Full Text AI-94-018 MECHANISMS OF AIDS PATHOGENESIS NIH GUIDE, Volume 23, Number 17, May 6, 1994 RFA: AI-94-018 P.T. 34 Keywords: AIDS Pathogenesis 0705048 National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: September 16, 1994 Application Receipt Date: November 16, 1994 PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) invites applications from single institutions or consortia of institutions for research project grants focusing on a hypothesis for AIDS-related pathogenesis. This Request for Applications (RFA) specifically solicits applications for in vivo research of AIDS-related pathogenesis utilizing state-of-the-art methods and approaches. In vivo research includes studies of human clinical or epidemiologic cohorts, of animal models, or of appropriate specimens from humans or animals. Research supported by this RFA is limited to one or more of three scientific areas: (1) non-human primate models of HIV immunopathogenesis, (2) sexual/mucosal transmission of HIV or SIV, and (3) host factors that modulate HIV or SIV infection or disease. Where scientifically justified, applicants are encouraged to include both human and animal studies. Although the research necessary to test a proposed pathogenesis hypothesis may be possible within a single laboratory, highly competitive applications may require separate components at the same or different institutions specializing in different scientific disciplines (e.g., molecular biology, biochemistry, cellular biology, cellular immunology, genetics and biophysics). HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Mechanisms of Aids Pathogenesis, is related to the priority area of HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit, public and private organizations, such as universities, colleges, hospitals,laboratories, units of State or local government, and eligible agencies of the Federal government. Successful applications from foreign institutions are limited to three years of support for direct costs; domestic applications may include international components, but these components will receive no support for indirect costs. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT Awards made under this RFA will use the National Institutes of Health (NIH) individual research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for applications submitted by domestic institutions may not exceed four years; the total project period for applications submitted by foreign institutions may not exceed three years. Applicants are strongly encouraged to coordinate, through the use of consortium arrangements or subcontracts, integrated approaches with individuals or institutions having relevant reagents and expertise in their use, demonstrated ability in a particular area of relevant research, or access to relevant animal or patient populations. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included in the application. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for awards under this RFA will be $6 million. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of the awards will vary also. The NIAID anticipates 8 to 16 awards under this RFA. It is the intent of the NIAID to fund applications in each of the three scientific areas described in RESEARCH OBJECTIVES below. The number of awards and the levels of support will depend upon the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Continued funding beyond the first and subsequent years of a grant will be contingent upon satisfactory progress and availability of funds. Applicants are encouraged to discuss budget requests with Division of AIDS (DAIDS) program staff (listed under INQUIRIES) prior to submission. Requests for expensive equipment are not encouraged. Investigators are encouraged to use animals efficiently and to minimize expenses for animal purchase and/or support. The purchase of animals must be strongly justified. This RFA is a one-time solicitation. Future competing continuation applications will compete with unsolicited investigator-initiated applications and be reviewed by an appropriate Study Section according to the customary NIH referral and peer review procedures. RESEARCH OBJECTIVES A. Background Non-Human Primate Models of HIV Immunopathogenesis Non-human primate models of HIV disease are vital tools for pathogenesis research. Where no single animal model satisfies all investigative requirements, comparison of data from multiple models may contribute to the understanding of the pathogenic aspects of HIV disease. The simian immunodeficiency virus (SIV) and chimeric SIV-HIV infections of macaques are well described. Clues to HIV pathogenesis also may be discovered from analyses of lentivirus-infected non-human primates in which there is little or no apparent disease, e.g., HIV-infected chimpanzees and African green monkeys infected with African Green Monkey (AGM) lentiviruses. Sexual/Mucosal Transmission The overwhelmingly predominant mode of transmission of HIV is through exposure of mucosal surfaces to infected sexual fluids (semen, cervical/vaginal, rectal) and during birth. However, epidemiological data suggest that sexual transmission, in general, is relatively inefficient, in that exposure does not always produce infection. Some individuals who are exposed to HIV via mucosal surfaces over prolonged periods remain seronegative. The likelihood of transmission is increased by factors that decrease the integrity of the mucosal epithelium. Epidemiologic studies have implicated sexually transmitted diseases that produce genital ulcerations or inflammation, use of intrauterine devices, and lack of male circumcision as cofactors facilitating HIV transmission. Studies in the SIV monkey model indicate that 100- to 1,000-fold more infectious virus is required to produce infection following application to intact genital mucosal surfaces than by intravenous injection. Studies of mucosal infection in the SIV model suggest that mucosal dendritic cells may be the first cells infected. Subsequently, infected dendritic cells may migrate to lymph nodes where they infect other cells. Host Resistance to Infection or Disease Genes that confer host resistance to retroviral infection in