ZIA BC 011464 (ZIA) | |||
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Title | Clinical Interventional Studies of HIV Reservoirs | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Maldarelli, Frank | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $554,151 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (100.0%) Interferon (15.0%) |
Anus (100.0%) | ||
Research Type | |||
Systemic Therapies - Clinical Applications Development and Characterization of Model Systems |
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Abstract | |||
Fundamental gaps in our understanding of HIV reservoirs preclude a precisely targeted approach to eradication. HIV is neither eliminated nor often controlled by the human immune system, and the immunologic defect(s) responsible for this lack of control are unknown. Two key issues in understanding HIV persistence during therapy are (1) characterizing the relative contributions of active replication and chronic reservoirs to HIV persistence and (2) describing the cell type and activation state of cells chronically infected with HIV, which may identify new approaches to identify, disrupt, and eliminate persistently infected reservoirs. Ultimately, these approaches must be evaluated in vivo in clinical trials. ___Previously, we developed a standard clinical approach to investigating persistence using a strategy of frequent sampling to quantify HIV viremia during an extended baseline evaluation, followed by intensive monitoring of viremia during a targeted intervention, and evaluation of a post-treatment period. This strategy is optimized to quantify the level and variability of viremia prior to intervention, detect the presence of statistically significant changes during intervention, and determine whether any persistent effects or rebound occur after intervention is discontinued. ___In this project, we have developed a number of new studies to explore interventions using the intensification design. These studies will assess the initial efficacy of potential approaches and provide a wealth of patient-derived material to investigate the source and characterize the mechanisms of HIV persistence. ___We have also developed a series of clinical studies to investigate the relative effects of generalized and specific immune activation on persistent HIV viremia and latency reactivation. We hypothesize that HIV reactivation from latently infected cells can occur as a consequence of nonspecific immune activation or activation from anamnestic responses from specific antigenic stimulation. ___To investigate the role of generalized immune activation in HIV persistence, we are investigating processes that lead to nonspecific immune activation in HIV-infected individuals. One prominent mechanism described for such activation is the translocation of bacterial cell products across the gastrointestinal barrier into the systemic circulation; the presence of these bacterial products leads to generalized immune activation and may contribute to activation of immune cells, including HIV-infected cells, leading to persistent viremia. We are investigating the effects of the non-absorbable antibiotic, rifaximin, which reduces bacterial flora within the gastrointestinal tract. In a multisite randomized, double-blind, placebo-controlled crossover study, we are determining whether reductions in bacterial flora in the gut reduces translocation of bacterial cell products, cellular immune activation, and the level of persistent viremia in patients with viral RNA levels suppressed below 50 copies/ml plasma on combination antiretroviral therapy. The protocol ""A Double Blind Randomized Placebo Controlled Study Examining the Effects of a Non-absorbable (Rifaximin) Antibiotic on the Chronic Immune Activation Observed in HIV-infected Subjects"" (13-I-0062) is open at NIH and at two additional sites, Walter Reed National Military Medical Center (A. Ganesan) and University of Pittsburgh (D. McMahon). The NIH is the coordinating center for this study. These studies will directly address the role of chronic immune activation in persistent viremia. ___In the past year we successfully applied for new Bench to Bedside funds to investigate the sources of HIV persistence. In the new study ""Localizing Reservoirs of HIV Persistence in Lymphoid Tissue,"" we will be collaborating with B. Wood, A. Venkatesan, and D. Hammoud from InterventionalRadiology to localize and biopsy metabolically active tissue obtained using PET scanning and a specific targeting biopsy technique pioneered by |