Neurons are not infected by HIV </li></ul>
  25. 25. AIDS CNS involvement <ul><li>Soluble neurotoxins act by triggering excessive Ca2+ entry into neurons through glutamate-activated ion channels </li></ul>
  26. 26. Natural Hx of HIV infection <ul><li>Langerhans cell </li></ul><ul><li>Mucosa--------------------------  regional LN </li></ul><ul><li>Blood-----------------------------  LN, spleen </li></ul><ul><li>virus initially replicates in lymphoid organs, then spills over into blood </li></ul><ul><li>*early, acute phase </li></ul><ul><li>*Middle, chronic phase </li></ul><ul><li>*final, crisis phase </li></ul>
  27. 27. Natural Hx of HIV infection <ul><li>1. Early, acute phase </li></ul><ul><li>Initial response of immnocompetent individual to HIV </li></ul><ul><ul><li>High level of virus production </li></ul></ul><ul><ul><li>Viremia (high levels of HIV p24 Ag in serum) </li></ul></ul><ul><ul><li>Abrupt reduction of CD4+ T-cells--  later return to near normal </li></ul></ul><ul><ul><li>Development of virus-specific immune response(“serocnversion”) </li></ul></ul><ul><ul><li>Widesperead seeding in lymphoid tissues </li></ul></ul>
  28. 28. Natural Hx of HIV infection <ul><li>1.early, acute phase </li></ul><ul><li>Clinical Sx. </li></ul><ul><ul><li>Develop 3 to 6 wks after infection </li></ul></ul><ul><ul><li>Last for 2 to 4 wks with spontaneous resoliving </li></ul></ul><ul><ul><li>Self limited acute illness----seen in 50-70% </li></ul></ul><ul><ul><ul><li>Sore throat, rash, myalgias, cervical adenopathy, fever, diarrhea, wt. Loss, vomiting, fatigue </li></ul></ul></ul>
  29. 29. Natura Hx of HIV infection <ul><li>1.early, acute phase </li></ul><ul><li>At the end of acute phase, the viral load is a reflection of virus-host equilibrium, that remains stable for several years </li></ul><ul><li>“ viremia” as HIV-1 RNA is the best surrogate marker of HIV disease progression </li></ul><ul><li>If viral load is: </li></ul><ul><ul><li>Less than 4,350 copies mRNA/mm3 </li></ul></ul><ul><ul><li>-  8% will progress to full-blown AIDS in 5 years </li></ul></ul><ul><ul><li>More than 36,270 copies </li></ul></ul><ul><ul><li>--  62% will progress </li></ul></ul>
  30. 30. Natural Hx of HIV infection <ul><li>2. Middle, chronic phase </li></ul><ul><li>Stage of relative containment of virus, continuing battle between HIV and the host immune system </li></ul><ul><ul><li>May last for several years </li></ul></ul><ul><ul><li>Associated with clinical latency </li></ul></ul><ul><ul><li>Largely intact immune system, but gradual erosion of CD4+ T-cells </li></ul></ul><ul><ul><li>Continuous HIV replication, predominantly in lymphoid tissue </li></ul></ul>
  31. 31. Natural Hx of HIV infection <ul><li>2.middle, chronic phase </li></ul><ul><li>Stage of relative containment of virus, continuing battle between HIV and the host immune system </li></ul><ul><ul><li>May last for several years </li></ul></ul><ul><ul><li>Associated with clinical latency </li></ul></ul><ul><ul><li>Largely intact immune system, but gradual erosion of CD4 T-.cells </li></ul></ul><ul><ul><li>Continuous HIV replication, predominantly in lymphoid tissue </li></ul></ul>
  32. 32. Natural Hx of HIV infection <ul><li>2. Middle, chronic phase </li></ul><ul><li>CDC classification of HIV infection </li></ul><ul><ul><li>=500 CD4+ cells/ ul </li></ul></ul><ul><ul><ul><li>Early symptoms </li></ul></ul></ul><ul><ul><ul><li>200 cells/ul </li></ul></ul></ul><ul><ul><ul><ul><li>Severe immunosupression </li></ul></ul></ul></ul>
  33. 33. Natural Hx of HIV infection <ul><li>2. Middle,chronic phase </li></ul><ul><li>Clinical Sx: </li></ul><ul><ul><ul><li>Asymptomatic (CDC group II) </li></ul></ul></ul><ul><ul><ul><li>Persistent generalized </li></ul></ul></ul><ul><ul><ul><li>Lymphadenopathy (CDC group III) </li></ul></ul></ul><ul><ul><ul><li>Minor opportunistic infection (thrush, Herpes Zoster) </li></ul></ul></ul><ul><ul><ul><li>Thrombocytopenia </li></ul></ul></ul>