animals have been described and include both immune response genes and non-immune response genes. For example, the product of the Fv-1 allele prevents the development of leukemia in inbred mice infected with specific MuLV strains. Recent experimental evidence suggests that host genes may also modulate infection or disease caused by lentiviruses including HIV. In vitro evidence for the relative resistance of human T lymphocytes to HIV infection has been described. Resistance of PBMCs from individual monkeys to infection by SIV has also been observed and has been reported to be predictive of disease course. Investigation of these and other resistance mechanisms may reveal novel events in infection or replication of lentiviruses and could lead to novel prevention or therapeutic strategies. The NIAID Multicenter AIDS Cohort Study (MACS) has shown that the median time from infection with HIV to development of AIDS is approximately 10 years, although this time period is highly variable among different individuals. A small proportion of the cohort participants who seroconverted in the study developed AIDS and died within two or three years of HIV infection, while others have maintained stable, high CD4+ cell counts ten or more years following HIV infection. To date, no independent epidemiologic factor or set of host or viral factors has been identified that reliably predicts disease progression or a state of relative "immunologic non-progression" (as judged by CD4+ cell stability). Studies of host factors and other determinants of HIV infection and disease are needed to gain a better understanding of the pathogenesis of HIV. B. Goals The NIAID HIV/AIDS Research Agenda (October 1993) identified eight critical areas of research in HIV pathogenesis: o molecular biology of viral and cellular processes; o cellular biology and immunology related to the course and dynamics of HIV infection; o viral genetic and phenotypic correlation with disease; o host factors affecting infection and/or progression; o external factors affecting infection and/or progression; o mechanisms of HIV-related immunodeficiency; o animal models of HIV infection and/or pathogenesis; and o mechanisms of sexual transmission and mucosal immunity. Reviews of the DAIDS pathogenesis programs by an ad hoc committee and by the AIDS Research Advisory Committee (ARAC) concurred with these eight critical areas of research and recommended that three receive particular emphasis, specifically: non-human primate models of HIV immunopathogenesis, sexual/mucosal transmission of HIV or SIV, and host factors that modulate HIV or SIV infection or disease. The reviews strongly encouraged NIAID to promote studies of in vivo pathogenesis in these areas utilizing state-of-the-art in vitro approaches. This RFA is intended to foster applications for integrated, multi-disciplinary pathogenesis research linking in vitro studies to in vivo disease and focusing specifically on these three scientific areas. The most relevant studies are expected to examine molecular and cellular biology, virology, and immunology within the context of animal models and/or well-defined human cohorts or patient samples. C. Research Scope Research grant applications responsive to this RFA should provide innovative focused approaches to test a hypothesis of HIV pathogenesis in non-human primate models, HIV or SIV sexual/mucosal transmission, or host factors that modulate HIV or SIV infection or disease. The NIAID anticipates that investigators will propose studies testing hypotheses using state-of-the-art methods on specimens from human and/or animal models. Although the research necessary to test a proposed pathogenesis hypothesis may be possible within a single laboratory, highly competitive applications may require separate components at the same or different institutions specializing in different scientific disciplines (e.g., molecular biology, biochemistry, cellular biology, cellular immunology, genetics, and biophysics). If applicable, applicants are encouraged to select component leaders based on scientific excellence rather than proximity. If multiple components are proposed, the interactive role of each component in investigating the hypothesis should be described. The following are examples of major issues or gaps in knowledge in the three RFA scientific areas that were identified in the NIAID HIV/AIDS Research Agenda: Pathogenesis In Humans And Non-Human Primates o Course of infection (infected cells, non-productively infected cells, virus production, altered biology of infected and uninfected cells) in different organ systems (blood, thymus, lymph nodes, gastrointestinal tract, bone marrow, spleen, nervous system, etc.) from early to systemic disease. o Clinical course and mechanisms of disease following infection with viruses of differing tropisms (macrophage, T-cell, neurotropic), high/low replication properties, or syncytium /non-syncytium inducing abilities. o Role of accessory viral genes (vif, nef, vpu, vpr, etc.) in infection, cellular tropism, and disease progression in vivo. o Steps in T-cell development and/or regulation that are affected by lentivirus infection and the lentivirus genes or gene products that are responsible. o Mechanisms of defects in T-cell signalling in uninfected and SIV (SHIV or HIV) infected cells. o Differences in pathogenesis between control and treated infected non-human primates in ongoing (already funded) therapeutic and vaccine SIV or SHIV studies. HIV or SIV Sexual/Mucosal Transmission o Mechanisms of mucosal transmission by free virus, cell-associated virus, or both. o Genetic composition of HIV in the donor compared to HIV phenotype/genotype that is sexually transmitted to the recipient. o Types of cells initially infected (i.e., lymphocytes, macrophages, and dendritic cells). o Mechanisms, time course, and pathways of viral spread from site of initial infection. o Differences, if any, in the mechanisms of establishment of HIV infection by rectal, vaginal, oral, or other mucosal routes. o Host mechanisms operative at mucosal surfaces that protect exposed individuals from HIV infection. o Role of co-factors other than STDs in facilitating or hindering mucosal