Title: Cross-Cutting Translational Research on the interaction of HIV and Alcohol

Authors: Kendall Bryant, Ph.D., Joe Wang, Ph.D., Division of Metabolism and Health Effects

Mechanism: RFA: R01, R21, R34

Purpose: The purpose of this research initiative is to encourage mechanistic studies that explore alcohol’s effects on the gut-liver-brain interactions and their pathological consequences among HIV/AIDS patients that can be translated into interventions (e.g., pharmacological and behavioral).

The primary focus of the proposed projects should be on the pathophysiological and molecular mechanisms involved in dysregulated interactions between the gut, liver, and/or brain induced by alcohol that could mutually disturb their respective functions, leading to tissue injury among PLWH. It is anticipated that this NOFO will encourage interdisciplinary and collaborative research and new approaches to gain insights into the complex mechanisms of organ pathology and preventive strategies for Alcohol and HIV induced pathology.

Background: The NIH Plan for HIV/AIDS Research FY2020-2025 has identified the importance of basic behavioral and biological research that can be translated into interventions. This high-priority area has been identified as the Cross-Cutting initiative. Basic research provides the underpinning for HIV science in all other prevention and treatment priority areas. It also may identify gaps and emerging areas where additional work can improve our understanding of how HIV is transmitted and persists (e.g. in viral reservoirs) in the context of alcohol use that has a direct impact on translation (e.g. therapeutics and vaccines).

Statement of Work or Scope of Research Projects: The future NOFO will solicit alcohol-focused biological research projects that examine pathophysiological alterations in the gut-liver-brain axis in the  development of liver/organ disease and cognitive impairment in people living with HIV/AIDS (PLWH) with multiple patterns of alcohol drinking. The NOFO will also support applications that deal with determination of relevant biomarkers for diagnosis and therapeutic targets for prevention/treatment of HIV/alcohol-associated liver/organ disease and pathogenic sequelae resulting in increased frailty and mortality. Studies considered responsive to the NOFO must:

• utilize systems biology approach;
• integrate data from functional metagenomics, metabolomics, gut barrier dysfunction, and immunological alterations.

Outcome and Justification: Research under this initiative is directly relevant to Cross-Cutting research initiatives outlined in the NIH Plan for HIV/AIDS Research FY2020-2025. This research should obtain translatable insights from specific dynamic aspects of gut microbial dysbiosis and accompanying metabolomic and inflammatory changes. These changes may contribute to liver disease and other organ injury in PLWH  and assess ancillary impact on brain function and cognitive impairment by:

• collecting data from cross-sectional and longitudinal cohorts, and investigating the relationship among functional metagenomics of the gut microbiome, metabolomics, gut barrier dysfunction, and systemic and mucosal immunological alterations and markers of liver/organ disease and injury and for brain and cognitive functioning in HIV;
• determining the effects of gut microbial dysbiosis on fecal and serum metabolites, intestinal barrier dysfunction, mucosal immune dysfunction and HIV latency, gut and systemic inflammatory changes, and/or
• developing and testing intervention strategies and approaches, including repurposing FDA approved medications, in proof-of-principle models that could mitigate some of intermediate outcome measures including metabolic and inflammatory conditions associated with HIV/alcohol pathology (including further understand the role of existing alcohol-related pharmacotherapies on HIV outcomes).

Research Scope not responsive to NOFO: Research which is not interdisciplinary and directly relevant to Cross-Cutting priorities outlined under the NIH Plan for HIV/AIDS Research for FY2020-2025 is  unresponsive.