WOMEN’s HIV PATHOGENESIS PROGRAM Release Date: April 5, 2000 RFA: HD-00-006 National Institute of Child Health and Human Development Letter of Intent Receipt Date: June 1, 2000 Application Receipt Date: July 12, 2000 PURPOSE The National Institute of Child Health and Human Development (NICHD) invites program project (P01) grant applications to conduct focused research on the pathogenesis of HIV-1 infection in women. A Women’s HIV Pathogenesis Program will be established to address gender-specific research on HIV pathogenesis and women. The purpose of this Program is to increase our understanding of the causal relationships between HIV-1 pathogenesis and factors unique to women, such as their reproductive physiology. Studies conducted within the Program projects will focus on identification of gender-specific biological factors that could impact on HIV-1 transmission, disease acquisition and manifestations in women. Applications in response to this solicitation should be multidisciplinary in scope. Within the research program as a whole, NICHD plans to address these pathogenesis research questions in a variety of female populations, including minority women, substance abusers, perimenopausal women, and lesbian women. Indeed, since the vast majority of the women infected in the United States are black or Hispanic, these studies will be directed primarily at answering questions in minority populations. The results of the studies supported through this initiative are anticipated to have practical implications for improving the care of HIV-infected women. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This RFA is related to several priority areas. Potential applicants may obtain "Healthy People 2010" at http://www.health.gov/healthypeople. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible to apply, but units collaborating with applicants may be located at foreign sites. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Potential applicants are encouraged to contact the program staff listed under INQUIRIES prior to submission. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) program project grant (P01) award mechanism. Responsibility for the planning, direction, and execution of the proposed projects will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The P01 supports broadly based multidisciplinary research programs that have a well-defined central research focus or objective. An important feature is that the interrelationships among the individual projects will result in a greater contribution to the overall program goals than if each project were pursued independently. The program project grant requires a minimum of three interrelated individual research projects that contribute to the overall program objective. The application may request support for certain common core resources. Complete guidelines for the NICHD Program Project Grant are available at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. These guidelines must be followed in preparing applications in response to this RFA. FUNDS AVAILABLE The NICHD intends to commit approximately $3.5 million Total Costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2001 to fund three to four new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $750,000 in the first year, excluding F & A costs on consortium arrangements. Annual budgets for Years 02 to 05 should not exceed the first year budget plus a three percent yearly increase. Equipment requests are discouraged and must be well justified. Because the nature and scope of the research proposed may vary, it is anticipated that the size of awards also will vary. Although the financial plans of the NICHD provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. RESEARCH OBJECTIVES Background In the U.S. and worldwide, HIV-1 infection in women is increasing in incidence. Worldwide, 90 percent of new HIV-1 infections are now transmitted through heterosexual intercourse. In the U.S., women of color are disproportionately affected. Of women recently diagnosed with AIDS, 81 percent are black or Hispanic. Data are continuing to emerge that suggest or demonstrate that some aspects of HIV-1 disease in women, including routes of transmission, differ markedly from those in men. The gender-specific features of HIV-1 infection in women, such as later diagnosis of infection, cervical disease, and disease progression with lower viral loads, among others, require special attention. To date, two major efforts have addressed the questions relevant to women with regard to HIV infection and disease. In 1993, to carry out epidemiology-based investigations on the impact of HIV infection in women, the NIH established the Women’s Interagency HIV Study (WIHS). A similar effort was coordinated by the U.S. Centers for Disease Control and Prevention (CDC) as the HIV Epidemiology Research Study (HERS). A related program announcement (PA-97-105) offered investigators an opportunity to collaborate with WIHS investigators in conducting studies of HIV pathogenesis within the WIHS cohort. The purpose of this RFA is to complement the current epidemiological studies and other research in the area of HIV-1 and women. There are many pathogenesis questions that require additional resources beyond that possible under existing mechanisms. Additionally, there are presently no clinical trials systems that integrate research on the social and behavioral issues that could influence the outcome of pathogenesis studies. In 1996, pilot studies were undertaken for laboratory-intensive investigations nested within the epidemiology cohorts. Several institutes [NICHD, the National Institute of Dental and Craniofacial Research (NIDCR), and the National Institute of Allergy and Infectious Diseases (NIAID)] funded these studies through a variety of mechanisms. The pilot studies focused on HIV pathogenesis in women, including factors affecting HIV-1 shedding in the genital tract, oral cavity, and other compartments, and the effect of the menstrual cycle on virologic and immunologic parameters in HIV-infected women. Additionally, some aspects of gender-specific research relevant to this RFA were discussed at a satellite workshop during the Retrovirus meetings held in 2000, sponsored by the NIH Office of AIDS Research, NIAID, and NICHD. The summary of this workshop is available at http://www.nichd.nih.gov/rfa/hd-00-006/hd-00-006.htm. The program projects