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ID#: RFA-AI-12-004, Reissue of RFA-AI-05-001,      Posted: 27 Feb 2012
Leadership Group for a Clinical Research Network on Therapeutics for HIV/AIDS and HIV-associated Infections in Adults (UM1)
Deadline: 28 Sep 2012
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Type of Grant: Research
Topics/Fields of Support: HIV transmission and acute infection, Preclinical and clinical vaccine trials
National Institutes of Health (NIH, NIAID, NIHCD, NIDA, NIMH, NINDS)

The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the nation’s medical research agency—making important medical discoveries that improve health and save lives.

Thanks in large part to NIH-funded medical research, Americans today are living longer and healthier. Life expectancy in the United States has jumped from 47 years in 1900 to 77 years today, and disability in people over age 65 has dropped dramatically in the past 3 decades. In recent years, nationwide rates of new diagnoses and deaths from all cancers combined have fallen significantly.

Scientific Leadership

NIH is the largest source of funding for medical research in the world, creating hundreds of thousands of high-quality jobs by funding thousands of scientists in universities and research institutions in every state across America and around the globe.

NIH is made up of 27 Institutes and Centers, each with a specific research agenda, often focusing on particular diseases or body systems. NIH leadership plays an active role in shaping the agency's activities and outlook.

The Office of the Director is the central office at NIH, responsible for setting policy for NIH and for planning, managing, and coordinating the programs and activities of all the NIH components. The NIH Director, with a unique and critical perspective on the entire agency, is responsible for providing leadership to the Institutes and for constantly identifying needs and opportunities, especially for efforts that involve multiple Institutes. The NIH Director is assisted by the NIH Deputy Directors including the Principal Deputy Director, who shares in the overall direction of the agency's activities.

More than 80% of the NIH's budget goes to more than 300,000 research personnel at over 3,000 universities and research institutions. In addition, about 6,000 scientists work in NIH’s own laboratories, most of which are on the NIH main campus in Bethesda, Maryland. The main campus is also home to the NIH Clinical Center, the largest hospital in the world totally dedicated to clinical research.

Successful biomedical research depends on the talent and dedication of the scientific workforce. NIH supports many innovative training programs and funding mechanisms  that foster scientific creativity and exploration. The goal is to strengthen our nation’s research capacity, broaden our research base, and inspire a passion for science in current and future generations of researchers.

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The purpose of this FOA is to encourage applications for the Leadership Group (LG) for a Clinical Research Network on Therapeutics for HIV/AIDS and HIV-associated Infections in Adults.  The LG will have overall responsibility for: (i) developing, implementing and adapting the network’s clinical research agenda to address NIAID’s HIV/AIDS scientific priorities described below in Part 2, Section I, #3, (ii) overseeing and managing the network’s scientific/clinical research activities and associated laboratory and statistical/data management support functions, (iii) allocating network resources, and (iv) evaluating network performance using a LG proposed/Division of AIDS (DAIDS) approved process and evaluation standards.

The Program Director(s)/Principal Investigator(s) PD(s)/PI(s) and senior/key personnel of the LOC, LC and SDMC together form the LG. The LG coupled with the Program Directors/Principal Investigators PD(s)/PI(s) and senior/key personnel of the affiliated Clinical Trial Units/Clinical Research Sites (CTUs/CRSs) collectively constitute the Clinical Research Network on Therapeutics for HIV/AIDS and HIV-associated Infections in Adults (herein referred to as the “network”). The three different parts of the LG (LOC, LC and SDMC) will be required to work together collaboratively and with the network-affiliated CTUs/CRSs to carry out the activities that are essential to achieving the network’s clinical research agenda.

Clinical Trial Units (CTUs) provide the scientific and administrative expertise as well as the infrastructure to contribute to NIAID Clinical Research Networks.  A CTU is an organization/institution composed of at least one, but no more than eight Clinical Research Site(s) (CRSs) that can contribute to at least two HIV/AIDS Clinical Research Networks.  The CTU PD(s)/PI(s) is/are responsible for all CTU/CRS activities and performance, and also serve(s) as scientific and administrative representative(s) to the CTU’s affiliated network(s).

