IMMUNOLOGY OF HIV INFECTION AND AIDS. Interactions between HIV and the immune system

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1 IMMUNOLOGY OF HIV INFECTION AND AIDS Interactions between HIV and the immune system

2 Basic Statistics United States In the U.S. in 2010, 1.1 million people were living with HIV infection. About 50,000 people become infected with HIV each year in the U.S. Through 2010, 1,129,127 acquired immunodeficiency syndrome (AIDS) cases were reported. Of those, 619,400 have died (current death rate ~17,000 per year). (Worldwide, 25 million have died.) Worldwide, it is estimated that over 34 million people are infected with HIV. ~2.7 million were infected with HIV in 2010, including ~390,000 children under 15. ~1.8 million died of HIV/AIDS in

3 Trends in Annual Rates of Death due to the 9 Leading Causes among Persons Years Old, United States, Note: For comparison with data for 1999 and later years, data for were modified to account for ICD-10 rules instead of ICD-9 rules.

4 Estimated numbers of AIDS cases in children <13 years of age, by year of diagnosis, states and the District of Columbia

5 Total = 47,129 new cases Groups representing <2% of total are not shown. Source: CDC, statistics_basics_factsheet.pdf

6 LENTIVIRUSES Virus Human Immunodeficiency Virus (HIV) Simian Immunodeficiency Virus (SIV) Visna/maedi Virus Equine Infectious Anemia Virus (EIAV) Caprine Arthritis/Encephalitis Virus Disease Human AIDS AIDS in monkeys Neurologic disease in sheep Horse anemia Goat encephalitis

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9 HIV Proteins Envelope (env) glycoproteins - gp160 precursor gp120, gp41 Group antigen (gag) proteins - p24 (core), p17 (scaffold) Polymerase (pol) proteins - p66 and p51 (reverse transcriptase), HIV protease, p32 (endonuclease) Regulatory proteins - tat, rev, vif, nef

10 HIV Replication Binding and Internalization Reverse transcription & DNA incorporation Transcription & translation of viral genes Assembly and budding Cell activation and its role in viral replication

11 CCR5, CXCR4 Coreceptors

12 Receptors involved in HIV Binding/Internalization CD4 gp120 binds to CD4 on T cells or monocyte/macrophage lineage cells, promoting removal of gp120 and internalization of virus Chemokine receptors CCR5 and CXCR4 act as important coreceptors The glycolipid galactosyl ceramide can also promote binding Antibodies bound to HIV can enhance uptake of virus through binding to Fc receptors

13 gp120 gp41 HIV1-Bal HIV1-Bal + CD4 +17b Dr. Jun Liu, Dept. of Pathology & Laboratory Medicine

14 gp120 Fab 17b (binds coreceptor binding site) CD4 (soluble Form) Dr. Jun Liu

15 Chemokine Receptors that also act as HIV Coreceptors CCR5 Receptor for RANTES, Mip1α, Mip1β Found on macrophages Coreceptor (with CD4) for Macrophage Tropic HIV 32-CCR5 32 bp deletion mutation, decreases HIV transmission and slows disease progression during HIV infection CXCR4 Receptor for stromal derived factor-i Enhances binding, internalization of Lymphotropic HIV

16 MIP-1 P also affects HIV infection CCL3LI encodes Migration Inhibition Protein - 1αP (MIP-1αP), the major ligand for CCR5 MIP-1αP is a major inhibitor of HIV infection, may compete with HIV for CCR5 binding Humans have varying number of CCL3LI gene duplications; individuals with low copy numbers are more susceptible to HIV infection Science 307: (March 4, 2005)

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18 Effect of activation on virus protein expression (as measured by reverse transcriptase activity)

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20 Cell to Cell Transfer of HIV

21 Infected vs. Virus-Producing Cells Autoradiographs showing grains over T cells infected with HIV (A) and those expressing HIV RNA and producing virions (B) Note that many more cells are infected than are actively producing virus particles.

22 Clinical Course of HIV Infection Stage Viral Load Anti-HIV Antibodies CD4+ Levels Symptoms Primary High + Variable 40-60% of patients Asymptomatic (Stage 1) Early Symptomatic (Stage 2) Late Symptomatic (AIDS, Stage 3) Moderate/Low ++ Normal/High >500/µl Moderate + Low /µl High + Very Low <200/µl None + ++

23 HIV+ people look like everyone else

24 HIV in body fluids

25 HIV-Infected Cells in Semen

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28 Example Maculopapular rash during early HIV Infection

29 Viral Load during Stages of HIV Infection

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31 Infections and malignancies that are common in AIDS (Geha and Notarangelo, Case Studies in Immunology, Case 10: AIDS)

32 Progression to AIDS

33 Immune Responses Antibody Neutralizing Enhancing CD4+ T cells Loss of helper, DTH, cytotoxic function Decrease in cell numbers CD8+ T cells Cytotoxicity - lysis/apoptosis HIV-infected cells Uninfected CD4+ cells Cell Antiviral Factor (CAF)

34 ELISA for detection of anti-gp120 antibodies (Geha and Notarangelo, Case Studies in Immunology, Case 10: AIDS )

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37 CD8 cytotoxic activity declines before decreases in CD4+ numbers

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39 Effects of apoptosis: disruption of nucleus, organelles; DNA fragmentation

40 Immunotherapy and Vaccination Immunotherapy Immune reconstitution Passive immunotherapy Vaccination Recombinant gp160 (VaxSyn HIV-1) Recombinant live-vector vaccines (vaccinia, canarypox) Virus-Like Particles (VLPs) Peptide vaccines (V3 and CD4 binding regions) Live, attenuated HIV viruses Inactivated viruses

41 Vaccine target gp120 V3 loop most immunoprotective, but also highest variability CD4-binding region antibodies against this region may block binding of HIV to CD4 prevent infection of CD4 + cells

42 Problems with HIV Vaccines

43 Animal Models Animal Virus Result Used to study: Chimpanzee HIV-1 Latent Infection Vaccine efficacy Macaques SIV AIDS-like wasting disease Vaccine efficacy, therapy, pathogenesis Rabbits HIV-1 Defective infection Latent infection Mice- HIV genome -- AIDS-like illness Pathogenesis transgenic Mice - tat transgenic -- Kaposi s sarcoma Carcinogenesis SCID-human lymphoid HIV-1 AIDS-like disease Pathogenesis, therapy cell chimera Sheep Visna Chronic Lentivirus pathogenesis neurodegeneration Goats Caprine arthritis, encephalitis Lentivirus pathogenesis Horses EIAV hemolytic anemia Lentivirus pathogenesis

44 The Berlin Patient (Timothy Brown) only person that has been cured of HIV infection Baylor College of Medicine, Sept. 23, 2011

45 Summary - Immunology of AIDS HIV-1 and HIV-2 infect CD4+ T cells, macrophages and other cells, leading to virus production, cytolysis, or latent infection. HIV infection progresses through primary, asymptomatic, early symptomatic, and late symptomatic (AIDS) stages. Depletion of CD4+ T cells leads to profound defects in helper and DTH activities. Antibody and cytotoxic lymphocyte activities combat HIV infection, but do not prevent progression. Immunotherapy and vaccination strategies are under development.

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