Discovery of HIV-1. HIV causes AIDS. HIV and AIDS 12/3/07. Goals

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1 HIV and AIDS 12/3/07 Overview Big Picture HIV Structure & Replication HIV pathogenesis HIV diagnosis Goals Know the main points of HIV global epidemiology and transmission Know the basics of HIV structure, gene structure & replication - and how they relate to diagnostics and therapy Know the basics of HIV pathogenesis Know the basics of HIV diagnosis 1 2 Discovery of HIV-1 HIV causes AIDS R. Gallo, USA L. Montagnier, France P. Duesberg, USA 3 4

2 HIV (human immunodeficiency virus) Is a retrovirus (enveloped ss RNA virus) ssrna converted to dsdna by reverse transcriptase (major antiviral target) HIV-1 has spread worldwide; HIV-2 is found in west Africa; HIV-1 entered humans as SIV from chimps Spread through sexual intercourse, exposure to contaminated blood, and from mother to 5 6 fetus/infant 7 8

3 Important HIV-1 proteins p24 capsid protein The virion HIV Reverse transcriptase Protease Integrase Envelope protein 9 10 HIV Genome HIV life cycle gag - structural pol - enzymatic env - attachment 11 12

4 HIV assembly & release by HIV protease Key features of HIV-1 replication PA-457 Coreceptor needed for CD4+ cell entry Macrophage (CCR5); T-cells (CXCR4)! High mutation rate (~ 1 mutation/3 rounds of replication) Impt. aspects of HIV-1 infection and replication CD4+ cells are targets for HIV infection Coreceptors needed for infection mutations in these genes can affect infection and disease progression Coreceptor usage switch occurs during course of infection: M-tropic R5 (NSI) virus to T-tropic X4 (SI) virus 15 16

5 Impt. aspects of HIV-1 infection and replication HIV population turnsover daily, generating many mutants (10 billion viruses made/day) HIV RNA level proportional to rate of virus production Anti-HIV drugs reduce HIV replication (lower viral RNA load) and slow CD4+ cell loss 17 Lab Diagnosis Antibody assays ELISA; western blot (used for detect infection) Virus assays p24 assay; PCR RT-PCR; cell culture (used to monitor drug therapy) 18 Tomorrow Treatment Vaccines Mutation HIV and AIDS 12/4/07 Treatment Vaccines Mutation 19 20

6 Goals Identify the major classes of drugs currently used in the treatment of HIV infection Know what HAART is Know the basic sides effects associated with antiviral therapy Know the basics of HIV drug resistance Know the basics of AIDS vaccine approaches 21 Million First cases of unusual immune deficiency are identified among gay men in USA, and a new deadly disease noticed 2 Acquired Immune Deficiency Syndrome (AIDS) is defined for the first time 3 The Human Immune Deficiency Virus (HIV) is identified as the cause of AIDS 4 In Africa, a heterosexual AIDS epidemic is revealed 5 The first HIV antibody test becomes available 6 Global Network of People living with HIV/AIDS (GNP+) (then International Steering Committee of People Living with HIV/AIDS) founded 7 The World Health Organisation launches the Global Programme on AIDS 8 The first therapy for AIDS zidovudine, or AZT -- is approved for use in the USA years of AIDS People living with HIV Children orphaned by AIDS in sub- Saharan Africa 9 In , HIV prevalence in young pregnant women in Uganda and in young men in Thailand begins to decrease, the first major downturns in the epidemic in developing countries 10 Highly Active Antiretroviral Treatment launched 11 Scientists develop the first treatment regimen to reduce motherto-child transmission of HIV 12 UNAIDS is created 13 Brazil becomes the first developing country to provide antiretroviral therapy through its public health system 14 The UN General Assembly Special Session on HIV/AIDS. Global Fund to fight AIDS, Tuberculosis and Malaria launched 15 WHO and UNAIDS launch the "3 x 5" initiative with the goal of reaching 3 million people in developing world with ART by Global Coalition on Women and AIDS launched 22 Number of people on antiretroviral therapy in low- and middle-income countries, People in sub-saharan Africa on antiretroviral treatment as percentage of those in need, People receiving 1000 therapy (thousands) North Africa and the Middle East Europe and Central Asia East, South and South-East Asia Latin America and the Caribbean Sub-Saharan Africa End 2002 Mid End 2003 Mid End 2004 Mid End 2005 Source: WHO/UNAIDS (2005). Progress on global access to HIV antiretroviral therapy: An update on 3 by Source: WHO/UNAIDS (2005). Progress on global access to HIV antiretroviral therapy: An update on 3 by