transmission in vivo. Host Factors that Modulate HIV or SIV Infection or Disease o Mechanisms for differences in susceptibility of cells from different hosts to HIV or SIV infection in vitro. o Identification of host genes (alleles) and/or factors that prevent or enhance infection, resistance to infection, and/or disease progression. Investigations of variations in normal immune response are not included under this topic. o Mechanisms by which host factors prevent or enhance infection, provide resistance to infection, and/or disease progression in vitro and in vivo. o Mechanisms by which primates are resistant to lentivirus disease; i.e., chimpanzees infected with HIV and African Green monkeys infected with AGM virus. o Mechanisms responsible for observed variations in susceptibility to HIV or SIV infection and/or rates of progression in different individuals. o Comparison of known mechanisms of resistance to retroviruses in non-primates (mice, chickens, etc.) with observations in primates. D. Restrictions and Exclusions Descriptive, non-hypothesis driven, research is not within the scope of this RFA. For example, natural history epidemiologic studies in many DAIDS-supported cohorts are critically important for collecting information on cause and course of disease. The information provided by such studies may provide a foundation for hypotheses that may be tested in research supported by this RFA. This RFA is intended to support the next step in research, the testing of these hypotheses. This initiative will not support drug or vaccine trials in animals or humans. Proposed studies should minimize expenses for animal support and maximize the use of animals in ongoing non-human primate research. For example, the applicant may be able to coordinate SIV pathogenesis projects with DAIDS-supported vaccine or drug development studies in macaques. The applicant is responsible for establishing components and/or collaborative arrangements. A list of Principal Investigators who have access to non-human primates in NIAID-sponsored research is available from DAIDS program staff (see INQUIRIES) upon request, but these investigators are under no obligation to collaborate with RFA applicants. Clinical trials involving the recruitment or retention of cohorts will not be supported under this RFA. However, costs for patient visits, sample storage, and handling specific to the applicant's proposed research are appropriate. Analyses of samples acquired from epidemiologic or clinical trials are also appropriate. Proposed studies should maximize the use of epidemiologic or clinical cohorts in ongoing research to minimize expenses. A list of Principal Investigators who have access to epidemiologic or clinical cohorts in NIAID-sponsored research will be available from DAIDS program staff (see INQUIRIES) upon request, but these investigators are under no obligation to collaborate with RFA applicants. Special Requirements A. Travel -- NIAID AIDS Pathogenesis Meeting Principal Investigators and other key members of the projects will be requested to attend an annual NIAID AIDS Pathogenesis Meeting, a grantees of the Mechanisms of AIDS Pathogenesis RFA, to be held each year at a site designated by NIAID (Bethesda, Maryland is anticipated). Principal Investigators and component leaders will be requested to present significant findings in symposium format. Data are to be selected by the individual presenters in consultation with their Principal Investigator thus affording appropriate protection of proprietary or commercially sensitive information. At the discretion of the DAIDS program staff, other investigators may also be invited to attend. Funds for the Principal Investigator and key scientific personnel to travel to these meetings should be included in the application budget. For budgetary purposes, applicants should anticipate lodging for three nights in the Bethesda, Maryland area (estimated food and lodging costs for 1994 = $158/night) and travel at economy airfares. B. No Initial Review Site Visit One important factor that should influence the care and detail with which applications in response to this RFA are prepared is a long-standing NIAID policy that there will be no site visits in the initial review of applications. Peer reviewers will base their comments and recommendations solely on the written application, which must be complete and prepared according to the RFA guidelines. Applicants are strongly encouraged to discuss research plans and organizational structure with DAIDS program staff in the early stages of preparation of the application. (See program contact list in INQUIRIES.) STUDY POPULATIONS 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 is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 9, 1994 (FR 59 11146-11151), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.] Investigators may obtain copies of the policy from program staff listed in INQUIRIES, who may also provide additional information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by September 16, 1994, a letter of intent that includes a descriptive title of the project; the names, addresses, telephone numbers, and EMAIL addresses (if available) of the Principal Investigator, component leaders, and other key personnel; the names of the primary institution and component institutions (if different); and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of the application, the information that it contains is helpful in planning for the review of expected applications. It allows NIAID to estimate the potential workload for reviewers and to avoid possible conflict of interest in the review process. The letter of intent is to be sent to Dr. Diane Tingley at the address listed under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on form PHS 398 (rev. 9/91), the standard application form for research grants. Application kits are available at most institutional offices of sponsored research and may also be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267. Applicants must adhere to the format and requirements specified in the PHS 398 application kit. For purposes of identification and processing, mark "YES" in item 2a on the face page of