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Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249.

TitleTropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249.
Publication TypeJournal Article
Year of Publication2008
AuthorsVeazey RS, Ketas TA, Klasse PJohan, Davison DK, Singletary M, Green LC, Greenberg ML, Moore JP
JournalProc Natl Acad Sci U S A
Volume105
Issue30
Pagination10531-6
Date Published2008 Jul 29
ISSN1091-6490
KeywordsAnimals, Anti-Infective Agents, Dose-Response Relationship, Drug, Female, HIV Fusion Inhibitors, HIV Infections, HIV-1, Humans, Inhibitory Concentration 50, Leukocytes, Mononuclear, Macaca, Models, Genetic, Simian Acquired Immunodeficiency Syndrome, Simian immunodeficiency virus, Vagina
Abstract

We have assessed the potential of the fusion inhibitory peptide T-1249 for development as a vaginal microbicide to prevent HIV-1 sexual transmission. When formulated as a simple gel, T-1249 provided dose-dependent protection to macaques against high-dose challenge with three different SHIVs that used either CCR5 or CXCR4 for infection (the R5 virus SHIV-162P3, the X4 virus SHIV-KU1 and the R5X4 virus SHIV-89.6P), and it also protected against SIVmac251 (R5). Protection of half of the test animals was estimated by interpolation to occur at T-1249 concentrations of approximately 40-130 muM, whereas complete protection was observed at 0.1-2 mM. In vitro, T-1249 had substantial breadth of activity against HIV-1 strains from multiple genetic subtypes and in a coreceptor-independent manner. Thus, at 1 muM in a peripheral blood mononuclear cell-based replication assay, T-1249 inhibited all 29 R5 viruses, all 12 X4 viruses and all 7 R5X4 viruses in the test panel, irrespective of their genetic subtype. Combining lower concentrations of T-1249 with other entry inhibitors (CMPD-167, BMS-C, or AMD3465) increased the proportion of test viruses that could be blocked. In the PhenoSense assay, T-1249 was active against 636 different HIV-1 Env-pseudotyped viruses of varying tropism and derived from clinical samples, with IC(50) values typically clustered in a 10-fold range approximately 10 nM. Overall, these results support the concept of using T-1249 as a component of an entry inhibitor-based combination microbicide to prevent the sexual transmission of diverse HIV-1 variants.

DOI10.1073/pnas.0802666105
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID18647836
PubMed Central IDPMC2492474
Grant ListR01 AI41420 / AI / NIAID NIH HHS / United States
RR000164 / RR / NCRR NIH HHS / United States
U19 AI65413 / AI / NIAID NIH HHS / United States

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