A Clinical Research Site (CRS) is a component of a CTU and is defined as a discrete location (e.g. hospital, outpatient clinic, community health center, private practice, local health department clinic) with appropriate identified and characterized potential trial participants (e.g. demographics, incidence and prevalence of HIV/AIDS) where participant recruitment and retention, protocol management and other clinical research activities are conducted. The CRS must be staffed by qualified professionals capable of conducting clinical research for one or more clinical research networks in accordance with Good Clinical Practice (GCP), local regulatory requirements, and other applicable NIH requirements.  In addition, each CRS must participate in one or more HIV/AIDS clinical research network(s). The activities of each CRS will be directed by a CRS Leader with the experience and qualifications to oversee clinical activities and the day-to-day clinic operations will be overseen by a CRS Coordinator with relevant clinical research experience and qualifications.  An individual CRS and/or CRS Leader may be proposed in only one CTU application.


NIAID currently supports six HIV/AIDS clinical research networks: the AIDS Clinical Trials Group (ACTG), the HIV Prevention Trials Network (HPTN), the HIV Vaccine Trials Network (HVTN), the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT), the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), and the Microbicide Trials Network (MTN).

Over the past 30 years, HIV/AIDS research has led to phenomenal scientific advances.  Scientists uncovered the structure and genetic organization of HIV and began to understand the mechanisms by which HIV causes disease.  This understanding led to the development of (i) tests to detect HIV infection, measure HIV viral load and monitor immune function, and (ii) highly active antiretroviral therapies (HAART).

Despite these scientific advances, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS), 33 million people globally are estimated to be living with HIV, of whom 22 million are living in sub-Saharan Africa.  Slightly more than half of all people living with HIV are women and girls.  In sub-Saharan Africa, more women than men are living with HIV, and young women aged 15–24 years are as much as eight times more likely than men to be HIV-infected.

The NIAID therapeutics networks have played a pivotal role in improving the clinical management of HIV infection and its co-morbidities throughout the world. They contributed to the development of guidelines for: 1) treatment of HIV infection and associated infections; 2) prophylactic regimens for secondary infections; 3) use of biological markers, such as CD4+ cell counts and HIV viral load, for monitoring response to therapy and disease progression; and 4) the use of antiretroviral drugs for preventing mother-to-child transmission.

In the vast majority of infected individuals adherent to treatment, combination antiretroviral regimens are capable of suppressing HIV viral load and partially restoring immune function, reducing HIV morbidity and mortality. Nevertheless, HIV infection has not been cured by antiretroviral therapy and the virus persists even in patients who are adherent to their HAART regimens. The persistence of HIV infection has been attributed to latent but replication-competent provirus in resting CD4+ lymphocytes, cryptic viral expression below the limits of detection and viral sanctuary sites, and leads to chronic immune activation and inflammation. To find a cure, all HIV reservoirs must be identified and eliminated. Alternatively, in the absence of complete sterilization, a functional cure would achieve viral suppression without the need for antiretroviral therapy.

Inhibition of HIV replication by antiretroviral drugs leads to a reduction in the levels of markers of immune activation, but the levels remain above those seen in individuals without HIV infection. Chronic immune activation leads to immune senescence, with eventual loss of response to antigens and increased frequency of infectious diseases. Loss of integrity of the enteric barrier permitting microbial translocation and dysfunctional response to enteric flora may also contribute to chronic inflammation. Chronic inflammation, in turn, appears to contribute to disruption of tissue architecture, leading to impaired end-organ function, with the resulting higher risk for AIDS and non-AIDS related co-morbidities.

A large number of biomarkers are being studied to identify correlates of risk for end-organ disease, such as cardiovascular, liver, renal and neurologic disease outcomes, that have been seen to accompany HIV expression, immune activation, pro-inflammatory cytokine release and adhesion molecule expression. It may be that chronic inflammation also is a factor in the increased rates of virally induced malignancies, which are seen in HIV infected individuals. Research in HIV-disease therapeutics must expand to include novel approaches targeting one or more steps in this disease cascade.

