Full Text HL-96-008 REGULATION OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) ACTIVATION IN THE LUNG NIH GUIDE, Volume 25, Number 4, February 16, 1996 RFA: HL-96-008 P.T. 34 Keywords: AIDS Biology, Cellular Respiratory System Pulmonary Diseases National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: April 23, 1996 Application Receipt Date: June 11, 1996 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites research grant applications for support of research on the regulation of activation of HIV in the lung and mechanisms by which co-factors may lead to increased HIV-associated pulmonary disease. The primary objectives of this special grant program are to understand the cellular and molecular mechanisms involved in activation of HIV in lung cells and the subsequent effects this has on the course of HIV disease, especially in the lung. Among the disciplines and expertise that may be appropriate for this research program are virology, molecular biology, cell biology, immunology, molecular immunology, infectious diseases, pathology, pulmonary medicine, and pediatrics. 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), Regulation of Human Immunodeficiency Virus (HIV) Activation in the Lung, is related to the priority area of immunization and infectious 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 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 and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. Awards under this RFA to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) and the First Independent Research Support and Transition (FIRST) award (R29) mechanisms of support. Specific application instructions have been modified to reflect the "MODULAR GRANT" and the FIRST (R29) award requirements. They will BOTH incorporate the "JUST-IN-TIME" streamlining efforts being developed by the NIH. Multidisciplinary approaches are encouraged, but it is not the intent of this RFA to solicit applications for large studies encompassing a variety of individual subprojects, i.e., program projects. If collaborative arrangements through subcontracts with other institutions are planned, consult the program staff listed under INQUIRIES. Streamlining features of applications for both the R01 or R29 mechanisms are as follows: Instructions for completing the Biographical Sketch have been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, other support and checklist information will be requested by NHLBI staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. Applicants are expected to furnish their own estimates of time required to achieve the objectives of the proposed research project. 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. Up to five years of support may be requested on R01 applications. FIRST award applications must request five years of research support. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. It is anticipated that support for this program will begin in September 1996. Administrative adjustments in project period and/or amount may be necessary at the time of the award. 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 with the application. The National Institute of Allergy and Infectious Diseases (NIAID) also has interest in regulation of HIV activation. Therefore, applications that are of mutual interest are likely to be given a secondary assignment to NIAID in accordance with the NIH referral guidelines. FUNDS AVAILABLE It is anticipated that for fiscal year 1996, approximately $2,000,000 total costs will be available for the first year of support for this initiative. Award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that as many as eight new grants may be awarded under this program. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Direct costs for R01 applications will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. FIRST Awards (R29) will be awarded according to the standard program guidelines, i.e., five years, $350,000 maximum direct costs with no single budget period to exceed $100,000, and no less than a 50 percent commitment from the Principal Investigator, less any overlap or other necessary administrative adjustments. All Indirect costs will be awarded based on the negotiated rates. RESEARCH OBJECTIVES Background The AIDS epidemic continues to spread and pulmonary disease associated with HIV infection continues to be a major cause of morbidity and mortality. Although it has been demonstrated that cells in the lower respiratory tract can contain virus early after HIV infection begins, pulmonary complications in HIV infected individuals seem to occur later in the disease process. HIV proteins can be demonstrated in the lungs of patients with AIDS as well as in HIV seropositive subjects without respiratory symptoms. The mechanisms which may lead to the activation or continued quiescence of HIV in the lung have not been clearly defined. Several factors, both intrinsic to the virus and external, have been proposed to influence the activation of HIV in the lung. Intrinsic viral factors include viral tropism and ability to produce certain gene products that may affect viral replication in lung macrophages (e.g., vpr gene product). External influences include concurrent bacterial and viral infections, environmental exposures, hormones and cytokines and their networks. In vitro systems have shown that macrophages latently infected with HIV can be stimulated to produce infectious virus by exposure to phorbol esters, cytokines such as interleukin 1, interleukin 6, TNF-alpha, TNF-beta, GM-CSF, mitogens, endotoxin, and other viruses. Concurrent HIV and cytomegalovirus (CMV) infections have been noted in the brain at sites which show the greatest areas of inflammation and the highest concentration of HIV infection, suggesting CMV may be an important cofactor in HIV related disease processes. Dual infections with HIV and CMV are common in the lung, appear to affect the function of the alveolar macrophages, and may influence the progression of HIV disease. Macrophages located in the lung may play a very important role as a reservoir in that they can harbor HIV for long periods of time. This may be important, not only in the context of HIV-associated lung disease, but also for understanding the temporal expression of systemic HIV disease. Lung macrophages are known to be major producers of cytokines thought to activate HIV replication. In turn, HIV infection either alone or in the presence of other viruses has been shown in vitro to influence regulation of cellular function including cytokine production and accessory cell function. The effect of concurrent viral infection on