HIV: A 60 Year Retrospective1959 Serum from Bantu Male @ Kinchasa DRC => ZR59Suggests single trans-species jump in 1940-1950 and radiation after WWIIYBF30 is a sequence outlier isolated from a patient in CameroonDisease ProgressionClinical PictureModes of Horizonal TransmissionAlso Vertical Transmission!(11-60% depending on severityof maternal infection and±breastfeeding)Incidence and Prevalence• 36.1 million worldwide are infected• Another 21.8 million have died• 13.2 million children currently are “AIDS Orphans”• 14,000 new infections daily (5.3 million in 2000)• 70% of cases in sub-Saharan Africa where seroprevalence can exceed 25%• Carribean, Southeast Asia and Eastern Europe are other trouble areasVirus TaxonomyHIV belongs to the lentivirus subclass of retroviruses• 2 copies of the +RNA strand; goes through a dsDNA intermediate• icosahedral capsid• enveloped• 80-130 nm virionAnatomy of a Retrovirus-NEF AttenutationViral Replication Cycle• 109 copies/day in fulminant AIDS• Every single-base mutation of the genome occurs at least once per day per patientRT InhibtorsNucleoside:Non-Nucleoside:Protease InhibitorsRetroviral Drug Resistance in New PatientsHIV Vaccine• >50 preparations have entered clinical trials (HIV Vaccine Trials Network)• 1997 Clinton’s HIV vaccine challenge: 10 years• NIH currently spends >500 million/year on trying to find an HIV vaccine• NOTHING! (punctuated equilibrium)• Do aspects of the immune response facilitate HIV pathogenesis?Broadly Neutralizing Antibodies•mAB b12: convex recombining site• 447-52D: V3 GPGR motif and main-chain (MHC)• mAb 2G12: domain-swap binds oligomannose•2F5, 4E10: TM epitopesWhere Else to Attack?HIV Association with Targets• CCR5 Homozygous Mutants are HIV resistant and otherwise healthy• RANTES promoter overexpression mutants are HIV resistantSNARE proteins Mediate Membrane Fusion Inside CellsEnergy from Helix Coiling Drives FusionThe Model for Viral FusionPreventing HIV Entry• PRO542 (Progenics): gp120 tetramer to IgG Fc that blocks CD4-gp120 interaction• BMS-806 (Bristol-Myers Squibb): small molecule that targets the CD4 binding site on gp120• TNX-355 (Tanox): an anti-CD4 antibody• SCH-C, SCH-D (Schering-Plough) and UK-427,857 (Pfizer:) block CCR5• AMD3100, AMD070 (AnorMED): block CXCR4Other Ideas• TRIM5a: a species restriction factor that is an E3! (J. Vir. 79(14): 8870-8877 2005)• Target HIV immunomodulators (Vpr, Vpu, etc.)• Block inflammatory response1. Lalezari, J.P. et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIVinfection in North and South America. N Engl J Med 348, 2175-2185 (2003).2. Lau, A. et al. Suppression of HIV-1 infection by a small molecule inhibitor of the ATMkinase. Nature Cell Biology 7(5), 493-500 (2005).The Future of the Arms
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