IMPACT OF HIV VARIATION ON IMMUNOLOGICAL RECOGNITION NIH Guide, Volume 26, Number 38, November 21, 1997 PA NUMBER: PA-98-011 P.T. National Institute of Allergy and Infectious Diseases PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), invites applications through this Program Announcement (PA) to support research to address the impact of HIV variation on immunological recognition. The objective is to foster investigations to provide information that will ultimately be useful for identifying the strain(s) of HIV that should be used for vaccine development. Increased understanding of the mechanism of HIV neutralization, identification of neutralization immunotypes, and understanding of the impact of viral variation on CTL recognition is sought. 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 PA, Impact of HIV-1 Variation on Immunological Recognition, is related to the priority area(s) of immunization and infectious diseases; HIV infection; sexually transmitted diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY Applications may be submitted by 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. Domestic and foreign institutions are eligible to apply for R01 grants. Foreign institutions are not eligible for FIRST (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grant (R01) and FIRST award (R29) applications may be submitted in response to this program announcement. Applicants for the FIRST award must comply with the NIH Guidelines for FIRST awards and the Just-in-Time procedures announced in the NIH Guide, Vol. 25, No. 10, March 29, 1996. Applications for R01 grants may request up to five years of support; applications for R29 grants must request five years of support. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. RESEARCH OBJECTIVES Background Antigenic variability of HIV has been identified as a major obstacle to AIDS vaccine development. The rapidly changing structure of HIV-1 envelope proteins may necessitate a series of AIDS vaccines tailored for the virus strain(s) prominent in a geographic area even though they change as the virus evolves with time. This genetic heterogeneity is reflected in changes in susceptibility to neutralization by given antisera or monoclonal antibodies, and may also affect immune recognition of the virus by T-cells. However, studies have also shown that there are conserved neutralization and cytotoxic T-lymphocyte epitopes shared by diverse isolates even across clades, suggesting the possibility that broadly cross-reactive vaccines could be developed. To study the potential impact of HIV variation on vaccine efficacy, the Division of AIDS has supported an HIV Variation Program consisting of two laboratories, one for genetic cloning and sequencing and another for isolation and neutralization analysis. Utilizing HIV isolates and blood samples derived from sites around the U.S. and the world, it has been shown that HIV-1 contains both type-specific and broadly cross- reactive neutralization epitopes. However, two developments have altered the kind of research that is now required to understand antigenic variation. First, the identification of co-receptors for HIV infection has significantly altered and advanced our concepts of blocking HIV infection with antibody and other humoral factors. Second, the greater realization of the potential role of CTL in protection widens the scope of antigenic variation to include T-cell epitopes. While the isolation/neutralization arm of the Variation Program was previously carried out under the contract mechanism, it is felt that future work on this theme, which remains essential to the design of an efficacious vaccine, would more effectively be carried out through investigator-initiated research. Research Objectives and Scope This initiative will fund basic research to explore the impact of variation on both humoral and cellular immune recognition. Examples of areas of research that examine the impact of HIV variation on immune recognition include, but are not limited to, the following: o Studies of humoral immune recognition designed to identify the specificity of the neutralizing components present [a] in high-titer HIV-1 (+) sera, and [b] in broadly cross-reactive HIV-1 (+) sera; o Studies to determine the epitopes and conformation of the HIV-1 antigen(s) needed to induce a high-titer and/or broadly cross-reactive neutralizing response; o Studies designed to determine if neutralization immunotypes exist for HIV, and to identify isolates representing each immunotype; o Analysis of the degree of conservation of CTL epitopes required to allow CTL from individuals infected with one clade of HIV to lyse MHC-matched cells infected with HIV of another clade; o Analysis of HIV T-cell epitopes recognized in different HIV clades by individuals of different HLA types, especially from international 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 are provided that inclusion is inappropriate with respect to the health of the subjects of 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", which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application for PHS 398 (rev. 5/95) and will be accepted on the standard application AIDS deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@od.nih.gov. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES". The PA number and the PA title must also be typed in section 2. The completed, signed original and five legible, single-sided copies of the application and five copies of appendices must be sent or delivered to: CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants) NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) FIRST ((R29) award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST award applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Applicants from institutions that have a General Clinical Research Centers (GCRC) funded by the NIH National Center for Research Resources may wish to identify the Center as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC Program Director must be included in the application material. REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR). Incomplete applications will be returned to the applicant without further consideration. Applications will be reviewed for scientific and technical merit by study sections of the CSR, in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other favorably recommended applications. The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance among research areas of the announcement, and availability of funds. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic (research scope and eligibility) issues may be directed to: James A. Bradac, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2A32 Bethesda, MD 20892-7640 Telephone: (301) 402-0121 FAX: (301) 402-3684 Email: jb68k@nih.gov Direct inquiries regarding fiscal matters to: Dianne E. Tingley, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C04 Bethesda, MD 20892-7610 Telephone: (301) 496-8206 FAX: (301) 402-2638 Email: dt15g@nih.gov AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citation is (No. 93.855 - Immunology, Allergy, and Transplantation Research [or] No. 93.856 - Microbiology and Infectious Disease Research [or] both of the preceding. Awards will be 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 review. The PHS strongly encourages all grant and contract 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 cases, 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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