RFA-DE-00-002: HIV/AIDS ASSOCIATED ORAL VIRAL INFECTIONS

Department of Health
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HIV/AIDS ASSOCIATED ORAL VIRAL INFECTIONS Release Date: February 7, 2000 RFA: DE-00-002 National Institute of Dental and Craniofacial Research http://www.nidcr.nih.gov/ Letter of Intent Receipt Date: May 15, 2000 Application Receipt Date: August 18, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Institute of Dental and Craniofacial Research (NIDCR) invites new and experienced scientists to submit research grant applications for basic, behavioral, epidemiological or clinical investigations to study the pathogenesis, infectivity, transmission, reactivation and pathotropic spread of viral infections in the oral cavity of the immunocompromised host. This RFA is intended to solicit a broad range of research proposals on oral opportunistic infections with viruses, including human herpesvirus (HHV), Epstein Barr virus (EBV), cytomegalovirus (CMV) varicella-zoster virus (VZV), and human papillomavirus (HPV) in HIV-infected/AIDS individuals. The Institute encourages collaborative projects that bring together investigators from all relevant scientific disciplines including microbiology, immunology, biochemistry, and pathology interested in studying viral infections of the oral cavity. Applications that include collaboration with foreign scientists conducting unique research on this topic are also encouraged. 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), HIV/AIDS Associated Oral Viral Infections, is related to the priority area of Oral Health. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Although an application must be submitted from a single institution, collaborative arrangements with other institutions are encouraged. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. 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. New investigators without prior R29 or R01 support are strongly encouraged to apply. They should identify their status on the cover page for the application. The anticipated award date is February 1, 2001. FUNDS AVAILABLE The NIDCR intends to commit approximately $2 million in FY 2001 to fund 6 or 7 new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $200,000 per year. Applicants with collaborative agreements at other domestic universities can apply for direct costs of up to $225,000, since facilities and administrative (F&A) costs on the consortium are included in the direct costs of the applicant. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIDCR provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Oral viral infections and lesions may develop during the acute phase of HIV-1 infection, early in the transition from HIV-1 infection to full blown AIDS, and if untreated, these infections and ulcerations may persist throughout the disease and add to the morbidity and mortality of the illness. As the number of CD4+ T lymphocytes decline, the HIV-1 infected person becomes increasingly susceptible to infection with a wide variety of opportunistic oral pathogens including viruses and Candida species. Highly active anti-retroviral therapy (HAART) has dramatically reduced the oral complications of AIDS, including viral infections, for patients who adhere to the regimen. Patients who fail or do not have access to HAART treatments, patients during the acute phase of the HIV-1 infection and those transiting from HIV-1 infection to full blown AIDS are still at great risk of developing oral opportunistic infections. The NIDCR has recently requested submission of applications for research on the host immune response to Candida albicans [see NIH Guide to Grants and Contracts, December 17, 1999; http://grants.nih.gov/grants/guide/1999/99.12.17/index.html]. The present RFA encourages the submission of applications to study the viruses that cause oral complications associated with HIV infection/AIDS. These viruses include herpesviruses (EBV, HSV-1, 2, 6 and 8, CMV, VZV), and papillomaviruses (HPV- 6, 11, 13 and 30). Among the most severe, persistent, frequent, and recurrent infections in the oral cavity of the HIV-infected patient are those caused by herpesviruses. Four of the eight identified herpesviruses that cause human disease are responsible for oral ulcerations: HSV-1, HSV-2, VZV and CMV. These ulcers are particularly aggressive and are slow to heal in the immunocompromised individual. There is a greater tendency for oral infections to become systemic in HIV positive patients than in immunocompetent individuals. The symptoms of herpetic lesions include fever, malaise, cervical lymphadenopathy, multiple oral ulcerations and intensely painful gingival erythema. In those who are severely immunocompromised, infections can be caused by the reactivation of latent HSV infection in the oral tissues. The oral lesions of most HSV infections are most commonly found on the hard palate, gingival keratinized epithelium or alveolar ridges. The incidence of VZV infections increases with age and immunosuppression in HIV positive individuals (<200 CD4+ cells/mm3). VZV causes severe, life threatening infections in immunocompromised patients. The first manifestation of the disease is vesicles that rupture and form ulcers. Lesions appear as multiple small shallow ulcers on an erythematous base, usually on the palate. Cytomegalovirus is the most common opportunistic viral pathogen among people with AIDS. In the oral cavity it causes ulcers that usually appear as single ulcers without the initial formation of vesicles. Almost all homosexual males who are HIV positive show evidence of previous exposure to CMV. In 1996, CMV caused 53% of the oral ulcers found in HIV infected people. Approximately one quarter of HIV infected individuals are co-infected with both CMV and HSV, making diagnosis difficult and complicating the course of disease. Individuals who are severely immunocompromised (<100 CD4+ cell/mm3) frequently have intraoral CMV ulcers, and these lesions may be the first sign of disseminated HIV infection. CMV has increased pathogenicity in immunosuppressed individuals and along with other Herpes viruses has immunosuppressive qualities. Among the other herpesviruses involved in oral lesions, HHV-8 has been implicated as the etiological agent of Kaposi’s sarcoma (KS), which is the most common intraoral malignancy seen in HIV infected individuals. Almost 90% of severely immunosuppressed HIV positive patients (<100 CD4+ cells/ mm3) develop oral KS. The herpesvirus, EBV, is considered to be one of the etiological agents responsible for oral hairy leukoplakia (OHL). OHL develops as a white shaggy patch on the lateral surface of the tongue, and may extend to the dorsal and ventral surfaces. Candida albicans infections may be superimposed on the OHL lesion, making it a painful lesion not easy to diagnose or treat. EBV infection has also been implicated in the development of lymphomas in the oral cavity. HPV is a cause of a multiform group of oral hyperplastic nodular or papular lesions, including oral papillomas, verruca vulgaris (warts), focal epithelial hyperplasia, and condyloma acumininatum, a sexually