Tuberculosis (TB) research is a high priority for NIAID. Globally, HIV and TB are the first and second most common causes of death by single infectious agents overall and TB is the leading cause of death for HIV-infected persons.Mycobacterium tuberculosis, the causative agent of TB, is readily transmissible, with one-third of the world’s population thought to be infected. The convergence of the HIV and TB epidemics has substantially increased the incidence, morbidity and mortality of TB, and in turn, TB accelerates progression of HIV disease. Increasing rates of drug resistance, including the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) M. tuberculosis strains, have greatly diminished the success rate of standard therapy for TB and have significantly increased the duration and cost of treatment. Together, escalating rates of HIV-associated TB and both MDR and XDR TB threaten global TB and HIV control. There is an urgent need therefore to investigate better diagnostics, treatments and prevention methods.

Infectious hepatitis research also is a high priority for NIAID. As reported by the CDC, more than 1.2 million Americans have chronic hepatitis B infection (HBV) and more than 3.2 million have chronic hepatitis C infection (HCV).  As compared to the general population, a significantly higher proportion of people living with HIV also have HBV or HCV. Those co-infected with HIV/HBV or HIV/HCV may have a more rapid progression of liver disease, a tendency to respond less well to current hepatitis treatment and the course and management of HIV disease may be negatively impacted. Developing effective and better tolerated treatment strategies, vaccines and diagnostics remains an urgent need.

In recognition of the frequent occurrence of HIV related oral diseases, both in treated and untreated HIV infected individuals, the NIAID in collaboration with the National Institute of Dental and Craniofacial Research (NIDCR) seeks for the inclusion and implementation of an oral health research agenda, in which clinical interventions are linked to, and integrated within, the HIV/AIDS research priority areas. 

In summary, with the use of many classes of antiretroviral drugs, HIV has become a chronic disease with its own challenges. HIV-infected people are living longer and are experiencing conditions associated with aging at younger ages than non-infected individuals.  Thus, in addition to developing strategies for cure and/or functional cure, and mitigating sequelae of HIV-induced immune activation and chronic inflammation, it is essential to continue research both in the U.S. and internationally to discover and develop novel therapeutic agents with improved delivery, decreased toxicity, different resistance profiles and readily accessible to those at greatest need, as well as to test novel approaches and interventions to promote durable viral suppression including through sustained antiretroviral adherence.  Furthermore, as co-infection of HIV and tuberculosis has become common in limited resource settings and treating co-infection with HIV and viral hepatitis has gained importance in higher resource settings, new treatment modalities for these infections also are urgently needed. These needs have led NIAID to refocus the HIV/AIDS adult therapeutics research agenda.

The clinical research on therapeutics for HIV/AIDS and HIV-associated infections in adults will be conducted in HIV-infected individuals and, where informative to NIAID’s research priorities in this area, in HIV-uninfected individuals.

Research Priority Areas

NIAID has identified four overarching scientific priorities:

  • Identify strategies to cure and/or achieve a functional cure for HIV
  • Improve the diagnosis and treatment of tuberculosis, especially in those co-infected with HIV
  • Identify  strategies to cure infectious hepatitis
  • Improve the treatment of, or prevent, non-infectious co-morbidities and evaluate novel interventions targeting HIV Infection

Options for Scope of Application

The three linked applications must address all four of NIAID’s scientific priorities listed above. The scope of responsive research that will promote achieving the above scientific priorities includes, but is not limited to:

Cure and/or Functional Cure of HIV:

  • Evaluate new or combinations of therapies administered during acute infection to prevent establishment or reduce the size of reservoirs; and during chronic infection to promote clearance of reservoirs
  • Evaluate immune-based therapies (e.g. therapeutic vaccines), gene therapies and other novel interventions
  • Within context of clinical trials
    • Quantify viral reservoirs including assay validation
    • Evaluate new tools for viral reservoir quantification
    • Investigate host, viral or other factors that influence the size of viral reservoirs

This unique activity for a clinical trials network will require different skill sets, assays and types of trials than those required for the other scientific areas. 


Research may be conducted in HIV-infected or uninfected individuals.

  • Evaluate new drugs and combination treatments for drug sensitive and drug resistant TB
  • Develop improved TB/HIV co-treatment regimens
  • Evaluate point of care diagnostics (particularly for extra pulmonary disease) and rapid, accurate, inexpensive drug susceptibility testing
  • Develop more effective chemoprevention for drug resistant and multi-drug resistant TB within presence or absence of HIV infection
  • Evaluate prognostic biomarkers for disease progression, treatment response and immune reconstitution inflammatory syndrome
  • Investigate the pathogenesis of TB and HIV/TB co-infection using specimens from a treatment trial

Infectious Hepatitis:

Research may be conducted in HIV-infected or uninfected individuals.

