CD4 RESPONSES TO ANTIRETROVIRAL THERAPY (ART) ALONE OR ART WITH VACCINATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis and Objectives: Investigators of the pathogenesis of HIV infection agree that one of the most critical questions in HIV disease is why immune responses ultimately do not control HIV replication in the vast majority of infected individuals. The absence of large lymphocyte proliferation response (LPR) to HIV antigens in individuals with established infection, the development of these responses in subjects treated during acute infection, and their presence in long term nonprogressors (LTNPs) with low viral loads, provide strong associations between this type of CD4 immune response and the control of viral replication. A correlation exists between LPR to HIV antigens and virologic control, but the relationship between other measurements of HIV-specific CD4 cells and virologic control is less clear. The sequential measurements of multiple CD4 functions during primary HIV infection in this protocol, combined with the enumeration of CD4 cells with T-cell responses (TCR) recognizing HIV-class II tetramers in the intensively studied subset should provide data on the levels at which CD4 function is inhibited. Similarly, a comparison of HIV-specific CD4 function as it develops in subjects treated during acute infection and CD4 function in subjects who decline treatment or who have recent infection in whom treatment has been delayed, may provide insight into factors inhibiting the development of full CD4 function, or accounting for its loss. The investigators estimate that 80% of subjects initiating antiretroviral therapy (ART) during the acute phase of their infection will develop robust HIV-specific CD4 responses as measured by LPR, and that a majority of these will control viral load to some degree after stopping ART. The frequency and magnitude of LPR to HIV antigens that will develop when treatment is delayed, and the shape and slope of the curve of declining CD4 responsiveness as a function of the time before starting ART are unknown, but data in a small number of patients suggests that the responsiveness of HIV-specific CD4 cells will be will be lower, but may occur in some patients when ART is delayed as long as 180 days after the onset of acute infection (34). Primary Objective: To determine the proportion of subjects in each stratum whose viral load was initially suppressed with ART that are subsequently able to control plasma HIV RNA to a mean value of <5,000 copies/mL as measured at weeks 16 and 18 after stopping ART in the final analytical treatment interruption (ATI). Secondary Objectives: a) To determine the mean value of all measurements of plasma HIV-RNA in a given patient from the initiation of the ATI until protocol criteria for restarting ART have been reached, or until week 48 of the ATI, which ever comes first. b) To determine the percent of subjects in each stratum that control viral load to<1,000 copies/mL, to <400 copies/mL, and to <50 copies/mL mean value at weeks 16 and 18 of the ATI. c) To determine the percent of subjects in the vaccine arm and placebo arm of the acute stratum that control viral load to <5,000 copies/mL. d) To determine the percent of subjects in the vaccine arm and placebo arm of the recent infection stratum that control viral load to <5,000 copies/mL. e) To determine the median time from presumed onset of HIV infection to initiation of ART which is associated with the subsequent ability of subjects to control viral load after interruption of ART. f) To determine the median time from presumed onset of HIV infection to initiation of ART, which is, associated with the subsequent development of strong lymphocyte proliferative responses (LPR) to HIV antigens. g) To determine the median time before a subsequent virologic relapse that requires restarting ART in the vaccine and the placebo arms for subjects in either stratum who controlled viral load to a mean value of <5,000 copies/mL at 16 and 18 weeks. Study Design and Methods: This is a randomized controlled clinical trial of effective antiretroviral therapy (ART) alone versus ART plus therapeutic HIV vaccination, both with monitored treatment interruptions, in acutely and recently HIV infected subjects. This study contains a diagnosis phase, an ART alone treatment phase, an ART plus vaccination phase, a brief scheduled treatment interruption phase and an analytical treatment interruption, with provisions for retreatment with ART or vaccination or both. Approximately 92 subjects will be enrolled (46 acute and 46 recent infections). The study will last 5 years.