7 HIV drug targets: current and potential Current Antiretroviral Drugs (2007) NRTI Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudine ZDV Tenofovir TDF NNRTI Delavirdine DLV Efavirenz EFV Nevirapine NVP Integrase Inhibitor Raltegravir RTV PI Amprenavir APV Atazanavir ATV Darunavir DRV Fosamprenavir FPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV hard gel HGC tablet INV Tipranavir TPV Fusion/Entry Inhibitors Enfuvirtide T-20 Maraviroc MVR 25 HAART: Highly active antiretroviral therapy HIV reverse transcriptase: catalytic domain Drug cocktails or combination therapy is the current approach for the treatment of HIV infection: HAART Three main categories: 1 NNRTI + 2 NRTIs 1 PI + 2 NRTIs 3 NRTIs Combination of NNRTI or PI plus 2 NRTIs preferred for most patients Advantages and disadvantages to each type of regimen 28

8 29 30 Therapy: RT inhibitors Drug AZT ddi ddc 3TC Nevirapine Side Effects neutropenia, anemia, headache, nausea peripheral neuropathy severe pancreatitis peripheral neuropathy frequent rash 31 32

9 Therapy: Protease inhibitors Saquinavir Ritonavir Indinavir Nelfinavir Side effects: Hyperlipidemia Hyperglycemia Abnormal fat distribution PI side effects HIV drug classes Integrase Injectable EI Selzentry (maraviroc) Isentress (raltegravir) 35 36

10 Fusion/Entry inhibitors Chemical formulas Therapy: Fusion/Entry inhibitors T-20 Maraviroc (UK ) T-20 Maraviroc (UK ) Side effects: Skin redness; sore cough, fever, colds, rash, muscle and stomach pain, dizziness Integrase inhibitors Chemical formulas Therapy: Integrase inhibitors Raltegravir (MK-0518) Raltegravir (MK-0518) Side effects: Diarrhea, nausea, headache, fever 39 40

11 HIV drug resistance Drug therapy does not lead to cure Vaccines Long-term therapy commonly results in drug resistance Salvage therapy required after failure Latent virus reservoirs and transmission of drug-resistant virus are threats to therapy Why therapy fails is complicated (not always poor compliance) Merck vaccine trial Vaccine consisted of an adenovirus type 5 vector expressing 3 HIV genes (subtype B): gag, pol and nef; vaccine was supposed to boost CTL response to HIV-infected cells International trial (N. & S. America, Carribean, Australia) involved 3,000 HIV-neg. volunteers, most being at high-risk for infection 24/741 volunteers who got vaccine became infected with HIV; 21/762 volunteers who got placebo became infected with HIV ---- Trial ends 43 HIV genetic variation, vaccines & antiviral therapy For RNA viruses is particularly high (no proofreading) High mutation rates are likely to greatly contribute to this high variation While there are examples of successful therapeutic intervention or prevention against viruses (eg, polio, smallpox), in other cases there has be modest or no progress made (HIV, flu) The high genetic variability of HIV populations is the underlying reason why no effective vaccine exists and why drug resistance is a major problem with antiviral therapy 44

12 Prevention Change behavior Educate Easy access to condoms and clean needles Caution in handling contaminated blood or fluids 45