Full Text HL-94-004 HEMATOLOGIC CONSEQUENCES OF HIV INFECTION OF MARROW CELLS NIH GUIDE, Volume 22, Number 44, December 10, 1993 RFA: HL-94-004 P.T. 34 Keywords: Bone Marrow AIDS National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: February 4, 1994 Application Receipt Date: March 15, 1994 PURPOSE The purpose of this initiative is to increase our understanding of the cellular and molecular mechanisms that lead to the hematologic abnormalities seen following HIV infection. Investigators who are well-trained in the modern techniques of cellular and molecular biology will be encouraged to focus their expertise on issues directly related to the understanding of cytopenia following HIV infection, the role of hematopoietic stem and progenitor cells in the development of AIDS, and to develop gene therapy strategies to protect the hematopoietic stem/progenitor cell from being infected with HIV or to promote intracellular suppression of HIV gene expression. 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 Request for Applications (RFA), Hematologic Consequences of HIV Infection of Marrow Cells, 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 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 or the NIDDK. It is anticipated that support for the present program will begin on September 30, 1994. 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 connection with this RFA. FUNDS AVAILABLE Fiscal year 1994 financial plans for the NHLBI include $1.5 million for this program. The NIDDK plans to allocate an additional $1.0 million. 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 about six new grants under this program, and the NIDDK about five. 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 announcement, 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. RESEARCH OBJECTIVES Background The Centers for Disease Control estimates that approximately one million people in the United States are infected with the HIV-1. Therefore, AIDS and AIDS-related complex (ARC) are among the most important public health challenges confronting not only the United States, but the world today. AIDS is characterized by opportunistic infections and by opportunistic neoplasms such as Kaposi's sarcoma. In addition, AIDS patients frequently experience hematologic abnormalities such as bone marrow dysplasia, anemia, thrombocytopenia, and leukopenia. The hematologic abnormalities contribute to worsening the clinical condition and also limit the use of antibacterial as well as antiviral agents. The exact mechanisms by which HIV-1 contributes to the characteristic cytopenias are presently unknown. Both ineffective hematopoiesis and peripheral destruction of blood cells may lead to cytopenia commonly seen in AIDS patients. However, multiple mechanisms are likely responsible for the cytopenias observed in HIV-1 infected individuals. Cytopenias may be due to accelerated utilization and destruction of cells due to opportunistic infections, reticuloendothelial cell dysfunction, or to specific autoimmunity. Ineffective hematopoiesis in patients with AIDS may also be associated with the direct action of HIV-1 on (a) hematopoietic stem/progenitor cells; (b) more mature blood cells; and (c) bone marrow accessory cells, such as macrophages, endothelial cells, and T-lymphocytes. Other potential causes include the suppressive effects of infections and the formation of circulating inhibitors of hematopoiesis. Differences remain in the field regarding direct infection of CD34+ bone marrow cells by HIV-1 with some groups reporting infectibility (1,2) and other groups reporting an absence of infectibility (3,4). The low levels of infectibility reported is insufficient to explain the defective biological activity of stem/progenitor cells (5,6). Exposure of normal CD34+ bone marrow cells to certain HIV-1 isolates induces defects in BFU-E, CFU-GM, CFU-Meg, and CFU-TL derived colony formation (7,8). Therefore, more pertinent to mechanisms of cytopenias in HIV-infected individuals may be the ability of HIV-1 to directly induce defects in stem/progenitor cells. Symptomatic anemia is the most common cytopenia and occurs in the presence and absence of myelosuppressive drug therapy such as AZT. The lack of reticulocyte response seen in these patients may be due to a hypoproliferative anemia or to ineffective hematopoiesis. Low erythropoietin levels and associated abnormalities seen in some AIDS patients may be a contributing factor to anemia. Thrombocytopenia is also commonly seen in HIV infected patients, and immune thrombocytopenic purpura has been recognized as a diagnostic category of ARC. Separate studies have shown that megakaryocytes may be a target for HIV infection (9,10) suggesting a role for megakaryocytes as viral reservoirs in the bone marrow and a potential mechanism for defective thrombocytopoiesis. Neutropenia is also common in HIV infected individuals. Attempts to reduce the impact of AIDS on the bone marrow failure discussed above have focused on dose reduction of ganciclovir, AZT, and chemotherapy, and the use of recombinant hematopoietic growth factors and cytokines such as erythropoietin, G-CSF (granulocyte colony-stimulating factor), GM-CSF (granulocyte macrophage