Reservoirs of drug-resistant HIV-1

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): 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. Even though these mutants "fade" when assessed by consensus sequencing, recent Thai studies suggest that they may compromise the efficacy of subsequent 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 1.) 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. 2.) Determine 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.