  34. 34. <ul><li>Persistent lymphadenopathy </li></ul><ul><li>+ </li></ul><ul><li>Constitiutional symptoms </li></ul><ul><li>(fever,rash,fatigue)--------------------------------  onset of immune system decompensation (onset of crisis phase) </li></ul>
  35. 35. Natural Hx of HIV infection <ul><li>, crisis phase </li></ul><ul><li>Breakdown of host defense </li></ul><ul><li>Dramatic increase in plasma virus </li></ul><ul><li>Clinical disease </li></ul><ul><ul><li>Long lasting fever (>1month) </li></ul></ul><ul><ul><li>Fatigue </li></ul></ul><ul><ul><li>Weight loss </li></ul></ul><ul><ul><li>diarrhea </li></ul></ul>
  36. 36. CDC AIDS-defining conditions <ul><li>Serious oportunistic infections </li></ul><ul><li>Seconday neoplasms </li></ul><ul><li>Clinical neurologic disease </li></ul><ul><li>CD4+ T-cells<200 cells/ul </li></ul>
  37. 37. Natural Hx of HIV infection <ul><li>Viral replication continues in all three phases (HIV infection lacks microbiologic latency, although patients appear having “clinical latency”) </li></ul><ul><li>Therefore, anti-retroviral therapy must be commenced early in the course of disease, before clinical symptoms appear </li></ul>
  38. 38. CD4+ cell count Vs viral load <ul><li>CD4+ T cell count: </li></ul><ul><li>Tells you where in the spectrum of infection at the time of measurement </li></ul><ul><li>HIV viral load: </li></ul><ul><li>Tells you the direction in which the disease is heading (prognosis) </li></ul>
  39. 39. Natural Hx of HIV infection <ul><li>“ Long-term non-progressors” </li></ul><ul><ul><li>Long period (10 yrs) of asymptomatic state </li></ul></ul><ul><ul><li>Low levels of viremia </li></ul></ul><ul><ul><li>Stable CD4+ cell counts </li></ul></ul><ul><ul><li>Having deletions or mutations in nef gene </li></ul></ul>
  40. 40. HIV disease clinical features <ul><li>AIDS: </li></ul><ul><li>Opportunistic infections account 80% of deaths in AIDS </li></ul><ul><ul><ul><li>P. Carinii : </li></ul></ul></ul><ul><ul><ul><ul><li>50% of AIDS pts develop the infection at some time during the course. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Candida : </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Most common fungal infection in AIDS </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Usually seen in oral cavity or esophagus </li></ul></ul></ul></ul><ul><ul><ul><ul><li>In asymptomatic Pts, oral candidiasis is a sign of immunologic decompensation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Invasive candidiasis is not common in AIDS </li></ul></ul></ul></ul>
  41. 41. HIV disease clinical features <ul><li>CMV : </li></ul><ul><ul><li>Almost exclusively seen in pts with CD4+ cell count below 50/mm3 </li></ul></ul><ul><ul><li>Cryptococcosis: </li></ul></ul><ul><ul><ul><li>Seen in 10% of AIDS pts </li></ul></ul></ul><ul><ul><ul><li>Meningitis is the major manifestation </li></ul></ul></ul><ul><ul><ul><li>T. Gondi: </li></ul></ul></ul><ul><ul><ul><li>frequently involves CNS </li></ul></ul></ul><ul><ul><ul><li>accounts 50-60% of all CNS mass lesion in AIDS </li></ul></ul></ul>
  42. 42. HIV disease clinical features <ul><li>JC virus: </li></ul><ul><ul><li>Causes progressive multifocal leukoencephalopathy </li></ul></ul><ul><ul><li>Herpes simplex virus: </li></ul></ul><ul><ul><ul><li>Causes mucocutaneous ulcerative lesions </li></ul></ul></ul><ul><ul><ul><li>Protozoans: </li></ul></ul></ul><ul><ul><ul><li>diarrhea is a frequently caused by protozoans and/or bacteria (cryptosporidium, Isospora belli, Microsporidia)(Salmonella, Shigella) </li></ul></ul></ul>
  43. 43. HIV disease clinical features <ul><li>Neoplasms </li></ul><ul><ul><li>Kaposi sarcoma </li></ul></ul><ul><ul><li>Non-hodgkin lymphoma (B-cell lymphoma) </li></ul></ul><ul><ul><li>Cervical scc </li></ul></ul>
  44. 44. AIDS-associated neuropathy <ul><li>90% of pts demonstrate some form of neurologic involvement at autopsy </li></ul><ul><li>40-60% clinically show neurological dysfunction </li></ul><ul><ul><li>Self limited meningoencephalitis </li></ul></ul><ul><ul><li>Aseptic meningitis </li></ul></ul><ul><ul><li>Vascular myelopathy </li></ul></ul><ul><ul><li>AIDS-dementia complex </li></ul></ul>