to be established through this RFA are intended to create a more formal infrastructure for the next generation of investigator- driven pathogenesis studies in HIV-infected women. The program project mechanism was selected because it is ideal for combining multiple clinical and basic component projects with a central theme, focus or objective, and for fostering interactions and collaborations between basic and clinical scientists. Furthermore, the nucleus of multidisciplinary scientists in each program project will provide a fertile environment for cross-training basic and clinical scientists. Research Scope The Program is intended to establish and foster ongoing productive relationships between clinical and laboratory investigators in the area of women"s HIV pathogenesis. Research in the area of the pathophysiology of HIV in women has been limited. The effect of the reproductive health of women on disease presentation, diagnosis, and acquisition is largely unknown. The relationship of immune decline in women and conditions such as female genital tract and reproductive organ infections needs to be determined. There is limited information on the effect of therapy or prevention on gender-specific aspects of HIV infection and disease manifestation. Conditions such as esophageal candidiasis and bacterial pneumonia that occur more frequently in women than in men may have a differential impact on immune function and decline. The interaction of unique gender-specific social and behavioral attributes, including maternal stress factors, on disease manifestation, progression, diagnosis, and pathophysiology is also unknown. Knowledge about gender-specific variation in biological markers for diagnosis, patient monitoring, and understanding pathophysiology is limited. The causal relationships between HIV pathogenesis and factors unique to women need to be addressed. The Program is not intended to be a cohort study, however, study subjects may be recruited from existing cohorts. The goals of the program projects will be to: (1) recruit women (nationally and, where necessary, internationally) from all racial and ethnic groups, ages, HIV exposure groups, and lifestyles, (2) establish productive working relationships between clinical and laboratory investigators, and (3) where appropriate, be capable of making comparisons, both prospectively and retrospectively, with male control groups. Similarly, these program projects are not intended to address HIV treatment as a primary end-point. However, there may be occasions where randomization of patients will be necessary to address a pathogenesis question in order to understand an association more fully in terms of what is the cause and what is the effect. Examples of research topics that might be addressed in the application include, but are not limited to: 1. Effects of endogenous and exogenous hormones on HIV-related immunologic and virologic factors in the plasma and female genital tract, as well as other aspects of the biology of HIV infection in women. Research may include, for example: o Study of the combined effects of exogenous hormones [hormone replacement therapy (HRT), contraceptives] and antiretroviral therapy. o Generation of normative data regarding differences in the total number of lymphocytes, lymphocyte turnover/distribution, and impact of hormonal cycles on both viral and cellular dynamics. o Comparative studies between different age groups of HIV-infected women to assess the effect of natural hormonal changes on virologic and immunologic parameters of infection. 2. Interrelationships among the factors determining HIV detection in the genital tract micro-environment, including antiretroviral therapy, cytokines, bacterial flora and co-infections, hormones, epithelial integrity, and local antibody production. Research may include, for example: o Determination of the origin and impact of viral dynamics in the blood and at the tissue level. o Studies designed to elucidate the fundamental underlying mechanisms of estrogen, progesterone, and other hormones on HIV replication in the genital tract. 3. Effects of spermicides/microbicides on HIV detection in the genital tract, with some emphasis on studying effects on local milieu. These studies may be designed to complement larger Prevention Trials Network studies. Research may include, for example: o Study of the effect of treatment and/or prophylaxis on the microenvironment and on the virologic and immunologic parameters associated with HIV. 4. The factors and mechanisms determining the manifestations of HIV in the oral cavity and reproductive tract and other body compartments, and its ability to persist at latent reservoir sites despite potent antiretroviral therapy. Research may include, for example: o Study of the relationship between cell-free and cell-associated virus in various reservoirs and the possible variation of this relationship over time. Attention should be directed to examination of the factors that influence this relationship. o Development and evaluation of new sampling and/or quantitative technologies for measurement of HIV in potential reservoirs. o Study of the interrelationships between and among antiretroviral therapy, development of resistance, sequence diversity and local drug levels, and their impact on genital HIV. Studies might also focus on examination of these same factors and their impact on HIV in other protected sites. The topics listed above are only examples, are not in priority order, and are not intended to be all-inclusive. Investigators are encouraged to explore and develop new, innovative projects and research cores that are consistent with the overall objectives of this RFA. In addition to the primary focus on pathogenesis, the program projects will provide opportunities to implement studies of behavioral variables that could affect the measured primary outcomes. Such studies might include methods to improve recruitment and retention of participants, and examination of the impact of participation in the proposed projects upon individuals behavior change. Applicants are encouraged to work with existing epidemiology and clinical trial networks that have access to women, nationally and internationally, to complement ongoing research within the scientific agendas of those networks. Where appropriate, applications may propose research questions that would be answered by the program projects in