ACQUIRED SECONDARY IMMUNODEFICIENCIES HUMAN IMMUNODEFICIENCY VIRUS AND ACQUIRED

ACQUIRED (SECONDARY) IMMUNODEFICIENCIES

HUMAN IMMUNODEFICIENCY VIRUS AND ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

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 CD 4+ helper T cells, macrophages, and dendritic cells HIV epidemic was first identified only in the 1980 s HIV has infected 50 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

Molecular and Biologic Features of 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

HIV Structure and Genes

Viral Life Cycle

Most important chemokine receptors that act as coreceptors for HIV are CXCR 4 and CCR 5 More than seven different chemokine receptors are coreceptors for HIV entry into cells as the leukotriene B 4 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 gp 120 that binds to CCR 5, which is expressed on macrophages (and some memory T cells) Whereas, T cell-tropic viruses bind to CXCR 4, which is expressed on T cell lines

Pathogenesis of HIV Infection and AIDS

Clinical course of HIV disease

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 CD 4+T cells HIV-infected CD 4+T cells and target the cells for antibody-dependent cell- mediated cytotoxicity (ADCC) Defective maturation of CD 4+ 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

Proportion of IL-2 and IFN-γ-secreting (Th 1) T cells decreases and the proportion of IL-4 and IL-10 secreting (TH 2 -like) T cells increases Increased numbers of CD 4+ CD 25+ regulatory T cells Macrophages, dendritic cells, and follicular dendritic cells also play important roles in HIV infection and the progression of immunodeficiency

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

Clinical Features of HIV Disease

Immune Responses to HIV-specific humoral and cell-mediated immune responses, but imited protection Initial adaptive immune response CD 8+ 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 gp 120)

Mechanisms of Immune Evasion by HIV Extremely high mutation rate because of error-prone reverse transcription, A region of the gp 120 molecule, called the V 3 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

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 CD 4+ and CD 8+ T cell counts, do not require therapy, and have persistent viremia but no disease for at least 10 to 15 years

Treatment and Prevention of AIDS and Vaccine Development Three classes of antiviral drugs, used in combination First type of drug to be widely used consists of nucleoside analogues that inhibit reversetranscriptase 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)

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

“Entry inhibitors, ” which prevent viral entry by targeting either CD 4 or CCR 5 on the host cell or gp 41 or gp 120 on the virus, are another novel category of therapeutics