HIV CO-RECEPTORS IN THE CNS Release Date: January 29, 1999 PA NUMBER: PA-99-056 P.T. National Institute of Mental Health National Institute on Drug Abuse National Institute of Neurological Disorders and Stroke PURPOSE The purpose of this initiative is to stimulate research to increase understanding of the role of fusin co-factors in HIV infection of the CNS and to identify and develop analogs and related compounds of these co-factors as potential therapeutic agents. Recent evidence indicates that several members of the chemokine receptor family act as co-receptors for HIV infection. These distinct molecules show specific cytotropisms for different HIV isolates. This raises questions about transmission and pathogenesis, and identifies new potential targets for therapeutic intervention. The primary infected cell within the CNS is the microglia, although a low level of infection of astrocytes is evident. HIV infection of microglia is CD4-dependent, and occurs primarily with macrophage tropic HIV isolates. However, infection of astrocytes as well as other neural-derived cells is CD4-independent. Interaction of specific regions of HIV envelope with cells in the CNS may be responsible for the development of HIV-associated dementia in some infected individuals, although specific determinants mediating this dementia have not been identified. It also has been demonstrated that opioids interact with chemokines indirectly, possibly through interactions at the level of opioid and chemokine receptors. This is a likely mechanism for the observed effects of opioids on the growth of HIV within microglia within the brain. This Program Announcement solicits research on co-factors involved in HIV infection of cells within the CNS, what role these co-factors may play in disease pathogenesis, and how they may serve as targets for therapeutic interventions. 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 Program Announcement (PA), HIV Co- Receptors in the CNS is related to the priority area of HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Mechanisms that will be supported by this initiative are research project grants (R01) and program projects (P01). Because program projects grants (P01) have special application formats, and review criteria, applicants are strongly encouraged to consult with program staff (listed under INQUIRIES) and to obtain the appropriate additional announcements for those grant mechanisms. RESEARCH OBJECTIVES Summary It is well established that HIV invades the CNS, frequently within weeks of infection. Neurons are not infected, but rather productive infection of the brain occurs primarily via blood-derived macrophages and resident microglia. Recent evidence indicates that several members of the chemokine receptor family are used as co-receptors for HIV infection. These distinct molecules show specific cytotropisms for different HIV isolates. This raises questions about transmission and pathogenesis, and identifies new potential targets for therapeutic intervention. The primary infected cell within the CNS is the microglia, although a low level of infection of astrocytes is evident. HIV infection of microglia is CD4-dependent, and occurs primarily with macrophage tropic HIV isolates. However, infection of astrocytes as well as other neural-derived cells is CD4- independent. Interaction of specific regions of HIV envelope with cells in the CNS may be responsible for the development of HIV-associated dementia in some infected individuals, although specific determinants mediating this dementia have not been identified. Normal neuronal function requires the interaction of the neuron with the glial cells within its environment, much of which is mediated through cytokine/receptors interactions. The use of these receptors by HIV may interrupt this delicate balance of cellular communication. Research solicited by this Program Announcement include, but are not limited to, the following topics: o the identification of co-receptors that are expressed in the CNS and on the cell types on which they are expressed, o the primary HIV-1 strains that can be cultured and typed from the CNS and whether these strains use chemokine or other co-receptors, o the mechanism by which chemokine, drugs, or other co-receptors contribute to HIV infectivity of CD4 negative CNS cell types, o the function of chemokine receptors in the CNS under control conditions, and how their use by HIV impacts on this function, o how co-receptors contribute to viral tropisms switching, o which chemokine receptors expressed by microglia and astrocytes in vitro act as receptors for HIV, and whether they are sufficient or necessary, whether they work in concert with other molecules that bind HIV or are, in fact, co-receptors, o how chemokine/receptor interactions may be disrupted in other CNS inflammatory conditions, o the qualitative or quantitative differences in the expression of these molecules in different areas of the inflamed CNS, o the relationship between the expression of these molecules and pathology in the HIV-infected brain, o the level of constitutive expression of these co-receptors and the magnitude of induction by HIV infection, o which cells within the CNS express these molecules, o how binding of the virus to the co-receptors disturbs or alters signal transduction pathways, o mechanisms related to chemokine and other receptor modulation of HIV entry and growth and successive alteration of neural function, and o chemokine regulation of HIV entry, modulation of such actions by co-factors and sequential neural impairment. 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 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 in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994 available on the web at the following URL address: http://www.nih.gov/grants/guide/notice-files/not94-105.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 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" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://www.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 policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435- 0714, fax: (301) 480-0525 Email: GrantsInfo@NIH.GOV. The title and number of the program announcement must be typed in Section 2 on the face page of the application. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://www.nih.gov/grants/guide/notice-files/not98-030.html The completed original application and five legible copies must be sent or delivered 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board, when applicable. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application 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 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 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 methods? 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 provisions for the protection of human and animal subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dianne M. Rausch, Ph.D. Office of AIDS Research National Institute of Mental Health 6001 Executive Boulevard, Room 6209, MSC 9619 Bethesda, MD 20892-9619 Telephone: (301) 443-6100 FAX: (301) 443-9379 Email: dr89b@nih.gov Charles W. Sharp, Ph.D Division of Basic Research National Institute on Drug Abuse 6001 Executive Boulevard, Room 4284, MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 443-1887 FAX: (301) 594-6043 Email: cs107m@nih.gov A. P. Kerza-Kwiatecki, Ph.D. Division of Convulsive, Infectious, and Immune Disorders National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2117, MSC 9160 Bethesda, MD 20892-9160 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: ak45w@nih.gov Direct inquiries regarding fiscal matters to: Diana S. Trunnell Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov Paul Coulis, Ph.D. Center for AIDS and Other Medical Consequences of Drug Abuse National Institute on Drug Abuse 6001 Executive Boulevard, Room 5190, MSC 9593 Bethesda, MD 20892-9593 Telephone: (301) 443-1801 FAX: (301) 594-6566 Email: pc58q@nih.gov Dianna Jessee Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3261, MSC 9190 Bethesda, MD 20892-9190 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: dj35j@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.242 and 93.282 (NIMH), 93.279 (NIDA), and 93.853 and 93.854 (NINDS). 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 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. Awards will be administered under PHS grants policy as stated in the NIH Grants Policy Statement (October 1, 1998). PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the nonuse 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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