transmitted disease with manifestations as oral warts. An increased frequency of skin, anal and oral lesions or nodules due to HPV has been noted in HIV immunosuppressed children and adults. Although HAART therapy has somewhat contained the growth of certain opportunistic pathogens, HPV infections may in fact have increased in the oral cavity. Viral infections in HIV-infected individuals are often painful, esthetically displeasing, and impair the normal function of the mouth. Current medical practice does not have the means to adequately detect, diagnose and treat these oral viral lesions, nor can infection or reactivation be predicted or prevented. To improve health care for HIV-infected patients specifically, and immunosuppressed individuals in general, more research on oral virus diseases and conditions is clearly needed. Such research is expected to provide important information toward understanding the pathogenesis and treatment of oral viral infections in patients with immune compromise. Research Objectives and Scope The goal of this RFA is to increase our understanding of how virulence, infection, and host response is modified in the immune compromised patient to allow infection, activation or reactivation of opportunistic pathogens. This understanding can lead to improved diagnosis, prevention and treatment strategies, for the various opportunistic pathogens. Investigators are not limited to the examples given and are encouraged to propose other projects that are appropriate to the investigator-initiated grant mechanism and to the study of opportunistic viral infections of the oral cavity. Viruses other than those mentioned above might be appropriate for this RFA provided they specifically infect or cause oral lesions in the HIV-infected/AIDS individual. Areas of research interest include work to: o Elucidate the role of the immune response in control or exacerbation of oral viral infections and lesions. o Explore viral cellular transformation and induced oncogenesis in the oral cavity of HIV-infected patients. o Identify modes of passive and adaptive immune modulation to control oral viral infections. o Characterize the host genetic susceptibility to viral oral infections. o Elucidate the initiation and progress of viral pathogenesis in the oral cavity. o Explore the mechanisms of interactions between two or more viruses that may lead to different pathogenic outcomes. o Identify the mechanisms of reactivation of viral infections in the oral cavity. o Develop diagnostics for the early detection of sentinel lesions. SPECIAL REQUIREMENTS Awardees will be requested to attend a meeting to present the progress of the work funded under this program. Details of this meeting will be provided post-award. Applicants should include travel funds in their budgets for a two-day meeting every year, most likely to be held in Bethesda, Maryland, to meet with other NIDCR-supported researchers studying the oral complications of HIV infection and AIDS. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women, members of minority groups and their sub-populations 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", 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: http://grants.nih.gov/grants/guide/notice-files/not94-100.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://grants.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. LETTER OF INTENT Prospective applicants are asked to submit 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 a subsequent application, the information that it contains allows NIDCR staff to estimate the potential review workload and avoid conflicts of interest in the review process. The letter of intent receipt date is listed in the heading of this RFA and should be sent to the program staff listed under INQUIRIES. APPLICATION PROCEDURES The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form, PHS 398 (revised 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $200,000 per year ($225,000 for applicants with consortium arrangements with other domestic universities.) The modular budget request must be in accordance with the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $200,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, List key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include a Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. 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. The RFA label available in the PHS 398 (rev. 4/98) 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 (DE-00-002) must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, and three (3) signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH SUITE 1040 6701 ROCKLEDGE DRIVE, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two (2) additional copies of the application must be sent to: Dr. H. George Hausch Scientific Review Branch Division of Extramural Research National Institute for Dental and Craniofacial Research 45 Center Drive, Room 4AN-38D- MSC 6402 Bethesda, MD 20892-6402 Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) 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 CSR 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness and responsiveness by the CSR and NIDCR. Incomplete and/or non-responsive applications 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 NIDCR in accordance with the review criteria stated below. A process will be used by the initial review group in which all applications receive a written critique but only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Dental and Craniofacial Research Council. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. 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 method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups and children, as appropriate for the scientific goals of the research. Plans for the recruitment and retention of study subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. SCHEDULE: Letter of Intent Receipt Date: May 15, 2000 Application Receipt Date: August 18, 2000 Peer Review Date: September, 2000 Council Review: January, 2001 Anticipated Start Date: February 1, 2001 AWARD CRITERIA Award criteria that will be used to make award decisions include: o-scientific merit (as determined by peer review) o-availability of funds o-programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Denise Anne Russo, Ph.D. Infectious Diseases and Immunity Branch Division of Extramural Research, National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-18B Bethesda, MD 20892-6402 Telephone: (301) 594-2617 FAX: (301) 480-8318 Email: Denise.Russo@nih.gov Direct inquiries regarding fiscal matters to: Mr. Kevin Crist Grants Management Branch Division of Extramural Research National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-44A, MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-4800 FAX: (301) 480-8301 Email: Kevin.Crist@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.121, Oral Diseases and Disorders Research Awards. 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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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