the regulation of cellular function may also play an important role in the activation of HIV in the lung. The implications of this need to be defined in greater detail. Co-factors such as viral infections, cytokines, and environmental factors may enhance the ability of HIV to stimulate macrophages to produce cytokines, which in turn can up regulate HIV infectious processes. Non-viral co-factors that appear to enhance growth of HIV in vitro include pneumonias caused by Mtb, other bacteria or P. carinii, and cigarette smoke. Epidemiological data are consistent with this hypothesis in that HIV infected subjects who are cigarette smokers or who have active TB appear to do less well with their HIV infection than those who are nonsmokers or those without TB. Some co-factors may be unique in the lung due to the constant exposure to environmental stimuli. This is an area that is almost totally unexplored. Applications submitted in response to this RFA should focus on mechanisms by which the risk factors/co-factors, operating in the lung, lead to enhanced pulmonary disease and may also address how this may lead to the accelerated progression of HIV disease. Objectives and Scope The objective of this program is to elucidate mechanisms that activate HIV or allow the virus to remain in a quiescent state in pulmonary cells. These might include studies of viral, cellular, and immunological interactions, especially interactions at the molecular level, that affect activity of HIV in the lung. Examples of areas of research that might be included under this RFA are as follows: o determine mechanisms whereby specific cytokines permit or prevent activation of HIV in the lung; o determine the course and effects of activation of HIV in lung cells, via cytokine networks, and the extent to which this can be manipulated without interfering with essential cellular functions; o investigate factors within the viral genome that affect the course of viral activation and replication within lung cells; o examine genetic factors within the host lung cells that control activation of virus; o elucidate specific pathways whereby co-infection with other microorganisms, e.g., CMV, mycobacteria, Pneumocystis carinii, Streptococcus pneumoniae, and exposure to their products alters activation of HIV; o elucidate specific pathways and mechanisms related to activation of HIV by environmental exposures, e.g., cigarette smoke; o determine mechanisms of hormonal effects on activation of HIV. These are examples only. Investigators are not feel limited to the subjects mentioned above and are encouraged to submit other topics pertinent to the objectives of the RFA. This initiative may involve studies in human subjects, as well as investigations using animal models or in vitro systems. The initiative is relevant to black and Hispanic minority populations who are disproportionately affected by HIV in comparison to the total population. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the budget for the grant application, applicants should request travel funds for a one-day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. Applications that propose descriptive studies and do not contain hypothesis driven studies directed at understanding the mechanisms and consequences of activation of HIV in the lung will not be acceptable. This program will not support studies directed at development of animal models alone. The models must be used to study regulation and effects of activation of HIV in lung cells. Applications that focus on these mechanisms at the molecular level are of particular interest. 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 follow 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 also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by April 23, 1996, 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. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NIH staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be mailed or faxed, to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: james_scheirer@nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, 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: girg@drgpo.drg.nih.gov; and from Monique Rush at the address listed under INQUIRIES. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The RFA label found in the PHS 398 application form must be affixed to the bottom of the face page 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. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. R01 grants under this RFA will be awarded as modular grants. The modular grant concept establishes specific modules (increments) in which direct costs may be requested and a maximum level for requested direct cost. Only limited budgetary information is required in the application; a detailed budget need not be provided. The R01 application must request funds in $25,000 direct cost modules and a maximum of eight modules ($200,000 direct cost) per year may be requested. No escalation is provided for future years; all anticipated expenses for all years of the project must be included within the number of modules per year being requested. Any budget adjustments made by the Initial Review Group will be in modules of $25,000. FIRST (R29) applications submitted in response to this RFA are subject to the current FIRST award guidelines (DRG FIRST Award Guidelines, February 1994). This includes the requirement that FIRST Awards request five years of support not to exceed $350,000 direct costs for the entire project period and no more than $100,000 be requested in any one budget period. Include all letters of recommendation as outlined in the FIRST Award guidelines. The Principal Investigator must commit a minimum of 50 percent effort to the project. A detailed budget request should NOT be provided in the application. However, the anticipated level of effort (50 percent or greater) in all years and a brief description of responsibilities for the Principal Investigator and all key personnel must be specifically stated. The applicant should also include a narrative justification for any other budget items that are requested for the conduct of the project. No specific costs for items or categories are required. The following modifications are made to the standard PHS 398 application instructions: o INITIAL BUDGET PERIOD R01 APPLICATIONS: For R01 applications, no Form Page 4 is required and no categorical dollar information should be provided. The total direct cost must be requested in increments of $25,000. Applicants may not request a change in the amount of each module. A maximum of eight modules ($200,000 direct cost) per