collaboration with other pre-existing research groups. SPECIAL REQUIREMENTS Applications submitted in response to this RFA should be prepared in accordance with the instructions presented in the NICHD Program Project (P01) Guidelines, available at http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. Required Application Components The proposed program projects should include a minimum of three interrelated research projects and supporting core resources, including (1) a Clinical Core, consisting of infectious disease specialists, obstetrician/gynecologists, endocrinologists, epidemiologists, behavioral and social scientists, and/or other clinical researchers capable of recruiting, retaining, and studying HIV-infected women in complex protocols that address critical HIV pathogenesis research questions, (2) a Laboratory Core, composed of virologists, immunologists, pharmacologists, geneticists, pathologists, and/or other laboratory scientists with experience in basic science and the complex methodologies necessary to address questions of HIV pathogenesis, and (3) an Administrative Core composed of statisticians, programmers, and technical specialists, responsible for assisting in protocol implementation, monitoring, training, data management and analysis, and operational activities such as protocol development. Each application must include all components, however, one or more of the components may be located at collaborating institutions (see below). The disciplines to be included in the cores, as mentioned above, are examples of the types of expertise needed, proposed cores need not include representatives of all disciplines listed. For the purposes of this RFA, each core must be utilized by at least two component projects at all times during the period of award. This is an exception to the NICHD P01 Guidelines stating that each core should be utilized by three or more component projects. Collaborative Arrangements Two or more institutions that can demonstrate a credible plan for collaborative research may apply as a consortium. Evidence of prior collaboration and/or a plan for proposed collaborations between the clinical and laboratory investigators should be cited. A multi-institutional network application must be submitted by one applicant organization that will receive any resultant award. The application must provide details of agreements regarding sub-contracting arrangement, coordination, and support of activities at and among participating institutions, and must demonstrate the potential effectiveness of such a sub-network for the ongoing work of the program project. Research groups that have already established strong clinical/laboratory connections focusing on women-specific issues are encouraged to apply. It is also possible that these program projects would forge linkages to the various adult clinical trial networks and/or might conduct investigations of their own to facilitate or inform clinical trials. Applicants who have developed international relationships to augment existing national programs are encouraged to apply as one unit, combining a U.S. and a foreign component. Although the primary thrust of research carried out by the program projects will be domestic, some of the research questions of interest may benefit from an international component. However, the Principal Investigator of such a collaborative application must be based in the U.S. and the major focus of the application should be on scientific issues of general applicability, including women in the United States. Minimum Requirements for Applicants Applicants must have access to infectious disease specialists, obstetrical and gynecologic off protocol care, such as colposcopy, childcare, and case management workers capable of addressing the complex needs of the affected population. All applicants are expected to propose specific research projects that maximize the advantages of the applicant"s site, i.e., their patient population, previous research experience, and existing clinical and laboratory investigator networks. Clinical Core Requirements The clinical core should be multidisciplinary in scope, including both biomedical and, where appropriate, behavioral scientists, and demonstrate the ability to recruit and retain women for complex pathogenesis-based studies, that may or may not integrate a behavioral component. Individual units may develop special emphasis pilot projects related to their area of expertise or the nature of their patient population, e.g., substance abusers, women who have sex with women, older infected women. Clinical cores are expected to propose a Clinical Director, in one of the subspecialties (infectious disease, obstetrician/gynecologists, endocrinologists, epidemiologists, behavioral and social scientists) who has a primary role in providing care to HIV-infected women, who has access to the women referred to, and who has a strong interest in defining, developing, and implementing laboratory-based, focused pathogenesis studies in HIV-infected women. Investigators who have access to cohorts of HIV-infected women through multiple funded networks, including, but not limited to, AIDS Clinical Trials Groups, Women"s Interagency HIV Study, Community Program for Clinical Research on AIDS, HIV Epidemiology Research Study, Women"s and Infant"s Transmission Study, Prevention Trials Network, and other NIH- and Public Health Service-sponsored cohorts are encouraged to apply. Laboratory Core Requirements The laboratory core should include a multidisciplinary team of basic science investigators with a documented ability to develop and address HIV pathogenesis. Laboratory cores are also expected to propose a Laboratory Director who has expertise in laboratory analysis procedures including tests specific to women, who has had access to samples from women, and who has an interest in defining laboratory-based pathogenesis studies in HIV-infected women. In-house expertise is required in handling non-routine specimens, such as processing and analyzing genital tract specimens, breast milk, tears, or saliva. Applicants must demonstrate the ability for the laboratory core to maintain a close cooperative relationship with clinical investigators, particularly with regard to obtaining, processing, and shipping of clinical specimens. Applicants must document plans to utilize novel assays they may develop in the context of the project’s