Notice of Special Interest: SEARCH: Stimulating ExplorAtory Research on HIV/AIDS Contribution to Heart, Lung, Blood and Sleep Comorbidities (R01 - Clinical Trial Not Allowed)

Notice Number: NOT-HL-19-677

Key Dates
Release Date: March 14, 2019

Related Announcements
PA-19-056

Issued by
National Heart, Lung, and Blood Institute (NHLBI)

Purpose

The purpose of this Notice is to inform potential applicants of NHLBI’s interest in supporting innovative projects within HIV/AIDS research priority areas as described by the NIH Office of AIDS Research (NOT-OD-15-137) that align with the mission of the NHLBI (NOT-HL-18-642). Areas of special interest include research to investigate the fundamental mechanisms underlying the pathogenesis of HIV-related heart, lung, blood, and sleep (HLBS) diseases in the context of antiretroviral therapy (ART). Of particular importance is to achieve a better understanding of the underlying mechanisms of HIV driven immune activation and inflammation in the presence of ART. Mechanistic questions proposed can be pursued by individual investigators or multi-investigator teams, using a multiplicity of approaches including, but not limited to: in vitro/ex vivo model systems, utilization of existing datasets and biospecimens, generation of computational models, and animal models particularly those in existence in HIV research.

Background

The HIV/AIDS pandemic has been one of the most important global health challenges in modern history. Current ART has significantly evolved to effectively control HIV replication, prevent AIDS, and contribute to the prolonged life of infected individuals. ART does not eliminate the virus from the body, but in many cases, it can suppress it to undetectable levels, significantly reducing the risk of viral transmission. However, even with successful viral suppression while on ART, low levels of viral replication persist in HIV reservoirs residing in various tissues and can contribute to sustained systemic immune activation and inflammation in people living with HIV (PLWH). Furthermore, use of ART itself may promote or exacerbate immune dysfunction to negatively impact HLBS diseases, particularly in combination with inflammation and immune activation induced by residual HIV reservoirs. The impact of long-term ART use on HLBS diseases is an understudied but significantly important research area, and this Notice of Special Interest encourages applications to focus on research studies necessary to advance our understanding of the effect(s) of long-term ART use on HIV-related HLBS diseases.

Research objectives

This Notice informs potential applicants of NHLBI’s interest in applications that propose exploratory and innovative research on HIV-related HLBS comorbidities in order to bring new insights and deeper understanding of the pathobiology of HIV-related HLBS comorbidities in the ART era. The Notice also intends to promote productive interdisciplinary research collaborations between established and junior investigators, and reinforce interactions and communication between NHLBI and the HIV/AIDS research communities with a focus on HLBS comorbidities. Research applications that seek to perform exploratory research ideas and proof of concept projects with the objective of generating robust preliminary data for larger grant applications are encouraged. Thus, hypothesis driven projects with limited or very minimal preliminary data are acceptable. Such studies could leverage the analysis of existing data and biological specimens from established HIV observational cohort studies, pilot studies, and feasibility studies. Examples of HIV-cohorts that could be utilized, include, but are not limited to, the MACS/WIHS-Combined Cohort Study, cohorts affiliated with the North American AIDS Cohort Collaboration on Research and Design consortium (NA-ACCORD), the Pediatric HIV/AIDS Cohort Study (PHACS), the CFAR Network of Integrated Clinical Systems (CNICS), the International epidemiology Databases to Evaluate AIDS (IeDEA) and other U.S. and international HIV-cohort studies. Creation of new HIV cohorts is not supported.

NHLBI held a workshop in December of 2015 from which many recommendations have been proposed and gap areas identified. Topics and potential studies identified as high priority include, but are not limited to:

  • Understanding the combined effect of ART drugs and drugs to control HLBS comorbidities in the aging population
  • Studies to delineate viral, host, or ART treatment components as determinants that induce accelerated aging and the earlier onset of HLBS comorbidities
  • Determine the incidence and prevalence of, as well as viral, host, or ART treatment-related mechanisms contributing to sleep disorders in PLWH
  • Investigate and compare HLBS disease progression (e.g., coronary artery disease, lung function decline) in adolescents vs. adults living with HIV
  • Studies focused on the evaluation of risks for developing non-infectious HLBS comorbidities and complications in perinatally HIV-infected individuals (now adolescent and adults) who have received long-term ART
  • Studies aimed to identify biomarkers to better predict progression of lung disease (T-cells, HIV-specific immune responses, macrophage activation), and to better understand the mechanism of HIV-associated persistent inflammation in the lung
  • Host mechanisms of immune defense that might be subverted under ART, rendering the host more susceptible to pulmonary co-infections, including Tuberculosis
  • Understanding the role of viral proteins in HIV-related pulmonary hypertension in PLWH on ART
  • The impact of HIV on hematopoiesis, particularly megakaryocytic development and function, and the implications for bleeding and thrombosis
  • The role of inflammation, immune dysregulation, or endothelial, platelet, and coagulation activation in the etiology of vascular events in HIV infection
  • Evaluate the effects of HIV infection and ART on platelet function. Also, determine how ART, combined with tobacco smoke, further potentiates platelet dysregulation, chronic inflammation, and the development of cardiovascular disease.
  • Evaluate the effects of heart failure on HIV pathogenesis and disease progression
  • Develop novel biomarkers, imaging, and therapeutics to more accurately diagnose and treat HIV-related heart failure with preserved ejection fraction
  • Interplay and role of environmental, social, and lifestyle factors involved in promoting HIV-associated HLBS comorbidities among PLWH
  • Novel approaches and technologies to address these research questions

Application and Submission Information:

Applications in response to this Notice must be submitted through the NIH Parent Announcement PA-19-056: NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). All instructions for the Parent Announcement must be followed. Submissions should indicate that they are in response to NOT-HL-19-677 in Field 4.b on the SF 424 form.

Inquiries

Please direct all inquiries to:

Lis Caler, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0222
Email: lis.caler@nih.gov