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HIV/AIDS

HIV/AIDS. Donna Sullivan, PhD Division of Infectious Diseases University of Mississippi Medical Center. DENDRITIC CELLS, MACROPHAGES, AND HIV NEJM 340:1732. HIV-1 LIFE CYCLE. Nature Insight. Nature 410, 965 (01). Used with permission. THE GENOME OF THE HUMAN IMMUNODEFICIENCY VIRUS (TYPE 1).

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HIV/AIDS

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  1. HIV/AIDS Donna Sullivan, PhD Division of Infectious Diseases University of Mississippi Medical Center

  2. DENDRITIC CELLS, MACROPHAGES, AND HIVNEJM 340:1732

  3. HIV-1 LIFE CYCLE Nature Insight. Nature 410, 965 (01). Used with permission.

  4. THE GENOME OF THE HUMAN IMMUNODEFICIENCY VIRUS (TYPE 1)

  5. HIV DIAGNOSTIC TESTING • Enzyme linked Immunosorbent Assay (ELISA) • Sensitivity and specificity ar >98% • Confirmatory testing • Western blot, IFA (specificity >99%) • Home Testing/Rapid Testing • Salivary antibodies • Finger stick whole blood

  6. An ELISA plate

  7. ELISA Activity: ELISA data from three patients

  8. Western Blot Analysis Band pattern Interpretation Lane 1, HIV+ serum (positive control) Lane 2, HIV- serum (negative control) Lane A, Patient A Lane B, Patient B Lane C, Patient C

  9. Band Pattern Interpretation • No bands present Negative • Bands at either p31 OR Positive p24 AND bands present at either gp160 OR gp120 • Bands present, but pattern Indeterminate does not meet criteria for positivity

  10. WHEN TO MEASURE HIV RNA AND CD4+ T CELL LEVELS • Syndrome consistent with acute HIV infection • Initial evaluation of new HIV diagnosis • Every 3-4 months in untreated patient • Immediately prior to initiating therapy • 2-8 weeks after initiating therapy • Every 3-4 months in patients on therapy

  11. PLASMA HIV RNA - VIRAL LOAD • The number of HIV RNA strands in the plasma or serum of an HIV-infected persons • measured in logs (10,000 low risk, 100,000 high risk of progression to AIDS) • detectable after about 1-2 weeks at about 500 copies

  12. CHARACTERISTICS OF PLASMA HIV RNA ASSAYS

  13. AIDS DEFINING CONDITIONS (CDC) • HIV + test with: • CD4 lymphocyte count <200/mm3 OR • Opportunistic Infections • Oropharyngeal candidiasis • Pneumocystis carinii pneumonia (PCP) • Disseminated cryptococcal infection • CMV disease (retinitis) • Progressive multifocal leukoencephalopathy • Mycobacterium avium complex, disseminated

  14. 1. Viral attachment to CD4 of Helper T cells. 2. Attachment to co-receptor CXCR4 or CCR5. 3. Uncoating. 4. Reverse transcription of viral RNA to form DNA. 5. Synthesis of second strand of DNA. 6. Migration to the nucleus. 7. Integration and transcription of viral DNA. 8. Translation of viral RNA. 9. Viral protease enzyme activation, a site for protease inhibitors to block viral replication. 10. Assembly and budding to form new virus HIV Has Multiple Steps Available for Attack by Antiretroviral Drugs

  15. HAART THERAPY • Highly Active Anti-Retroviral Therapy • Combination of drugs • RT inhibitors (nucleoside analogs, non-nucleoside analogs) • Protease inhibitors • Given when patients CD4+ cells drop below 200

  16. ANTIRETROVIRAL DRUGS • Ritonavir (Norvir) • Saquinivir (Invirase) • Indinavir (Crixivan) • Amprenivir (Agenerase) • Nelfinavir (Viracept) • Lopinavir (Kaletra)

  17. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs) • Zidovudine (AZT, Retrovir) • Lamivudine (3TC, Epivir) • Didanosine (ddI, Videx EC) • Stavudine (d4T, Zerit) • Abacavir (Ziagen) • Tenofovir (Viread) nucleotide analog • Emtricitabine (Coviracil)

  18. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) • Delavirdine (Rescriptor) • Efavirenz (Sustiva) • Nevirapine (Viramune)

  19. PROTEASE INHIBITORS • Nelfinavir (Viracept) • Indinavir (Crixivan) • Saquinair (Fortovase, Invirase) • Ritonavir (Norvir) • Lopinavir/ritonavir (Kaletra) • Amprenavir (Agenerase) • Fosamprenavir (?) • Atazanavir (Rayataz)

  20. Column A Efavirenz Indinavir Nelfinavir Ritonavir+ Indinavir Ritonavir + Lopinavir* Ritonavir + Saquinavir Column B Didanosine + Lamivudine Stavudine + Didanosine Stavudine + Lamivudine Zidovudine + Didanosine Zodovudine + Lamivudine *Coformulated as Kaletra INITIAL TREATMENT: One Choice from Each Column

  21. INDICATIONS FOR INITIATION OF THERAPY: Chronic Infection

  22. INDICATIONS FOR INITIATION OF THERAPY: Chronic Infection

  23. Estimated proportion of persons surviving, by months after AIDS diagnosis during 1994–2001 and by year of diagnosis—United States

  24. BACTERIA M. tuberculosis M. avium complex S. pneumococcus M. catarrhalis H. influenza P. aeruginosa Nocardia Legionella pneumophila FUNGI Pneumocystis carinii Cryptococcus neoformans Histoplasma capsulatum Coccidiodes immitis Aspergillus fumigatus Penicillium marneffei Candida albicans PULMONARY INFECTIONS

  25. VIRUSES Cytomegalovirus Herpes simplex Adenovirus HIV Lymphocytic interstitial pneumonitis (in children) PROTOZOANS Toxoplasma gondii Cryptosporidium Microsporidia TUMORS Kaposi’s sarcoma (HHV8) Non-Hodgkin’s lymphoma PULMONARY INFECTIONS

  26. Pneumocystis carinii in Lung

  27. Pneumocystis carinii Pneumonia: Cavitary Change

  28. Gomori Methenamine Silver Stain at High Magnification: P. carinii

  29. TB IN AIDS PATIENTS: AFRICA

  30. CMV Inclusions in Lung

  31. Candida albicans Invasive Process in a Bronchus with H and E Staining

  32. C neoformans: Clear capsule surrounding the pale blue nucleus with H and E staining

  33. Histoplasma capsulatum

  34. Histoplasma capsulatum organisms in macrophages in liver with PAS stain

  35. INFECTIONS T. gondii PML (JC virus) M. tuberculosis C. neoformans CMV HSV-1 HIV Candida albicans NEOPLASMS Primary CNS lymphoma Metastatic Lymphoma Kaposi’s sarcoma UNIDENTIFIED Aseptic meningitis Non-specific gliosis Vascular myelopathy CNS/NEUROLOGIC COMPLICATIONS

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