  • Co-infected (HIV/viral hepatitis)
    • Evaluate new therapies for viral hepatitis treatment-naïve and treatment-experienced individuals
    • Evaluate new strategies for optimal timing and duration of treatment
    • Identify the viral characteristics and host factors affecting the course of disease using specimens from treatment trials
    • Evaluate non-invasive indicators of liver disease
  • Hepatitis mono-infected
    • Evaluate therapeutics and diagnostics
    • Evaluate new therapies for treatment-naïve and treatment-experienced individuals
    • Identify viral changes and host responses during the course of treatment or using specimens from a treatment trial

Non-infectious Co-morbidities/Novel interventions targeting HIV infection:

Non-infectious Co-morbidities

  • Study interventions that address the role of immune activation, inflammation, and immune senescence in the development of co-morbidities, the effect of these factors on CD4+ cell recovery, investigation of potential therapies targeting these factors
  • Within the context of clinical trials
    • Evaluate other chronic viral infections in relation to the immune activation and immune senescence seen in HIV infection and evaluate their impact on treatment success
    • Investigate host genetics, aging, and other factors that impact treatment response and disease trajectory

Novel interventions targeting HIV infection

  • Evaluate novel anti-HIV compounds and immune-based therapies (e.g. therapeutic vaccines)
  • Evaluate compounds aimed at ameliorating the effects of HIV infection
  • Evaluate highly innovative drug formulations and/or delivery platforms and research tools based on emerging technologies
  • Evaluate novel approaches and interventions to promote durable viral suppression including assays of long-term drug exposure where appropriate, and sustained antiretroviral adherence
  • Advance strategies to reduce transmission of HIV from infected individuals to uninfected individuals
  • Explore novel therapies that block the replication of HIV and oral opportunistic pathogens in oral mucosal (e.g., lymphoid and epithelial) tissues

The network’s research agenda in the required four areas described above will be peer reviewed, and post award, will be reviewed and potentially revised by NIAID staff to ensure optimal synergy with existing programs in the DAIDS and the Division of Microbiology and Infectious Diseases (DMID), particularly in the areas of TB and viral hepatitis. 

It is expected that treatment-related protocols will incorporate valid assessments of treatment adherence, strategies to promote adherence to clinical trial protocols and investigational therapies, and concurrent scientific expertise, where appropriate.

In relation to the HIV related oral disease research agenda, special emphasis will be placed on addressing: 1) oral immune activation (IRIS), oral inflammation and oral immune dysregulation; 2) oral mucosal lesions including oral fungal-, HIV- and viral-opportunistic infections as well as eradication of these infections from oral mucosal reservoirs; 3) viral-related tumors and malignancies of the oral cavity.

In addition, the network will be required to contribute to the scientific agenda and provide capacity for trials that support the development of vaccines against infectious diseases that impact populations burdened by HIV, primarily TB and hepatitis C virus. The scientific agenda for those efforts will be developed post-award through cross-network, joint leadership efforts in conjunction with DAIDS and DMID and should not be included here.

Application Requirements

The LG will be responsible for all network activities and will ensure that all the constituent parts of the network fulfill their respective responsibilities in the most efficient and effective manner possible. Each linked application of the LG (LOC, LC, and SDMC) is expected to demonstrate scientific leadership, effective management and efficient utilization of resources.

Leadership Time Commitment.  When a single PD(s)/PI(s) is proposed in any of the three LG applications, the PD(s)/PI(s) will be required to devote at least 6 person months effort to the project. Applications proposing multiple PD(s)/PI(s) are permitted, but the roles and responsibilities of multiple PD(s)/PI(s) should be clearly delineated and justified. If two or more PD(s)/PI(s) are named in any application, each PD(s)/PI(s) must devote at least 3.6 person months effort to the project. The governance and organizational structure of the LG leadership team and the research project should be described, including communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PD(s)/PI(s) and other collaborators.

Research Agenda.  The LG’s clinical research agenda should be clearly articulated and directly related to achieving NIAID’s scientific priorities.  The LG is required to monitor and evaluate the need to refine and revise the research agenda. As part of this process, the LG is required to actively engage and solicit input from researchers and HIV-affected communities.

