Characterizing the virologic and immunologic signatures of HIV exceptional control

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PROJECT SUMMARY/ABSTRACT Typical elite control of HIV infection is no longer considered an optimal model for antiretroviral therapy (ART)- free remission due to increased transcriptional activity, chronic inflammation, and immune dysfunction in these individuals. “Exceptional control” is a related but distinct phenotype of natural HIV control that is now of great interest to the HIV cure community. The overarching objective of this proposal is to identify and characterize individuals exhibiting exceptional control in blood and tissues, and to initiate studies that seek to understand the mechanism by which this is achieved. We have several inter-related hypotheses: (1) exceptional controllers exhibit greater control over HIV replication in lymphoid tissues than typical elite controllers, despite comparable levels of control in peripheral blood, (2) exceptional controllers will have less systemic inflammation than typical elite controllers and ART-treated individuals and these levels will be similar to those in uninfected individuals, (3) in contrast to typical elite controllers, exceptional controllers who have initiated ART and then interrupt therapy in a highly monitored setting will exhibit no change in markers of residual viremia, inflammation, or immune activation. To investigate these hypotheses, we will begin by identifying natural HIV controllers in the UCSF SCOPE cohort who in the absence of ART have very low levels of intact proviral HIV DNA in a large number of peripheral blood CD4+ T cells; these will be the putative exceptional controllers. Individuals who have higher levels of intact proviral DNA will be considered typical elite controllers. In Aim 1, we will perform a cross-sectional study using gut biopsies and lymph node tissue aspirates to measure the size and distribution of the HIV reservoir at steady-state, comparing exceptional controllers with typical elite controllers. In Aim 2, we will perform a cross- sectional study of the immunologic consequences of exceptional control by measuring immune activation with PET-MR imaging and soluble and cell-associated markers of inflammation and immune system activation. We will compare exceptional controllers at steady-state with typical elite controllers, non-controllers on ART, and uninfected individuals. In Aim 3, we will analyze samples collected in an externally funded prospective study of HIV controllers and non-controllers interrupting ART to determine the virologic and immunologic changes that occur at the earliest timepoints when the host first encounters rebounding virus (the “intercept”). We anticipate that exceptional controllers interrupting therapy will demonstrate no substantial increase in these markers in contrast with the other groups. If our hypotheses are correct, we expect that exceptional controllers will demonstrate significant differences compared with typical elite controllers and non-controllers, will be indistinguishable from people without HIV infection, and will not have benefitted from ART. If this is the case, it will lead to further mechanistic studies to understand the process by which this level of control is achieved and might inform further work to develop a model for HIV “remission.”