Full Text HL-95-009 CYTOKINE EFFECTS ON HEMATOPOIESIS IN AIDS ANIMAL MODELS NIH GUIDE, Volume 23, Number 39, November 4, 1994 RFA: HL-95-009 P.T. 34 Keywords: AIDS Disease Model Biology, Cellular National Heart, Lung, and Blood Institute (NHLBI) Letter of Intent Receipt Date: December 16, 1994 Application Receipt Date: January 24, 1995 PURPOSE The Cellular Hematology Scientific Research Group, Blood Diseases Program, Division of Blood Diseases and Resources, NHLBI announces the availability of a Request for Applications (RFA) on the above subject. The purpose of this initiative is to study animal models of human acquired immunodeficiency syndrome (AIDS) to increase our understanding of clinical consequences and/or efficacy of hematopoietic factors used in HIV-1 infected persons. The complexity of HIV disease makes it difficult to assess cytokine effects exclusively in the patient. Thus, this initiative will primarily focus on animal models of human AIDS that could be directly related to future human clinical studies. However, focused cytokine studies in HIV-1 infected persons will be considered. 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 initiative, Cytokine Effects on Hematopoiesis in AIDS Animal Models, 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 202-782-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Awards in response to this RFA will be made to foreign institutions only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research project grant (R01) and FIRST (R29) award and is a one-time solicitation. Applicants, who will plan and execute their own research programs, are requested to furnish their own estimates of the time required to achieve the objectives of the proposed research project. Up to five years of support may be requested. At the end of the official award period, renewal applications may be submitted for peer review and competition for support through the regular grant program of the NHLBI. It is anticipated that support for the present program will begin in August 1995. Administrative adjustments in project period and/or amount of support may be required at the time of the award. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded in response to this RFA. FUNDS AVAILABLE Fiscal Year 1995 financial plans for the NHLBI include $1.5 million for this program. However, award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that the NHLBI will award approximately six new grants under this program. The specific amount to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Since a variety of approaches would represent valid responses to this RFA, it is anticipated that there will be a range of costs among individual grants awarded. If collaborative arrangements involve sub-contracts with other institutions, the NHLBI Grants Management Staff (tel: 301-594-7436) should be consulted regarding procedures to be followed. Designated funding levels are/or project period duration are subject to change at anytime due unforeseen budgetary administrative and/or scientific developments. RESEARCH OBJECTIVES AIDS remains among the most important public health challenges in the United States and abroad. The disease has managed to affect every segment of the population including the fetus and the newborn. Current estimates of HIV-1 prevalence place the number of HIV-1 infected individuals around one million. Early this fall, the Centers for Disease Control plans to release a new estimate of the prevalence of HIV-1 infection in the United States. The natural history of HIV infection is characterized by an abundance of hematologic complications. Anemia is the most frequent abnormality and is manifest at presentation in up to 20 percent of patients. By end-stage disease, 75 to 100 percent of patients become anemic (1,2). Thrombocytopenia and diminished marrow production are seen throughout all stages of AIDS. Leukopenia, consisting of monocytopenia. neutropenia, and lymphopenia, correlates with the stage of disease and as seen in anemia, is worsened with azidothymidine (3). Zidovudine, trimethoprim sulfamethoxazole, and ganciclovir all can produce or contribute to cytopenias. Reduced marrow reserves and cytopenias complicate treatment for not only HIV but also HIV related malignancies and opportunistic infections. The past decade has witnessed the cloning and characterization of multiple hematopoietic growth factors and cytokines. As a result, cytokines have been used clinically in HIV-1 infection to treat persons with HIV-related cytopenias resulting in improved management of these complications. Although cytokines have generally been well tolerated in clinical use, a number of important questions still remain regarding their use in HIV-1 infected individuals. Granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) are very frequently used to manage HIV-1-related neutropenia. In phase I trials, GM-CSF has produced an increase in peripheral neutrophils and eosinophils and a