Governance and Management.  The LOC, LC and SDMC, in their area of responsibility, must establish and define effective communication and decision making processes, identify clear lines of authority, and coordinate and collaborate effectively both within the network and with other NIH-supported networks or other Federal and private sector clinical research programs as appropriate to avoid redundancies and ensure efficiencies.  Governance or management by committees is permitted.  The governance and management should utilize effective approaches to project management, including project plans with identified key milestones; ongoing evaluation of projections against actual data and adjustments to project plans; and development and implementation of contingency plans. In addition, the LOC, LC and SDMC, in their area of responsibility, must establish processes to identify and resolve operational issues and develop training and education programs within the context of the network’s research agenda for network members, including new researchers, particularly from under-represented populations and those in low and middle income countries.

Bylaws, policies and standard operating procedures should not be included in the application, but must be provided, for approval, to NIAID within 90 days of Notice of Award.

Resource Utilization and Allocation.  The LOC, LC and SDMC, in their area of responsibility, must ensure optimal resource utilization and ensure that resource allocation supports the clinical research agenda.

Collaborative Responsibilities. The LG will be strongly encouraged to collaborate with other NIH-supported networks and other Federal and private sector clinical research programs, and to interact with government and non-government organizations, including the private sector, and committees to effectively develop and implement a clinically relevant, interdisciplinary and cost-efficient clinical research network. Such collaborations and interactions are essential for the development and implementation of a comprehensive research agenda that utilizes the strengths, experience and expertise of the various collaborating organizations. The sharing of expertise, resources and procedures is expected in key areas, including: development of clinical infrastructure in low-income countries; harmonization of laboratory resources and specimen management; harmonization of common data elements and data entry interfaces; community engagement, including development, training and support of community advisory boards. Examples of additional entities the LG will need to collaborate and/or communicate with include, but are not limited to: the NIAID Strategic Working Group (SWG), Scientific Review Committees (SRCs),  network LG Program Officers (NLGPOs) and Project Scientists, the DAIDS Enterprise System (DAIDS-ES), Office of Clinical Site Oversight (OCSO), the DAIDS Clinical Laboratory Oversight Team (DCLOT), the HIV/AIDS Network Coordination Office (HANC), other HIV/AIDS Clinical Research Network groups and the non-HIV/AIDS Research Network. 


Eligible Applicants
Eligible Organizations

Higher Education Institutions

  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

  • Hispanic-serving Institutions
  • Historically Black Colleges and Universities (HBCUs)
  • Tribally Controlled Colleges and Universities (TCCUs)
  • Alaska Native and Native Hawaiian Serving Institutions

Nonprofits Other Than Institutions of Higher Education

  • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
  • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

  • Small Businesses
  • For-Profit Organizations (Other than Small Businesses)


  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)
  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession


  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply. 
Non-domestic (non-U.S.) components of U.S. Organizations are  eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statementare  allowed.

Required Registrations

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) 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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 Application Guide.

When a single PD(s)/PI(s) is proposed in any of the three linked applications for the LG, the PD(s)/PI(s) will be required to devote at least 6 person months effort to the project. If two or more PD(s)/PI(s) are named in any application, each PD(s)/PI(s) must devote at least 3.6 person months effort to the project. 


NIH encourages inquiries concerning this funding opportunity and welcomes the opportunity to answer questions from potential applicants. 

Additional information and definitions of terms can be found at the following website:   

Application Submission Contacts

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939

Scientific/Research Contact(s)


Ellen DeCarlo, BSN
National Institute  of Allergy and Infectious Diseases (NIAID)
Telephone: 301-496-8212


Isaac Rodriguez-Chavez, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-7985


Shoshana Kahana, M.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-2261


Pim Brouwers Ph.D.
National Institute  of Mental Health (NIMH)
Telephone: 301-443-4526


May Wong, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1431

Peer Review Contact(s)

Peter R. Jackson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-496-8426       

Financial/Grants Management Contact(s)


Devon Bumbray-Quarles
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-6213


Mary Greenwood
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4808


Pam Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-253-8729


Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805


Tijuanna DeCoster, MPA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301- 496-9231