ACQUIRED (SECONDARY) IMMUNODEFICIENCIES

1. ACQUIRED (SECONDARY)IMMUNODEFICIENCIES

3. HUMAN IMMUNODEFICIENCY VIRUS AND ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

4. AIDS is the disease caused by infection with HIV and is characterized by profound immunosuppression with associated opportunistic infections and malignant tumors, wasting, and central nervous system (CNS) degeneration. HIV infects a variety of cells of the immune system, including CD4+ helper T cells, macrophages, and dendritic cells • HIV epidemic was first identified only in the 1980s • HIV has infected50 to 60 million people and has caused the death of more than 22 million adults and children. Approximately 35 million people are living with HIV infection and AIDS, of which approximately 70% are in Africa and 20% in Asia, and almost 2 million die of the disease every year

5. Molecular and Biologic Features of HIV • HIV, retroviruses, is a member of the lentivirus family of animal and long-term latent infection of cells and short-term cytopathic effects • Two closely related types of HIV (HIV-1 and HIV-2), have been identified • HIV-1 is by far the most common cause of AIDS, but HIV-2, which differs in genomic structure and antigenicity, causes a similar clinical syndrome

6. HIV Structure and Genes

7. Viral Life Cycle

8. Most important chemokine receptors that act as coreceptors for HIV are CXCR4 and CCR5 • More than seven different chemokine receptors are coreceptors for HIV entry into cells as the leukotriene B4 receptor • Macrophage-tropic (M-tropic), T-tropic and both T cell lines and macrophages (dual-tropic virus) HIV virus • Macrophage-tropic virus isolates express a gp120 that binds to CCR5, which is expressed on macrophages (and some memory T cells) • Whereas, T cell-tropic viruses bind to CXCR4,which is expressed on T cell lines

10. Pathogenesis of HIV Infection and AIDS

11. Clinical course of HIV disease

12. Mechanisms of Immunodeficiency Caused by HIV • An important cause is the direct cytopathic effect • Chronic activation of the T cells may predispose the cells to apoptosis • HIV-specific CTL can kill infected CD4+T cells • HIV-infected CD4+T cells and target the cells for antibody-dependent cell- mediated cytotoxicity (ADCC) • Defective maturation of CD4+ T cells in the thymus • Functional defects in the immune system include a decrease in T cell responses to antigens and weak humoral immune responses

13. Proportion of IL-2 and IFN-γ-secreting (Th1) T cells decreases and the proportion of IL-4 and IL-10 secreting (TH2-like) T cells increases • Increased numbers of CD4+ CD25+ regulatory T cells • Macrophages, dendritic cells, and follicular dendritic cells also play important roles in HIV infection and the progression of immunodeficiency

14. Transmission of HIV • Sexual contact is the most frequent • Mother- to-child • Inoculation of a recipient with infected blood or blood products • Major groups at risk for the development of AIDS in the United States include homosexual or bisexual males, intravenous drug abusers, heterosexual partners of members of other risk groups, and babies born of infected mothers

15. Clinical Features of HIV Disease

16. Immune Responses to HIV • HIV-specific humoral and cell-mediated immune responses, but imited protection • Initial adaptive immune response CD8+ T cells specific for HIV peptides • Antibody responses to a variety of HIV antigens are detectable within 6 to 9 weeks after infection (Neutralizing antibodies against gp120)

17. Mechanisms of Immune Evasion by HIV • Extremely high mutation rate because of error-prone reverse transcription, A region of the gp120 molecule, called the V3 loop, is one of the most antigenically variable components of the virus • Evade CTLs through down-regulation of class I MHC • Inhibit cell-mediated immunity

18. Elite Controllers and Long-term Nonprogressors:A Possible Role for Host Genes • Although most individuals infected with HIV eventually develop AIDS, approximately 1% of individuals who are infected do not develop disease • Such individuals have high CD4+ and CD8+ T cell counts, do not require therapy, and have persistent viremia but no disease for at least 10 to 15 years

19. Treatment and Prevention of AIDS andVaccine Development • Three classes of antiviral drugs, used in combination • First type of drug to be widely used consists of nucleoside analogues that inhibit reverse-transcriptase activity, as ‘-azido-3' -deoxythymidine (AZT) • Viral protease inhibitors have been developed that block the processing of precursor proteins into mature viral capsid and core proteins • New triple-drug therapy, HAART (highly active anti-retroviral therapy)

20. Such vaccines include nonvirulent recombinant hybrid viruses composed of part SIV and part HIV sequences or viruses that have been attenuated by deletions in one or more parts of the viral genome, such as the nef gene • live –attenuated virus vaccines • CTL-mediated immunity is the use of live recombinant non-HIV viral vectors carrying HIV genes • DNA vaccines are composed of combinations of structural and regulatory genes of SIV or HIV packaged in mammalian DNA expression vectors • Recombinant protein or peptide subunit vaccines that elicit antibodies

21. “Entry inhibitors,” which prevent viral entry by targeting either CD4 or CCR5 on the host cell or gp41 or gp120 on the virus, are another novel category of therapeutics