Micro 301 HIV/AIDS Shiu-Lok Hu hus@uw.edu December 3, 2012 Since its discovery 31 years ago Acquired Immunodeficiency Syndrome (AIDS) has killed >32 million people In 2011 34.0 million [31.4 35.9 million] people were living with HIV 2.5 million [2.2-2.8 2 2 million] new infections 1.7 million [1.5-1.9 million] died from AIDS-related causes Topics to be covered Epidemiology of AIDS and HIV infection Discovery of AIDS and HIV as the etiologic agent Life cycle of HIV infection Disease course of HIV infection Pathogenic mechanisms of HIV infection Therapy, vaccines and microbicide against HIV/AIDS Shiu-Lok Hu 1
Discovery of AIDS Opportunistic infection and rare forms of cancer reported in young homosexual men 1981 Pneumocystis carinii pneumonia: Common microbe; infection is pathogenic only in immunocompromised individuals 1982 Kaposi sarcoma: Previously only recognized in older men of Mediterranean ancestry Risk Factors Recognized by Case-Control Studies Number and frequency of sexual contact Sexual partner of people with AIDS or AIDS-Related Complex (ARC) Hemophiliacs IV drug users Sexually promiscuous men and women People with other sexually transmitted diseases People who have exposure to any of above Disease is caused by an infectious agent in blood and other body fluids Discovery of HIV as the Etiologic Agent From AIDS, Pathogenesis and Therapy. Levy, JA ed. Luc Montagnier * Françoise Barré-Sinoussi * Pasteur Institute, France Discovered HIV-1 (1983) and HIV-2 (1986) * 2008 Nobel Prize laureates Robert Gallo National Cancer Institute, USA Developed culturing methods that enable the diagnosis of HIV infection (1984) SIVmac HIV Virion and Genome Structure Mantled guereza Sykes monkey Sooty mangabey SIVsyk SIVsm SIVgsn SIVcol SIV Greater spot-nosed monkey SIVcpz HIV-2 envelope matrix p17 core p24 RT gp120 gp41 MHC lipid bilayer SIVver SIVrcm Chimpanzee RNA Vervet monkey SIVlho SIVmnd Red-capped mangabey HIV-1 Origin of HIV: Cross-species transmission of simian immunodeficiency viruses L-Hoest s monkey Mandrill Slide courtesy of Beatrice Hahn Shiu-Lok Hu 2
Binding & Entry CD4 CCR5 Uncoating HIV Life Cycle Integration Reverse Transcription Transcription Genomic DS viral RNA DNA m RNA Nucleus Translation Assembly & Release Life Cycle of HIV Infection HIV is a member of the Retrovirus family Enveloped virus with 2 identical single-stranded RNA as its genome: Viral envelope protein uses CD4 and several chemokine receptors as receptors (e.g. CCR5, CCR4) allowing it to target multiple cell types (memory and naïve T cells, macrophage, etc.) Encodes reverse transcriptase (RT): Information transcribed from RNADNARNAproteins RT is error prone: generating a large number of mutations in each replication, allowing it to adapt to selective forces Virus is integrated into the host genome: latency Natural History of HIV Infection Gut memory CD4 T cells Disease Course of HIV Infection Acute phase: 1-3 weeks after exposure Flu-like symptoms Detection by viral antigen or genetic material only, but not by HIV-specific c antibodies Asymptomatic phase: Duration is variable (6 mos to ~15 yrs; average 8-10 yrs) Gradually declining CD4 + T cell numbers with accompanying decline of immune functions Detection by HIV-specific antibodies and low levels of virus Time after infection Disease Course of HIV infection (cont.) Symptomatic phase: Without effective treatment, generally lasts <2 yrs until death Rapidly declining numbers of CD4 + T-cells and increasing amounts of virus Lymph node enlargement, weight loss, fever, diarrhea, opportunistic infection, malignancy Pathogenic Mechanisms of HIV Infection Direct effects: Massive and irreversible destruction of memory CD4 + T cells in the gut occurs within days of infection. In the asymptomatic phase of infection, the virus continues to replicate and destroy CD4 + T-cell, while the host tries to clear the virus and replenish CD4 + T cells, resulting in a quasi-equilibrium, with the virus steadily gaining on the host. Virus mutates rapidly, adapting to and eventually overcoming and exhausting the host s defense system. Plasma viral load (set point viremia) together with blood CD4 + T cell count are excellent prognosticators of disease progression. Shiu-Lok Hu 3
