Impacts of HIV Cure Interventions on Viral Reservoirs in Tissues

HIV reservoirs persist in infected individuals despite combination antiretroviral therapy and can be identified in secondary lymphoid tissues, in intestinal tissues, in the central nervous system as well as in blood. Clinical trials have begun to explore effects of small molecule interventions to perturb the latent viral infection, but only limited information is available regarding the impacts of HIV cure-related clinical interventions on viral reservoirs found in tissues. Of the 14 HIV cure-related clinical trials since 2012 that have evaluated the effects of small molecule interventions in vivo, four trials have examined the impacts of the interventions in peripheral blood as well as other tissues that harbor persistent HIV. The additional tissues examined include cerebral spinal fluid, intestines and lymph nodes. We provide a comparison contrast analyses of the data across anatomical compartments tested in these studies to reveal where peripheral blood analyses reflect outcomes in other tissues as well as where the data reveal differences between tissue outcomes. We also summarize the current knowledge on these topics and highlight key open questions that need to be addressed experimentally to move the HIV cure research field closer to the development of an intervention strategy capable of eliciting long-term antiretroviral free remission of HIV disease

Using animal models to overcome temporal, spatial and combinatorial challenges in HIV persistence research

Research challenges associated with understanding HIV persistence during antiretroviral therapy can be categorized as temporal, spatial and combinatorial. Temporal research challenges relate to the timing of events during establishment and maintenance of HIV persistence. Spatial research challenges regard the anatomical locations and cell subsets that harbor persistent HIV. Combinatorial research challenges pertain to the order of administration, timing of administration and specific combinations of compounds to be administered during HIV eradication therapy. Overcoming these challenges will improve our understanding of HIV persistence and move the field closer to achieving eradication of persistent HIV. Given that humanized mice and non-human primate HIV models permit rigorous control of experimental conditions, these models have been used extensively as in vivo research platforms for directly addressing these research challenges. The aim of this manuscript is to provide a comprehensive review of these recent translational advances made in animal models of HIV persistence

Self-reported cardiorespiratory fitness:prediction and classification of risk of cardiovascular disease mortality and longevity--a prospective investigation in the Copenhagen City Heart Study

BACKGROUND: The predictive value and improved risk classification of self‐reported cardiorespiratory fitness (SRCF), when added to traditional risk factors on cardiovascular disease (CVD) and longevity, are unknown. METHODS AND RESULTS: A total of 3843 males and 5093 females from the Copenhagen City Heart Study without CVD in 1991–1994 were analyzed using multivariate Cox hazards regression to assess the predictive value and survival benefit for CVD and all‐cause mortality from SRCF. The category‐free net reclassification improvement from SRCF was calculated at 15‐year follow‐up on CVD and all‐cause mortality. Overall, 1693 individuals died from CVD. In the fully adjusted Cox model, those reporting the same (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.04 to 1.32) and lower (HR, 1.91; 95% CI, 1.62 to 2.24) SRCF than peers had an increased risk of CVD mortality, compared with individuals with higher SRCF. Compared with individuals with higher SRCF, those with the same and lower SRCF had 1.8 (95% CI, 1.0 to 2.5) and 5.1 (95% CI, 4.1 to 6.2) years lower life expectancy, respectively. Individuals with lower SRCF had a significantly increased risk of CVD mortality, compared with individuals with higher SRCF, within each strata of leisure time physical activity and self‐rated health, and SRCF significantly predicted CVD mortality independently of self‐rated health and walking pace. A net reclassification improvement of 30.5% (95% CI, 22.1% to 38.9%) for CVD mortality was found when adding SRCF to traditional risk factors. Comparable findings were found for all‐cause mortality. CONCLUSIONS: SRCF has independent predictive value, is related to a considerable survival benefit, and improves risk classification when added to traditional risk factors of CVD and all‐cause mortality. SRCF might prove useful in improved risk stratification in primary prevention

Strategies for enhancing CAR T cell expansion and persistence in HIV infection

Chimeric Antigen Receptor (CAR) T cell therapies are tremendously successful in hematological malignancies and show great promise as treatment and curative strategy for HIV. A major determinant for effective CAR T cell therapy is the persistence of CAR T cells. Particularly, antigen density and target cell abundance are crucial for the engagement, engraftment, and persistence of CAR T cells. The success of HIV-specific CAR T cells is challenged by limited antigen due to low cell surface expression of viral proteins and the scarcity of chronically infected cells during antiretroviral therapy. Several strategies have been explored to increase the efficacy of CAR T cells by enhancing expansion and persistence of the engineered cells. This review highlights the challenges of designing CAR T cells against HIV and other chronic viral infections. We also discuss potential strategies to enhance CAR T cell expansion and persistence in the setting of low antigen exposure