Turning off HIV White Noise: Switching from Long-Lived to Short-Lived Reservoir

HIV persists in all treated individuals and in most cases viral rebound occurs promptly upon antiretroviral treatment interruption (ATI). Tissues are major sites of HIV persistence during cART and, notably, the gastrointestinal tract is the first site were rebound is detectable via SIV-end ImmunePET/CT in a live SIV infected animal upon ATI. However, a lot is still unknown about the mechanisms of viral persistence in tissues. This is mostly because of logistical barriers in sampling deep tissues and the focal nature of HIV/SIV infection. Our team has developed a PET/CT-guided sampling workflow that overcomes these difficulties and allows sampling of areas of “rebound-competent reservoir” in tissues in a live animal. TGF-β is an important immune suppressor factor, which orchestrates tissue immunity. Levels of TGF-β remain elevated in HIV infected individuals even after years of fully suppressive cART and contribute to immune suppression as well as to the development of non-AIDS-related, non-communicable disorders via pro-fibrotic mechanisms. TGF-β inhibits TCR-driven T cell proliferation and the maturation and function of other immune cell subsets. Importantly, TGF-β is currently being used to induce HIV latency in in vitro models with primary T cells. Our preliminary data demonstrate that blocking TGF-β signaling in vivo favors HIV latency reversal especially in tissues. Moreover, we found that TGF-β blockade stimulates SIV-specific immune responses and decreases BCL-2 expression in memory T cells both in vivo and in vitro. These exciting new data support a view of TGF-β as a critical factor in maintaining immune cells into a resting state mostly resistant to apoptosis. Hence, we hypothesize that blocking TGF-β will not only increase the frequency of latency reversal events, but also enhance the elimination of the viral reservoir by increasing its susceptibility to immune and viral-mediated cell death. We will test this hypothesis by focusing on 3 specific aims. Aim 1 will be an investigation of the mechanisms of TGF-β blockade in vivo. We will leverage PET/CT-guided sampling to obtain tissue areas where virus reverses following TGF-β blockade and analyze the cells in these tissues for their transcriptomic profiles in their own microenviroment. In Aim 2, we will dissect the mechanisms of TGF-β blockade ex vivo to understand the pathways dependence of the effect of TGF-β blockade on HIV latency and on the survival program of central memory T cells. Finally, in Aim 3, we will dissect the synergistic effect of TGF-β blockade and PD-1 blockade on the differentiation program and apoptosis sensitivity of the cells harboring the viral reservoir in vivo. In conclusion, we designed a comprehensive strategy that will help us understanding the potential of this novel strategy to bring us closer to an HIV cure.