gender-specific research agenda, efficiently and accurately report results, and perform quality assurance on the procedures employed in the laboratory. While it is anticipated that the laboratory cores of the program projects will include virologists, immunologists, pharmacologists, geneticists, pathologists, and/or other laboratory scientists, it is not expected that each core will have expertise in all of these areas. Annual Meetings The Program Director for the overall grant and the principal investigator for each component project should plan to attend an annual NIH-sponsored two-day meeting in Bethesda, MD. These meetings will be attended by investigators supported through this RFA and will provide an opportunity for investigators to communicate, discuss the progress of their research, exchange ideas and information, share resources, and foster collaborations that are relevant to the research goals of the NIH women’s pathogenesis initiative. This requirement is designed to establish an interactive network of investigators who are interested in multidisciplinary approaches to enhancing our understanding of the pathogenesis of HIV infection in women. Applications should include a request for funds to support attendance of the Program Director and project principal investigators at the annual meetings, as well as a statement of agreement to participate in these meetings and to cooperate with investigators at other program project sites. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research, published in the Federal Register of March 28, 1994 (FR 59 14508- 14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, and available at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and/or ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects, published in the NIH Guide for Grants and Contracts, March 6, 1998, and available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policies. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this RFA. Although the letter of intent is not required, is not binding, and is not a factor in the peer review of the application, the information it contains is helpful in planning for the review of applications. It allows NICHD staff to estimate the potential review workload and to avoid conflict of interest in the review process. The letter of intent is to be sent to Dr. Patricia Reichelderfer at the address listed under INQUIRIES by June 1, 2000. APPLICATION PROCEDURES The research grant application form PHS 398 (rev.4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, on the Internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone (301) 710-0267, E-mail: grantsinfo@nih.gov. Application Instructions Applicants for P01 grants must follow special application guidelines in the NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998) that is available from NICHD program staff listed under INQUIRIES, below, and on the Internet at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. These guidelines contain important information on the suggested format of applications and on review criteria. Submission Instructions The RFA label available in the PHS 398 (rev. 4/98) application form must be stapled to the bottom of the face page of the application and must display the number of this RFA, HD-99-006. A sample modified RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note that this is in pdf format. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA MD 20892-7710 BETHESDA MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all five sets of any appendices should be sent to: L.R. Stanford, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Blvd., Room 5E03, MSC 7510 Bethesda MD 20892-7510 Rockville MD 20852 (for express/courier service) Telephone: (301) 496-1485 Applications must be received by July 12, 2000. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This policy is intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Program Director and applicant institution. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NICHD. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Child Health and Human Development Council. Applicants will not be reviewed by a site visit. REVIEW CRITERIA For program projects, peer review of scientific and technical merit focuses on three areas: (1) review of the individual component projects, 2) review of the individual cores, and (3) review of the program as an integrated effort and the overall merit of the program. The review criteria to be used to evaluate applications submitted in response to this RFA are presented in APPENDIX II, GUIDELINES FOR REVIEWERS COMMENTS, of the NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998), available at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. SCHEDULE Letter of Intent Receipt Date: June 1, 2000 Application Receipt Date: July 12, 2000 Peer Review Date: September/October 2000 Advisory Council Review: January 2001 Earliest Anticipated Award Date: February 12, 2001 AWARD CRITERIA Criteria that will be used to make award decisions include scientific and technical merit as determined by peer review, programmatic priorities and relevance, program balance, and the availability of funds. INQUIRIES Applicants are strongly encouraged to contact program staff early in application development with any questions regarding the responsiveness of their planned application to the goals of this RFA. Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Frequently asked questions and additional resources for applicants will be made available at http://www.nichd.nih.gov/rfa/hd-00-006/hd-00-006.htm. Direct inquiries regarding programmatic issues to: Patricia Reichelderfer, Ph.D. Contraception and Reproductive Health Branch National Institute of Child Health and Human Development 6100 Executive Blvd., Room 8B13G, MSC 7510 Bethesda MD 20892-7510 Telephone: 301-496-1661 Fax: 301-480-1972 E-mail: pr20f@nih.gov Direct inquiries regarding fiscal matters to: Michael J. Loewe Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17J, MSC 7510 Bethesda MD 20892-7510 Telephone: 301-435-7008 Fax: 301-402-0915 E-mail: ml70m@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.864. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the inter-governmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some case, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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