slight rise in monocytes when it was administered to individuals with AIDS-related neutropenia (4,5). Although some investigators have reported that neutrophil function improves in these patients (6), others have reported that neutrophils released from the bone marrow after administration of the drug are dysfunctional (7). Also of some concern to clinicians, is the demonstration that in vitro, GM-CSF potentiates HIV-1 replication (8,9). G-CSF has also been used in the treatment of individuals with HIV-1 infection. Unlike GM-CSF, G-CSF has not been shown to increase the activity of HIV-1 in monocytes and macrophages (10) and also elicits fewer toxicities than GM-CSF (11). Although G-CSF has been shown to increase circulating neutrophils in patients with HIV infection (12), it is not clear if this response translates into fewer infections or increased survival. Other cytokines including M-CSF and interleukin-3 (IL-3) have also been characterized, but few studies detail their clinical use. M-CSF induces proliferation of mononuclear cells and has been shown to potentiate the infection of HIV-1 (13). Additionally, IL-3 has been shown to stimulate multiple hematopoietic cell lines (14), but it too has been associated with an increase in HIV proliferation in vitro by infected macrophages and monocytes. Alpha interferon has been reported to have an anti-viral effect when administered to individuals with HIV infection (15). Important questions still remain regarding the use of cytokines in HIV-1 infected individuals. Cytokine effects on hematopoietic cells and stromal elements have been primarily demonstrated in vitro with very little information available about their effects in vivo. Since these factors typically have multiple actions, some of these actions may be undesirable in a given case. In fact, when one gives a single factor, no less than three general events occur: (a) the blood level of the factor increases and the biological activity of that factor is exerted; (b) the factor induces auxiliary cells to release other cytokines; and (c) the administered factor will act synergistically with at least some of the endogenous factors it induces. Thus, the current view that hematopoietic growth factors simply stimulate the production of more white cells or the proliferation and/or differentiation of stem/progenitor cells, may inappropriately trivialize the physiologic events that take place in HIV-1 infected individuals when cytokines are administered. The many and complex opportunistic infections, neoplasms, and drug treatments, both prophylactic and active, make it difficult to unravel the pathogenesis of HIV disease. These phenomena significantly contribute to the difficulties in assessing the advantages and disadvantages of the use of cytokines in AIDS patients. Therefore, to gain insight into this important area, this RFA will focus primarily on the use of animal models of human AIDS. Recently, studies have demonstrated differences between the levels of viral burden and virus replication in peripheral blood versus lymphoid organs (16). Animal models could potentially provide a unique opportunity to assess these differences with larger numbers and to determine the impact of the use of cytokines on virus replication. In addition, animal models will undoubtedly continue to prove useful for studies of anti-HIV gene therapy strategies. The utility of animal models to study the pathogenesis of AIDS has been extensively reviewed (17,18). This RFA encourages applications that propose studies designed to better assess the use of hematopoietic factors in HIV-1 infected individuals. The primary focus of this RFA is to conduct the above assessment in animal models of human AIDS. The proposed studies should be directly related to evolution to future human clinical studies. Moreover, in vitro studies proposed should have an in vivo endpoint. Also, recent PCR technology would allow focused cytokine studies to be conducted in HIV-1 infected persons. Therefore, appropriate studies assessing the effects of cytokines in HIV-1 infected individuals will be considered. Research approaches that would be considered responsive to the program would include studies to (a) develop new animal models of human AIDS to better assess cytokine use in HIV-1 infected persons; (b) evaluate the effect(s) of cytokines used clinically in HIV-1 infected persons on viral burden, viral persistence, and viral infectivity of stem/progenitor cells and stromal elements; (c) evaluate the interplay of exogenously added cytokines and endogenous cytokines induced by HIV infection; (d) assess the different compartments of HIV-1 virus replication (i.e., peripheral blood vs. lymphoid tissue) and determine the impact of the use of cytokines on viral replication; and (e) evaluate the effects of cytokines on potential anti-HIV gene therapy treatment approaches (i.e., genetically altered stem/progenitor cell transplantation). The above examples of research approaches are not meant to be all inclusive or restrictive. Investigators are encouraged to develop their own innovative approaches to achieve the goals of this initiative. Exclusions Epidemiological studies, large-scale clinical trials, and large multi-project grant applications (program project grants) are specifically excluded from this RFA. Also, research focused on testing the effectiveness of vaccines for HIV infection is excluded. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will sponsor annual meetings to encourage an exchange of information among investigators who participate in this program. In preparing the budget for the grant application, applicants should request additional travel funds for one meeting each year to be held in Bethesda, Maryland. Applicants should also include a statement in the application indicating their willingness to participate in such meetings. 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 28, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by December 16, 1994, 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 the RFA in response to which the application may be submitted. Such letters are requested only for the purpose of providing an indication of the number and scope of applications to be received; therefore their receipt is usually not acknowledged. A letter of intent is not binding, it will not enter into the review of any application subsequently submitted, nor is it a necessary requirement for the application. This letter of intent is to be sent to: Dr. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 557A Bethesda, MD 20892 Telephone: (301) 594-7478 FAX: (301) 594-7407 Email: James_Scheirer@NIH.Gov APPLICATION PROCEDURES Application Receipt Date: January 24, 1995 Applications are to be submitted on the research grant application form PHS 398 (rev. 9/91). This form is available in at most institutional offices of sponsored research and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. Use the conventional format for research project grant applications and ensure that the points identified in the section REVIEW CONSIDERATIONS are fulfilled. FIRST applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The RFA label available in the PHS 398 application kit must be affixed to the bottom of the face page of the original copy of the application. 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. To identify the application as a response to this RFA, check "YES" on Item 2a of page 1 of the application and enter the title and RFA Number: CYTOKINE EFFECTS ON HEMATOPOIESIS IN AIDS ANIMAL MODELS RFA HL-95-009. Send or deliver the completed application and three signed, exact photocopies of it to the following, making sure that the original application with the RFA label attached is on top: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send an additional two copies of the application to the Chief, Review Branch at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants (DRG). Otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by January 24, 1995. An application not received by this date will be returned to the applicant without review. The DRG 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 DRG will not accept any application that is 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. Although this is an RFA from the NHLBI, the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) also have an interest in research focused on the role of cytokines in AIDS and the development of AIDS animal models. In addition, the National Cancer Institute (NCI) has an interest in the role of cytokines in AIDS pathogenesis particularly, in the development of AIDS- associated malignancies. Therefore, the NIAID, the NCI or the NIDDK may be given an institute assignment in accordance with NIH referral guidelines. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness and responsiveness by the National Institutes of Health (NIH). Incomplete applications and applications deemed not responsive to the RFA 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 NHLBI in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be promptly notified. The criteria used in evaluating the scientific merit of each application will be similar to those used in the review of traditional research-project grant applications, including the novelty, originality, and feasibility of the approach; the training, experience and research competence of the investigator(s); the adequacy of the experimental design; the suitability of the facilities; the appropriateness of the requested budget to the work proposed; and the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Applications should be prepared so that they can be reviewed without the necessity of interaction between applicants and reviewers since no site visit or reverse site visit will be part of the technical merit review. AWARD CRITERIA The anticipated date of award is August 1995. Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. Awards in response to this RFA will be made to foreign institutions only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. Designated funding levels are subject to change at any time prior to award, due to unforeseen budgetary, administrative and/or scientific developments. In order to more evenly distribute administrative workload and reduce the number of awards with July 1 or September 30 start dates, the NHLBI will award ten months of time and money for the first competing budget period of this project. This action results in a project period of 58 months rather than 60 months for R01 applications. Investigators should plan their research projects and budgets within these timeframes. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Helena O. Mishoe, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Federal Building, Room 5A12 Bethesda, MD 20892 Telephone: (301) 496-5911 FAX: (301) 496-9940 Email: Helena_Mishoe@NIH.Gov Direct inquiries regarding fiscal matters to: Ms. Jane R. Davis Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A11 Bethesda, MD 20892 Telephone: (301) 594-7436 FAX: (301) 594-7492 Email: Jane_Davis@NIH.Gov AUTHORITY AND REGULATIONS The programs of the Division of Blood Diseases and Resources, NHLBI, are described in the Catalog of Federal Domestic Assistance number 93.839. Awards are made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under PHS grant policies and Federal regulations, most specifically 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. References 1. Spivak JL, Bender BS, Quinn TC. Hematologic abnormalities in the acquired immune deficiency syndrome. Am J Medicine 77:224-228, 1974. 2. Zon, LI, Arkin C, Groopman JE. Hematologic Manifestations of human immune deficiency virus (HIV). Br J Haematol 66:251-256, 1987. 3. Fischl MA, Ricnman DD, Hansen N, Collier AC, Carey JT, Para MF, Hardy D. Dolin R. Powderly WG, Allan JD, Wong B, Merigan TC, McAuliffe VJ, Hyslop NE. Rhame FS, Balfour HH, Spector SA, Volberdino P, Pettinelli C, Anderson J. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. Annals Internal Med 112:727-737, 1990. 4. Groopman JE, Granulocyte-macrophage colony-stimulating tor in human immunodeficiency virus disease. Semin Hematol 27:8-14, 1990. 5. Groopman JE, Mitsuyasu RT, DeLeo MY, et al. Effect of recombinant human granulocyte-macrophage colony-stimulating factor on myelopoiesis in the acquired immunodeficiency syndrome. N Engl J Med 317:533-598, 1987. 6. Baldwin GC, Gasson JC, Quan SG, et al. Granulocyte-macrophage colonystimulating factor enhances neutrophil function in acquired immunodeficiency syndrome patients. Proceedings of the National Academy of Sciences of the USA 85:2763-2766, 1988. 7. Peters WP, Stuart A, Affronti MI, Kim KS, Coleman R. Neutrophil migration is defective during recombinant GMCSF infusion after autologous bone marrow transplantation in humans. Blood 72:1310-1315, 1988. 8. Perno CF, Yarchoan R, Cooney DA, et al. Replication of human immunodeficiency virus in monocytes; granulocyte/macrophage colonystimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2'3'-dideoxythymidine (AZT) and other dideoxynucleoside congeners of thymidine. J Exp Med 169:933-951, 1989. 9. Pluda JM, Yarchoan R, Smith PD, et al. Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection. Blood 76:463-472, 1990. 10. Koyanagi Y, O'Brien WA, Zhao JQ. Cytokines alter production of HIV-1 from primary mononuclear phagocytes. Science 241:1673-1675, 1988. 11. Davey RT, Davey V, Zurol J. A phase I/II trial of zidovudine interferon alpha and granulocyte-macrophage colony stimulating factor in treatment of HIV infection. 6th Int Conf on AIDS, San Francisco, June 11-24, 1990. 12. Miles SA, Milsuyasu R, Fink N. Recombinant G-CSF and recombinant erythropoietin may abrogate the neutropenia and anemia of AIDS and allow resumption of AZT. 5th Int Conf on AIDS, Montreal, June 4-9, p. 550, 1989. 13. Perno CF, Yarchoan R, Cooney DA, et al. Differential modulation of HIV replication and AZT activity in monocyte/macrophages by GM- CSF, M-CSF, G-CSF. 5th Int Conf on AIDS, Montreal, June 4-9, p. 536, 1989. 14. Alter R, Welniak LA, Jackson JD, Garrison L, Weisenburger DD, Kessinger, A. In vitro clonogenic monitoring of peripheral blood stem cell collections following interleukin-3 administration. Blood 76(10) Supplement 1:129a, 1990. 15. Lane HC, Davey V, Kovacs JA, et al. Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. Ann Intern Med 112:805-811, 1990. 16. Pantaleo G, Grazios C, Demarest JF, Butini L, HIV infection is active and progressive in lymphoid tissues during the clinically late stage of the disease. Nature 362(6418): 355-358, 1993. 17. Fultz P. Nonhuman primate models for AIDS. Clinical Infectious Diseases 17 (suppl 1): S230-S235, 1993. 18. Letvin, N. Animal models for the study of human immunodeficiency virus infections. Current Opinions in Immunology 4:481-485, 1992. .
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