colony-stimulating factor), M-CSF (macrophage colony-stimulating factor), IL-3 (interleukin-3), interferons, and stem cell factor. These efforts have been successful in correcting some of the cytopenias associated with HIV infections. However, compounds that interfere with viral replication, also appear to have damaging effects on the bone marrow (11,12). Thus, a number of AIDS patients, although under treatment with current anti-viral compounds, will become transfusion dependent. Combined therapy, using cytokines and anti-viral drugs, may allow the use of anti-viral compounds in patients intolerant of the hematologic effects that they cause. With the widespread use of recombinant growth factors and cytokines in AIDS treatment, there is a need to elucidate their role in modulating hematopoiesis and HIV infection. The growth and differentiation of hematopoietic stem/progenitor cells is primarily regulated by cytokines. Direct infection of other cell types in the marrow could lead to decreased production of stimulatory cytokines or increased production of inhibitory cytokines that act on stem/progenitor cells. Thus, it is likely that altered cytokine production in HIV-1 seropositive individuals could play an important role in the pathogenesis of the hematologic abnormalities characteristic of HIV-1 infected individuals. T-lymphocytes (CD4+) appear to be the primary reservoir for HIV in vivo although marrow cells belonging to the macrophage lineage also were infected at a lower level with HIV-1 (13,14,15). The ability of the HIV-1 tat protein to induce marrow macrophages to increase their expression of TGF-beta-1, a potent inhibitor of stem/progenitor cells has been reported (16). Therefore, determining the role of HIV viral proteins in the negative regulation of hematopoiesis is important to pursue. The use of the long term bone marrow culture system (17) will also continue to be extremely valuable in elucidating the hematologic abnormalities seen following HIV infection in the context of the stromal environment. Objectives The objective of this initiative is to solicit research grant applications on the cellular and molecular mechanisms that lead to the hematologic abnormalities seen following HIV infection. The following are only examples of the types of research approaches that would be responsive to this program: (a) determine the role of hematopoietic stem/progenitor cells in the development of AIDS; (b) elucidate the pathways of signal transduction in hematopoietic cells activated by cytokines that may regulate HIV processes in the infected cell; (c) develop gene therapy strategies using the hematopoietic stem cell as the target for transfection as a means for protecting the hematopoietic stem cell, and thus all blood cells, from becoming infected with HIV; (d) determine the role of HIV viral proteins in the negative regulation of hematopoiesis; and (e) development and testing of therapeutic modalities for bone marrow and hematologic abnormalities associated with HIV infection and AIDS. These examples are not meant to be all inclusive or restrictive. Investigators are encouraged to develop their own innovative approaches. 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 and the NIDDK will sponsor annual meetings to encourage the exchange of information among investigators who participate in this program. In the preparation of the budget for the grant application, applicants may request additional travel funds for one meeting each year to be held in Bethesda, Maryland. Applicants may also include a statement in the applications indicating their willingness to participate in such meetings. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 (rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, and Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit, by February 4, 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 any 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, and 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: Acting Chief, Centers and Special Projects Review Section Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 553 Bethesda, MD 20892 Telephone: (301) 594-7448 FAX: (301) 594-7407 APPLICATION PROCEDURES Applications are to be submitted on the research grant application form PHS 398 (rev. 9/91). This form is available in an applicant institution's office of sponsored research and from the Office of Grant 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 grant applications and ensure that the points identified in the section on REVIEW CONSIDERATIONS are fulfilled. FIRST (R29) 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. 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: HEMATOLOGIC CONSEQUENCES OF HIV INFECTION OF MARROW CELLS RFA HL-94-004-B 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. 