This application proposes to utilize the SIV/newborn rhesus macaque model to study the pathogenic properties of certain drug resistant mutants. The goals of the proposal are to identify and sequence drug resistant mutants that show attenuated properties, and to identify therapeutic strategies that when not successful at complete eradication, will select for attenuated virus. The investigators will concentrate on 3TC and FTC resistance, FTC being a 3TC analogue with improved pharmacologic properties. A resistance mutation in RT common to both drugs (M184V) arises following treatment in vivo. This mutation suppresses the mutations known to convey resistance to AZT, thus it is difficult to achieve resistance to an AZT/3TC combination. These mutants also display slow replication kinetics, the RT has increased fidelity, and they are hypersensitive to a third drug, PMPA. This suggests that 3TC mutants may be less fit, and that they may be effectively controlled with administration of PMPA. The investigators intend to use their animal model system to study aspects of 3TC/FTC resistance that might be helpful in development of improved therapeutic strategies. The investigators will determine whether 3TC/FTC resistant SIV is attenuated compared to wild-type virus. In addition, they will also evaluate efficacy of combination treatment of 3TC/PMPA, or the triple combination of AZT/3TC/PMPA, and will characterize any resistant mutants that arise following these treatments.
|Wadford, Debra A; Kauffman, Robert C; Deere, Jesse D et al. (2014) Variation of human immunodeficiency virus type-1 reverse transcriptase within the simian immunodeficiency virus genome of RT-SHIV. PLoS One 9:e86997|
|Van Rompay, Koen K A; Johnson, Jeffrey A; Blackwood, Emily J et al. (2007) Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection. Retrovirology 4:25|
|Murry, Jeffrey P; Higgins, Joanne; Matthews, Timothy B et al. (2003) Reversion of the M184V mutation in simian immunodeficiency virus reverse transcriptase is selected by tenofovir, even in the presence of lamivudine. J Virol 77:1120-30|
|Van Rompay, Koen K A; Matthews, Tim B; Higgins, Joanne et al. (2002) Virulence and reduced fitness of simian immunodeficiency virus with the M184V mutation in reverse transcriptase. J Virol 76:6083-92|
|Leutenegger, C M; Higgins, J; Matthews, T B et al. (2001) Real-time TaqMan PCR as a specific and more sensitive alternative to the branched-chain DNA assay for quantitation of simian immunodeficiency virus RNA. AIDS Res Hum Retroviruses 17:243-51|