With potent new combination antiretroviral therapies (cART), the life-span of HIV-infected persons has been steadily increasing, but is often complicated by premature onset of non-AIDS co-morbidities such as cardiovascular disease (CVD), attributed to persistence of immune activation (IA) despite suppression of plasma virus to undetectable levels. One mechanism of persistent IA is gut microbial translocation (MT) resulting from HIV-associated gut damage early in HIV infection, but why the gut recovery is delayed is unclear. While it is known that HIV establishes reservoirs early in infection necessitating life-long uninterrupted therapy to prevent virus rebound, our studies suggest that LLVR is in fact occurring despite plasma virus suppression and that it is associated with IA. Whether the virus reservoir per se is driving immune activation directly or indirectly is unknown. We are proposing a partnership between investigators in YRGCARE in Chennai, India and University of Miami, in Miami USA to examine a novel hypothesis that patients on cART with suppressed plasma viremia continue to have persistent low level virus replication that drives immune activation and gut damage. Further we hypothesize that lower nadir CD4 is associated with greater virus reservoir size, immune activation, co-morbidity and poorer immune reconstitution.
Aim 1 will determine the size of virus reservoir and level of residual viral replication in CD4 T cells of patients on suppressive ART;total and unintegrated HIV DNA will be quantified and CD4 T cells evaluated for HIV induction ex-vivo.
In aim 2, level of immune activation will be assessed by plasma measures of inflammatory cytokines, endothelial activation markers, MT, and cellular phenotyping.
In aim 3, the impact of nadir CD4 on virus reservoirs, immune activation, immune reconstitution and evidence of CVD will be investigated. For these aims, a cross-sectional study in patients on cART for>48 weeks, plasma VL<40 copies with varying nadir CD4 counts will be conducted. This study will establish novel state of the art immunology and virology assays at YRGCARE, provide preliminary data of global relevance and prepare us for future collaborative research, including studies aimed at eradicating reservoirs and curing HIV/AIDS.
Despite treatment with antiretroviral drugs (ARV) and suppression of HIV to undetectable levels, patients with HIV have a greater risk for developing disorders such as cardiovascular disease (CVD) that shorten their survival, and are believed to be caused by increased inflammation and immune activation (IA). We will establish the levels of IA and in ARV treated patients with differing levels of CD4 T cells and determine the cause of immune activation including hidden evidence of persistent virus. This research will provide leads to future treatment options including strategies for cure.