Pathogenic Mechanisms of HIV Infection Indirect effects on the immune system: Inactivate immune cells and/or immune functions: Anergy Co-opt normal process of programmed cell-death: Apoptosis Dysregulation of lymphokines and cytokines Turn the host on itself: Autoimmunity, by-stander killing Effect on other organs: Central nervous system: AIDS dementia Gastrointestinal system: Wasting; diarrhea Receptor & Coreceptor Blockade Binding & Entry Targets for Anti-HIV Therapy Fusion Inhibitor CD4 CCR5 Uncoating Reverse Transcriptase (RT) Inhibitors AZT (Zidovudine) Nevaripine Reverse Transcription Genomic RNA DS DNA Integrase Inhibitor Integration Transcription viral m RNA Translation Protease Inhibitors Assembly & Release Nucleus Anti-HIV Therapy Existing Drugs: Targets that are unique to the virus: Inhibitors of RT or its action: Nucleoside analogs: chain-terminators (FTC, TDF etc.) Non-nucleoside RT inhibitors (Nevirapine, Efavirenz) Protease inhibitors (Indinavir, Saquinavir, Ritonavir) Fusion inhibitor (Fuzion) Virus attachment: Antagonists of receptor and co-receptor interactions (Maraviroc) Integrase inhibitors (Isentress, Raltegravir) Combination of drugs against >2 targets: reduce viral escape New Targets: Regulatory elements essential for viral growth Since 1995, antiretroviral therapy has saved 14 million life-years in low- and middle income countries If antiviral drug treatment can suppress HIV viral load, can it be used to prevent acquisition of HIV infection? Grant et al., NEJM November 23, 2010 (10.1056/NEJMoa1011205) Shiu-Lok Hu 4
Anti-Retroviral Therapy Remaining Challenges are significant Toxicity Adverse effects due to long-term usage: e.g., g, cardiovascular and other metabolic diseases Selection for drug-resistant mutants, resulting in treatment failure Current treatment is not a cure : How to eliminate long-lived reservoirs of latently infected cells? Damage to the immune system: Can it be reversed? Percentage of population in low and middle income countries living with HIV in need of treatment who are receiving antiretroviral therapy by end of 2010 For every HIV infected individual receiving antiviral therapy, two more become infected Control of the global HIV/AIDS epidemic will likely depend on the availability of safe and efficacious vaccines Is it possible? Most successful vaccines made to-date are against pathogens that can elicit protective immunity as a result of natural exposure Evidence is lacking for HIVinfected individuals to mount an effective immune response capable of clearing infection or protecting against re-infection Some of the Major Scientific Challenges to AIDS Vaccine Development Virus is highly variable: A moving target Virion surface is covered by sugar molecules: Target is not easily accessible Virus can establish latency and persist in immune privileged sites: May need to prevent the initial infection Seeks and destroys immune cells: Weakens host defense Shiu-Lok Hu 5
HIV Vaccines Approaches recombinant protein (gp120) peptide scaffolds naked DNA live-recombinant vectors (poxvirus, adenovirus, bacterial) whole-inactivated virus live-attenuated virus Current Status Close to 100 candidate vaccines have been tested in the clinic and shown to be safe and immunogenic. Two stand-alone products have been tested for efficacy in humans Subunit protein (gp120) targeting viral surface antigen Recombinant adenovirus targeting viral core proteins Both have failed to show any evidence of efficacy No reduction of incidence of infection No reduction of viral load after infection RV144 Trial: First test-ofconcept trial for the prime-boost immunization approach in human Prime: Replication defective poxvirus (vcp1251) expressing multiple HIV-1 genes (gag-pol nef env) Boost: vcp1251 plus divalent (B/E subtype) gp120 protein (AIDSVA) What has the RV144 trial taught us? Vaccination against HIV/AIDS may be feasible Efficacy of the tested vaccines (~30%) is modest Correlate of protection ti has not been clearly l defined d Much more work is needed to understand the basis of the protective efficacy observed Better vaccines are needed! Microbicides Topical applications that prevent HIV infection An alternative to vaccines and other preventive approaches Advantages over condoms: greater control by women Candidates include antiviral compounds that inactivate the virus or interfere with virus infection or replication (e.g., Maraviroc, Tenofovir, etc.) Proof-of-concept has been demonstrated in animal models Shiu-Lok Hu 6
Take Home Messages AIDS remains a major pandemic, affecting men, women and children worldwide, especially in developing countries. AIDS is caused by HIV, a member of primate lentiviruses. HIV is a retrovirus. It targets key components of the immune system, mutates rapidly and is able to establish latency. Disease course of HIV infection is highly variable. High viral load and low CD4 + T-cell counts are predictive of rapid progression. Combination therapy with anti-viral drugs has resulted in significant prolongation of survival. However, virus is not cleared and damages to immune system need to be repaired. A prime-boost vaccine regimen has shown modest efficacy in humans. Results from animal models indicate that vaccine protection is possible. But, major challenges exist. Prophylactic use of antiviral drugs can reduce the rate of HIV acquisition in high-risk groups; effect of long-term use unclear Shiu-Lok Hu 7