the application and type in the RFA number AI-94-018 and the title "MECHANISMS OF AIDS PATHOGENESIS." The RFA label available in the form PHS 398 must be affixed to the bottom of the face page of the original application. Failure to use this label could delay the processing of the application such that it may not reach the review committee in time for review. Questions regarding the format for submission of an R01 package may be directed to the staff person listed under INQUIRIES. Submit a signed, typewritten original of the application, including the Checklist, and three exact, signed, single-sided photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission two additional copies of the application and five sets of appendices and reprints must also be sent to Dr. Dianne Tingley at address listed under INQUIRIES. To ensure their review, applications must be received by both the Division of Research Grants (DRG) and Division of Extramural Activities by November 16, 1994. Applications not received by the receipt date will be considered non-responsive and will be returned to the applicant without review. If the application submitted in response to this RFA is substantially similar to an application that has already been submitted to the NIH but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of essentially identical applications is not allowed nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been 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. REVIEW CONSIDERATIONS A. Review Procedures Applications will be reviewed by DRG staff for completeness and by NIAID staff for administrative and programmatic responsiveness to this RFA. To be considered responsive, the application must be directed towards the attainment of the stated programmatic goals (see RESEARCH OBJECTIVES). Therefore, applicants are encouraged to discuss their research plans with program staff before completing their applications. Those applications judged to be incomplete or nonresponsive will be returned to the applicant without review. Those applications that are complete and responsive may be subjected to a triage to determine their scientific competitiveness relative to the other applications received in response to this RFA, based on the review initial described below. The NIAID will remove from further competition those applications judged to be noncompetitive for award and will notify the applicant and institutional business official. Those applications judged to be competitive for award will be further reviewed for scientific and technical merit by a review committee convened by the Scientific Review Branch, Division of Extramural Activities, NIAID. A second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. In the event of multiple highly qualified applications, final funding recommendations will be based on program priorities. B. Review Criteria The factors, to be considered in evaluating the scientific merit of each application are: 1. Adequacy of preliminary data leading to the hypothesis of the proposed research including the adequacy of data for component studies. 2. Clarity and significance of the hypothesis to be tested. 3. Relationship of the Specific Aims to the hypothesis, e.g., o Will accomplishment of the Specific Aims provide significant proof or refutation of the hypothesis? o Does the application justify additional components to fulfill the Specific Aims? o Are necessary components included in the application? 4. Integration of in vitro and in vivo approaches and of components. 5. Innovativeness and technical merit of the experimental approach. 6. Availability and acquisition of clinical specimens (tissues/biological fluids), and cost savings achieved by utilization of resources not funded through this application. Documentation of the availability of the specimens. 7. Efficient use of animals, and utilization of animal resources not funded through this R01 application. Documentation of the availability of animals or animal specimens. 8. Adequacy of resources and environment including of biohazard containment facilities if relevant. 9. Documented research experience, accomplishments, and other qualifications of the principal Investigator, key personnel, and technical personnel in the proposed research areas. 10. Time commitment of the Principal Investigators (and Component Investigators) to conduct the proposed research; AWARD CRITERIA The number and specific amounts of awards to be made will depend upon the following: o Results of the initial scientific and technical merit review; o Potential contribution of the proposed research to the goals and objectives of the RFA; o Program balance within the three areas of research; and o Availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct written, telephone, or electronic mail (EMAIL) inquiries regarding scientific and responsiveness issues to: Dr. Gregory Milman Division of AIDS National Institute of Allergy and Infectious Diseases Solar Building, Room 2B35 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8378 EMAIL: MAPS@EXEC.NIAID.PC.NIAID.NIH.GOV Direct letters of intent, inquiries regarding the scientific review process and format of applications, and two copies of the application including five sets of appendices and reprints, to: Dr. Dianne Tingley Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard Solar Building, Room 4C16 Bethesda, MD 20892 Telephone: (301) 496-0818 EMAIL: MAPS@EXEC.NIAID.PC.NIAID.NIH.GOV Direct inquiries regarding fiscal matters and budget format to: Ms. Jane Unsworth Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard Solar Building, Room 4B22 Bethesda, MD 20892 Telephone: (301) 496-7075 EMAIL: MAPS@EXEC.NIAID.PC.NIAID.NIH.GOV Schedule Letter of Intent Receipt Date: September 16, 1994 Application Receipt Date: November 16, 1994 Scientific Review Date: March 1995 Advisory Council Date: June 1995 Earliest Award Date: Sep 1995 and/or Nov - Dec 1995 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, 93.856 - Microbiology and Infectious Diseases Research and 93.855 - Immunology, Allergy and Transplantation Research. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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