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ID#: PA-11-218     Posted: 7 Mar 2012
Mechanistic Studies of HIV-exposed Seronegative Individuals (HESN) (R01)
Deadline: 5 Jun 2013
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Type of Grant: Research
Topics/Fields of Support: HIV transmission and acute infection, Human genomics, Innate immunity, Mucosal immunity, T cell immunity
National Institute of Allergy and Infectious Diseases, NIH, HHS


The National Institute of Allergy and Infectious Diseases (NIAID) conducts and supports basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases. For more than 60 years, NIAID research has led to new therapies, vaccines, diagnostic tests, and other technologies that have improved the health of millions of people in the United States and around the world. NIAID is one of the 27 Institutes and Centers of the National Institutes of Health (NIH). NIH, like the Centers for Disease Control and Prevention (CDC), is part of the U. S. Department of Health and Human Services (HHS). NIH is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, please visit NIH (

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The purpose of this initiative is to support mechanistic studies of individuals who are repeatedly exposed to HIV but remain seronegative (HESN), or demonstrate resistance to infection.  Projects supported under this FOA could involve cellular, structural and systems biology; host and viral genetics; immunology, or virology.  All projects focusing on the phenomenon of HESNs are encouraged, including those involving mechanisms responsible for establishing and maintaining seronegativity or resistance to infection, new assay development, mathematical, cell, and animal model development, and development of new technologies needed for expansion of our understanding of HESNs.  Applicants are encouraged to show how proposed studies will explore the mechanisms underlying HIV seronegativity or resistance.


Over the last decade HIV infection has become a manageable and chronic disease due to highly effective antiviral treatment.  Fully effective prevention strategies have been a more elusive goal.  Understanding the earliest events during HIV transmission is critical to the design of an effective HIV vaccine and for improving promising microbicide strategies.  Through cohort studies individuals have been identified who appear resistant to infection, or who remain seronegative after repeated HIV exposure, but few studies have tackled the difficult problem of identifying host or viral factors that account for the failure of a host to become infected despite repeated or prolonged HIV exposure.  Thought-provoking observations have shown correlations of seronegativity or resistance, with: IgA qualitative and quantitative variation, serpin-protein family over expression at the genital mucosa, allo-immunity, HLA alleles, etc.  With the exception of the delta 32 homozygous mutations in the CCR5 gene, the HESN studies have been associative without mechanistic data that might predict prevention strategies applicable to larger at-risk populations.

A July 2010 “Workshop on HIV – Exposed and Resistant” sponsored by the Office of AIDS Research (OAR), the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute on Drug Abuse (NIDA) at the NIH, highlighted the gaps, challenges, and potential benefits of these studies (  It is expected that research supported by this FOA will determine if there are mechanisms responsible for the HESN phenotype that could inform new approaches to prevention strategy challenges.

Applicants should propose hypothesis-driven specific aims that directly address one or more of the objectives below. The range of research plans may be broad; however, each application must clearly describe how the proposed study would lead to a new approach, or improve existing concepts that could lead to the design of an effective prevention strategy to reduce or eliminate HIV acquisition or infection.

Objectives of this Research Program

Research projects and studies should address one or more of the following questions and/or topics and be directed toward identifying mechanisms rather than associations:

  • What mucosal parameters are distinctly different in the resistant population compared with those exposed in sero-converted populations?
  • What is the nature of the HESN immune response on exposure to HIV?
  • Are there host features (proteins/expression, patterns/genes) or viral features that are responsible for resistance?  Studies on association of new genes, host factors, and gene expression patterns with the HESN phenotype must propose to also identify mechanism(s) involved in protection and/or defense from HIV.  The ultimate goal is to identify a defensive factor that could be converted into an HIV prevention product.  
  • Development of new assays and animal models to accelerate mechanistic studies, including humanized mice and non-human primates.
  • Development of new mathematical/epidemiological models to measure HIV exposure risk in men who have sex with men (MSMs), discordant couples, and female and male sex workers.
  • Exploration of the potential relationship between drug use and HESNs

Note:  The areas below are NOT areas AI is seeking through this FOA.  If an applicant has scientific topics in the following areas please apply thru the parent FOA:

  • Clinical trials
  • Drug Development
  • Cohort development; however, recruitment of study subjects from existing cohorts is encouraged (please discuss with program)
  • Associative studies that propose solely to identify new genes but do not propose how the mechanism of protection and/or resistance will be investigated
  • Acute infection studies
Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director/Principal Investigator (PD/PI) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.


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