year may be requested. The exact cost of each budget item requested is not to be provided. However, the budget must be justified on Form Page 5. The budget justification should include the following: o The names, role, and their percent of effort on the project for all project personnel. o A narrative justification for any major budget item other than personnel (i.e., equipment or a major resource) that is requested o If sub-contracts are involved, state the name(s) of collaborating institutions and provide individual budgets (Form Page 5) as described in the "SUB-CONTRACTS" section below. R29 APPLICATIONS: FIRST (R29) Award applicants need not submit detailed budget requests. The names of all project personnel, their role on the project, and their percent effort should be presented in a narrative justification on Form Page 4. In addition, applicants should provide a narrative justification, beginning on Form Page 5, for the significant resources requested for the conduct of project (i.e., equipment). FIRST (R29) Award applicants are limited to $100,000 in any one budget period and may not exceed the overall maximum of $350,000 for the entire project period in accordance with the FIRST (R29) guidelines. Please note that for both the R01 or the R29 application, any large one-time purchases, such as large equipment requests, must be accommodated within these limits. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. o FUTURE BUDGET PERIODS - It is anticipated that direct cost budgets will remain constant throughout the life of the project for all R01 applications (i.e., the same number of modules requested for all budget periods). All necessary costs should be considered when determining the number of modules to be requested. However, in the exceptional event that the number of modules requested must change in any future year, appropriate justification must be provided. The "Budget for Entire Proposed Project Period" (top section of Form Page 5) should include Total Direct Costs requested for each year and the Total Direct Costs for the Entire Proposed Project Period. The Justification section should be completed based on instructions provided on Form Page 5. Because the FIRST (R29) Award applications may request different direct costs not to exceed $100,000 in any given budget period and are limited to a total direct cost cap of $350,000 for the entire project period, the applicant should show the TOTAL DIRECT COST for each of the five years listed on Form Page 5 of the 398 application form. These are the only cost elements required in the application. o SUBCONTRACTS - If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Initial and future year budgets for subcontracts should be prepared using the same guidelines as for the main grant except that total subcontract costs NEED NOT be in $25,000 modules. Requested amounts should be based on individual needs of the subcontract and should reflect both direct and indirect costs. When subcontract funds are added to the main R01 grant budget, the total amount must conform with the number of $25,000 modules requested. o BIOGRAPHICAL SKETCH - In addition to the standard information requested on Form Page 6, the applicant has the option of providing the title and source of any sponsored support relevant to the proposed research. o OTHER SUPPORT - No other support information is required on "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete other support information will be requested by NHLBI staff if there is a possibility for an award. o CHECKLIST - No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI staff if there is a possibility for an award. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Submit a signed, typewritten original of the application and three signed, photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express courier service) At the time of submission, two additional copies of the application must be sent to Dr. C. James Scheirer, at the listed under LETTER OF INTENT. Applications must be received by June 11, 1996. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (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 essentially 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. o If an application is determined to be unresponsive to the RFA, the principal investigator will be notified and may request that the application be returned or sent to DRG where it will be processed in the next available cycle as a regular grant application. o A sample budget is available upon request from Mr. Raymond Zimmerman at the number listed under INQUIRIES. REVIEW CONSIDERATIONS 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 NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a review in which only those applications deemed to have the highest scientific merit of the applications under review (usually two to three times the number of applications that the NHLBI anticipates being able to fund under the program) will be discussed, assigned a priority score, and receive a second level review by the National Heart, Lung, and Blood Advisory Council. The personnel category will be reviewed for appropriate staffing based on the requested percent effort and any changes requested in future years. The total budget request will be reviewed for consistency with the proposed methods and specific aims. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the recommended scope of the project. The review criteria are the following: o scientific, technical or medical significance and originality of proposed research o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research o availability of the resources necessary to perform the research o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA 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. The anticipated date of award is September 29, 1996. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct requests for the RFA to: Monique Rush Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0222 FAX: (301) 480-3557 Email: monique_rush@nih.gov Direct inquiries regarding programmatic issues to: Hannah H. Peavy, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0222 FAX: (301) 480-3557 Email: hannah_peavy@nih.gov Direct inquiries regarding fiscal matters to: Raymond L. Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: raymond_zimmerman@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.838. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, 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 a Health Systems Agency 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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