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, Centers and Special Projects Review Section 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. Otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by March 15, 1994. An application not received by this date will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this announcement 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for their responsiveness to the objectives of this RFA by the NHLBI and the NIDDK. Grant applications will be assigned according to standard referral guidelines. If an application is judged unresponsive to the RFA, the staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications may be triaged by an NHLBI peer review group on the basis of relative competitiveness. The NIH will withdraw from further competition those applications judged to be non-competitive for award and notify the Principal Investigator and institutional official. Those applications judged to be competitive will undergo further scientific merit review. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the Division of Extramural Affairs, NHLBI, solely to review these applications. The second level of review will be provided by the National Heart, Lung, and Blood Advisory Council, and the National Diabetes and Digestive and Kidney Diseases Advisory Council. The criteria used in the evaluation of 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; and the appropriateness of the requested budget to the work proposed. AWARD CRITERIA 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. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding this programmatic issues may be directed to: 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 Ralph L. Bain, Ph.D. Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 3A05 Bethesda, MD 20892 Telephone: (301) 594-7556 FAX: (301) 594-7501 Inquiries regarding fiscal and administrative matters may be directed 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 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 grants 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. Folks TM, Kessler SW, Orenstein JM, Justement JS, Jaffe ES, Fauci AS: Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow. Science 242:919-922, 1988. 2. Kitano K, Abboud CN, Ryan DH, Quan SG, Baldwin GC, Golde DW: Macrophage-active colony-stimulating factors enhance human immunodeficiency virus type 1 infection in bone marrow stem cells. Blood 77:1699-1705, 1991. 3. Molina JM, Scadden DT, Sakaguchi M, Fuller B, Woon A, Groopman JE: Lack of evidence for infection of or effect on growth of hematopoietic progenitor cells after in vivo or in vitro exposure to human immunodeficiency virus. Blood 76:2476, 1990. 4. Zauli G, Re MC, Visani G, Furlini G, Mazza P, Vignoli M, La Placa M: Evidence for an HIV-1 mediated suppression of uninfected hematopoietic (CD34 (+)) progenitor cells in vivo. J. Infect. Diseases 1666:710-716, 1992. 5. Zauli G, Re MC, Davis B, Sen L, Visani G, Guliotta L, Furlini G, La Placa M: Impaired in vitro growth of purified (CD34 (+)) hematopoietic progenitors in human immunodeficiency virus-1 seropositive thrombocytopenic individuals. Blood 79:2680, 1992. 6. Louache F, Henri A, Bettaieb A, Oksenhendler E, Raguin G, Tulliez M, Vainchenker W: Role of human immunodeficiency virus replication in defective in vitro growth of hematopoietic progenitors. Blood 80:2991-2999. 7. Ho DD, Moudgil T, Alam M: Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N. Eng. Jour. Med. 321:1621, 1989. 8. Steinberg HN, Crumpacker CS, Chatis PA: In vitro suppression of normal human bone marrow progenitor cells by human immunodeficiency virus. J. Virol 65:1765, 1991. 9. Zucker-Franklin D, Seremetis S, Zheng ZY: Internalization of human immunodeficiency virus type I and other retroviruses by megakaryocytes and platelets. Blood 75:1920-1923, 1990. 10. Kouri YH, Borkowsky W, Nardi M, Karpatkin S, Basch RS: Human megakaryocytes have a CD4 molecule capable of binding human immunodeficiency virus-1. Blood 81:2664-70, 1993. 11. Mitsuya H, Broder S: Inhibition of the in vivo infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV- III/LAV) by 2'3'-dideoxynucleosides. Proc. Natl. Acad. Sci. USA 83:1911-1915, 1986. 12. Richman DD, Fischl, MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom, JM, Groopman JE, Mildvan D, Hirsch MS, Jackson GG, Durack DT, Nusinoff-Lehrman S, and AZT Collaborative Working Group. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo- controlled trial. N. Engl. J Med. 317:192-197, 1987. 13. Davis BR, Schwartz DH, Marx JC, Johnson CE, Berry JM, Lyding J, Merigan TC, Zander A: Absent or rare human immunodeficiency virus infection of bone marrow stem/progenitor cells in vivo. J Virol, 65:1985, 1991. 14. von Laer D, Hufert FT, Fenner TE, Schwander S, Dietrich M, Schmitz H, Kern P: CD34 (+) hematopoietic progenitor cells are not a major reservoir of the human immunodeficiency virus. Blood 76:1281, 1990. 15. McElrath MJ, Pruett JE, Cohn ZA: Mononuclear phagocytes of blood and bone marrow: comparative roles as viral reservoirs in human immunodeficiency virus type I infections. Proc. Natl. Acad. Sci, USA 86:675, 1989. 16. Zauli G, Davis BR, Re MC, Visani G, Furlini G, La Placa M: Tat protein stimulates production of transforming growth factor-beta-1 by marrow macrophages: A potential mechanism for HIV-1 induced hematopoietic suppression. Blood 80:3036-3043, 1992. 17. Geissler RG, Ottman OG, Kleiner K, Mentzel U: Decreased haematopoietic colony growth in long-term bone marrow cultures of HIV-positive patients. Res Virol 144:69-73, 1993. .
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