Reservoirs of drug-resistant HIV-1

Seattle Children'S Hospital, Seattle WA

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Abstract

Treatment of HIV-1 infection with highly active antiretroviral therapy (HAART) can markedly improve immune function and general health. However, a significant proportion of HIV-1 infected individuals do not fully benefit from HAART due to drug-resistant virus. Once selected, drug-resistant virus is thought to persists, even when undetectable, and often it limits the efficacy of subsequent HAART due to cross-resistance between many available drugs. Our knowledge regarding the establishment and persistence of reservoirs of drug-resistant virus is incomplete, yet, it is these reservoirs that we need to understand and overcome for successful treatment of a large segment of the HIV-1 - infected population. Single-dose nevirapine has been adopted by many programs to reduce mother-to-child- transmission of HIV-1 (MTCT) due to its efficacy (50%) at a very low cost. Single-dose nevirapine selects for drug- resistant mutants in exposed women and infants. Eventhough these mutants "fade" when assessed by consensus sequencing, recent Thai studies suggest that they may compromise the efficacy of susequent NVP-based HAART (NVP-HAART), perhaps in a time-dependent fashion {Jourdain, 11th CROI, 2004; LB 41). We and others have data suggesting that most of the long-lived viral reservoirs are established during primary infection. We hypothesize that drug-resistant mutants become part of the long-lived reservoirs commensurate with the amount and duration of viral replication during selective pressure by antiretrovirals. When drug pressure is short-term, such as with single-dose nevirapine, we hypothesize that the selected mutants primarily reside in short-lived lymphocytes, and minimally perturb the long-lived viral reservoirs. As the short-lived cells decay, we hypothesize, that they eventually persist at clinically insignificant levels. To test these hypotheses, we propose to: Aim 1: Determine prospectively in Mozambican infants if the timing of single-dose NVP relative to the time of HIV-1 infection in infants (i.e. NVP after or during acute infection) affects the quantity of NVP-resistant mutants selected and the duration of their persistence. Aim 2: Thai study. Analyze (retrospectively, with Thai collaborators) if the level of NVP-resistant HIV-1 DNA in PBMC, at 10 d, 6 and 12 wk postpartum or at the time HAART is initiated, is predictive of subsequent "virologic failure". Mozambican studies ";'"; Quantify prospectively the selection and decay of NVP-resistant HIV-1 DNA in PBMC of Mozambican postpartum women taking single-dose NVP for prophylaxis of their infants. " /;'"; Dermine in an exploratory study of Mozambican women if the rekindling of NVP-mutants in plasma and PBMC or "virologic failure" during NVP-HAART is related to: the time interval between the administration of single-dose NVP and initiation of NVP-HAART, or the level of NVP-mutants in PBMC when HAART is initiated. The proposed studies should provide insight into the selection and persistence of NVP-resistant viral reservoirs associated with single-dose NVP, and the clinical effects of these mutants. These data assist in establishing complementary MTCT prophylaxis regimens and HAART for women and children.