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Antiretroviral targets in the viral life cycle Viral Replication and Drug targets Available Antiretroviral Agents Nucleoside RTIs • Zidovudine (ZDV) • Didanosine (ddI) • Zalcitabine (ddC) • Stavudine (d4T) • Lamivudine (3TC) • Abacavir (ABC) • Emtricitabine (FTC) Nonnucleos(t)ide RTIs Protease Inhibitors • Nevirapine (NVP) • Delavirdine (DLV) • Efavirenz (EFV) • Etravirine (ETR) • Tenofovir DF (TDF) • Saquinavir (SQV) • Ritonavir (RTV) • Indinavir (IDV) • Nelfinavir (NFV) • Amprenavir (APV) • Lopinavir/r (LPV/r) • Atazanavir (ATV) • Fosamprenavir (Fos-APV) • Tipranavir (TPV) • Darunavir (DRV) Integrase Inhibitors Boosters • Ritonavir (RTV) • Raltegravir (RAL) • Dolutegravir* • Elvitegravir* • Cobicistat* (cobi) * In expanded access or submitted for regulatory approval Fusion Inhibitor • Enfuvirtide (T-20) CCR5 Antagonist • Maraviroc (MVC) Effect of Cessation of Therapy On Viral Load Years Add HAART Limit of Detection Remove HAART Stevenson, M. Nature Med 9:853-860, 2003 HIV Lifecycle: Viral RNA gp120 p24 RT & other virion proteins A. Binding CCR5 CD4 CXCR4 Entry Inhibitors: CCR5 antagonist, maraviroc HIV Lifecycle: Viral RNA gp120 p24 RT & other virion proteins Fusion & uncoating B. Fusion Inhibitors: T20 HIV Lifecycle: Viral RNA gp120 p24 RT & other virion proteins C. Reverse Transcriptase (RT) Inhibitors: 1. Nucleoside RT inhibitors (NRTIs) 2. Non-Nucleoside RT Inhibitors NNRTIs) Reverse transcription HIV Lifecycle: Viral RNA gp120 p24 RT & other virion proteins Nuclear localization & entry HIV Lifecycle: Viral RNA gp120 p24 RT & other virion proteins D. Integrase Inhibitors: raltegravir Integration HIV Lifecycle: Viral RNA gp120 p24 RT & other virion proteins Integrated provirus HIV Lifecycle: Viral RNA gp120 p24 RT & other virion proteins Viral Gene Transcription HIV Lifecycle: Viral RNA gp120 p24 RT & other virion proteins Translation HIV Lifecycle: Viral RNA p24 RT & other virion proteins gp120 Post-translational processing HIV Lifecycle: Assembly Viral RNA p24 RT & other virion proteins gp120 HIV Lifecycle: Viral RNA gp120 p24 RT & other virion proteins Budding Inhibition of Virion Maturation E. Protease Inhibitors: e.g. Lopinavir, Indinavir Viral RNA gp120 p24 RT & other virion proteins Fusion & Entry Binding Reverse transcription CD4 CXCR4 Nuclear localization & entry Integration Viral RNA gp120 p24 Assembly RT & other virion prteins Post-translational processing Budding Translation Viral Gene Transcription
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