Delineating the viro-immunological factors contributing to transient HIV control during consecutive analytical treatment interruptions

Project Summary During effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) persists in memory T cells and the virus from this cellular reservoir rebounds when people living with HIV (PLWH) stop ART. When ART is discontinued, viral rebound takes place within 4 weeks in most PLWH (i.e., non-controllers). However, the time

to viral rebound varies and there are rare PLWH who maintain low levels of viremia for months or years after an analytic treatment interruption (ATI). Previous studies have identified several factors associated with a delayed time to viral rebound: 1) lower levels of total HIV DNA prior to treatment interruption; 2) lower pre-ART viral load;

and 3) initiation of ART during acute/early infection. In addition, CD8 T cell immune response directed against structurally important viral protein regions is also associated with viral control in the absence of ART. From the results of the PULSE clinical trial, where 68 PLWHs underwent three consecutive ATIs, we

observed that 10% of the participants controlled their viral rebound up to 6 months (i.e., transient controllers). Applying our novel near full-length HIV RNA sequencing assay to genetically characterize HIV from the plasma of two participants enrolled in this clinical study, we found that genetically distinct HIV populations emerged when

transient viral control was observed. In the current study, we will extend our full-length HIV sequencing analysis to all participants who experienced transient viral control during consecutive ATIs. In addition, to determine whether enhanced CD8 T cell response and functionality are essential to achieve transient viral control during

consecutive ATIs, we will compare the proportion of HIV-specific CD8 T cells and the magnitude of their response across pre-ART and ATI timepoints in both transient controllers and non-controllers. Furthermore, we will determine whether consecutive ATIs improve HIV-specific CD8 T cell response to structurally important and

genetically conserved viral protein regions shaping the genetic composition of rebound viruses and controlling viral infection. The proposed study will allow us to determine if consecutive ATIs enhance viral and immunological mechanisms contributing to transient viral control. Of note, we will define the immunological parameters of CD8

T cells that result in a transient virological control and delayed viral rebound when ART is discontinued. Moreover, this study will accelerate the development of new therapeutic strategies such as enhancing host immunity against structurally important and genetically conserved HIV protein regions with the ultimate goal of achieving virological

remission following the discontinuation of ART.