ROLE OF THE ORAL ENVIRONMENT IN HIV TRANSMISSION AND PATHOGENESIS NIH Guide, Volume 26, Number 38, November 21, 1997 RFA: DE-98-007 P.T. National Institute of Dental Research National Institute of Mental Health Letter of Intent Receipt Date: February 1, 1998 Application Receipt Date: March 12, 1998 PURPOSE The National Institute of Dental Research (NIDR) and the National Institute of Mental Health (NIMH) invite applications to support outstanding multidisciplinary research to: (1) determine whether or not HIV can be transmitted through the oral cavity; (2) elucidate the mechanisms of possible HIV and HIV-associated disease transmission through the oral cavity; and (3) identify socio-behavioral risk(s) associated with patterns and/or characteristics of oral-genital contact and design approaches to increase protective behaviors reducing risks of HIV transmission via the oral route. The Institutes are interested in supporting multidisciplinary research in these areas conducted by scientists from the fields of virology, immunology, genetics, oral biology, biochemistry, social and behavioral sciences, and epidemiology. 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 RFA, Role of the Oral Environment in HIV Transmission and Pathogenesis, 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 Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government 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, including universities, colleges, hospitals, laboratories, units of State and local governments and eligible agencies of the Federal government. Applications from investigators representing racial/ethnic minorities as well as from women and persons with disabilities. Although an application must be submitted from a single institution, collaborative arrangements with other institutions are strongly encouraged. Also, applications are not restricted to traditional dental, oral and craniofacial research settings. MECHANISM OF SUPPORT The mechanisms of support utilized will be the individual research project grant (R01). 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 five years. This RFA is a one-time solicitation for new and competing renewal awards. Future competitive renewal applications will compete with all investigator-initiated applications and will be reviewed according to customary referral and review procedures. New investigators without prior R29 or R01 support are strongly encouraged to apply. They should identify their status in a cover letter as well as in the application and provide evidence of institutional support for the research. FUNDS AVAILABLE The estimated total costs (direct plus indirect) available for the first year of support for awards under this RFA will be $3 million. The NIDR plans to support or contribute to the support of a total of approximately 12 grants in response to this RFA in fiscal year 1998. NIMH will allocate $750,000 in direct costs for FY 98 to support 2 to 3 individual R01s, provided the applications are of high scientific merit. It is possible that in a topic area that overlapped the interests of NIMH and NIDR could be co-funded by these two Institutes if the project was of high scientific merit. Grant awards will be contingent on the receipt of high quality applications and the availability of funds. Applications may not request more than three percent annual increases for inflation over subsequent years. Usual PHS policies governing grants administration and management will apply. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and the availability of funds. RESEARCH OBJECTIVES Background According to the World Health Organization, 22 million men, women and children are infected with HIV-1 worldwide, and the number of infected people is expected to exceed 40 million by the year 2000. It is estimated that 8,500 new HIV infections occur every day. In the United States, the demographics are changing with increased heterosexual transmission to women and a disproportionate increase in incidence of infection in racial and ethnic minorities. The death rate from AIDS for black men is four times that for white men and for black women it is nine times that for white women. This astonishing worldwide growth of the HIV pandemic is matched by an explosion of information in the areas of HIV virology, transmission, pathogenesis, prophylaxis and development of impressive treatment options for HIV and HIV-associated opportunistic infections. However, it is clear that the epidemic will continue to grow and extend particularly among ethnic minorities, the poor, the medically underserved, women and children in the United States and dramatically in much of the developing world, especially since the new HIV therapies are not economically feasible for many developing countries and not all people can manage the complicated treatment regimen. HIV infection is predominantly sexually transmitted. Although one-half of the reported cases of AIDS in the United States are still among homosexual men, heterosexual transmission is clearly the most common mode of infection worldwide, particularly in developing countries. It has become clear that the virus can be transmitted to either partner through vaginal or anal intercourse. Oral sex appears to be a much less efficient mode of transmission of HIV. In this regard there is a perception, particularly among some subgroups, that oral sex is a form of 'safe sex'. This presents a concern, as there have been reports of documented HIV transmission resulting solely from receptive fellatio and insertive cunnilingus. For example, one study reported that in 12 subjects where the precise date of seroconversion could be identified, 4 individuals reported oral- genital contact as their sole risk factor. In another study it has been shown that SIV infection can be transmitted by deposition of virus in the oral cavity. However, there is no convincing evidence that saliva is the vehicle by which HIV infection is accomplished through exposures of the oral cavity. Postnatal oral transmission of HIV to infants has been clearly documented, strongly implicating colostrum and breast milk as the vehicles of infection. However, the mechanisms of postnatal HIV infection during breast feeding are unclear. In breast-fed infants, where the upper intestinal mucosa is involved, it is critical to establish the mechanism by which HIV is transmitted from the mother to the neonatal host; for example, identification of the compartments harboring the virus, elucidation of the portal of HIV transmission, and identification of potential innate maternal and neonatal antiviral molecules (i.e., antibodies, chemokines, SLPI) which may account for protection in the infants who do not get infected and may provide important insights for augmenting defense against HIV infection. Rationale In order to identify current and future research opportunities in the areas of AIDS research relevant to the mission of the Institute, an ad hoc panel was convened on April 24-25, 1997 by the NIDR. The panel members were from academia, industry, the National Advisory Dental Research Council, and other NIH Institutes and Federal agencies. It was agreed that the NIDR is uniquely positioned to pursue three important areas of AIDS research, namely those involving oral transmission of HIV, opportunistic infections of the oral cavity, and mucosal immunity and the development of vaccines. Within the area of oral transmission, the following research initiatives were recommended: i) epidemiology to evaluate the possible contribution(s) of oral transmission of HIV; ii) the etiology and pathogenesis of virus entry after oral exposure, predisposing factors, immune dysfunction, assessment of oral viral load, virus tropism and iii) socio-behavioral factors in order to document types of sexual activity related to oral-genital contact and the design of effective approaches to reduce this pathway of risks of HIV infection. Proposed Research The following research topics are appropriate for this RFA. They are provided as examples and are not intended to be inclusive or restrictive. o Explore the mechanisms of virus entry after oral exposure. Key issues to be addressed are: i) elucidation of the site(s) of viral entry after oral exposure across mucosal surfaces of the oropharyngeal and gastrointestinal tract; ii) identification of the initial target cells and their receptors, initial site(s) of replication and the relative efficiency of oral infection compared to other routes of exposure. o Develop new or use existing animal models to study viral entry and to follow the progression of virus from the initial interaction to the establishment of HIV pathogenesis. The SIV model can be exploited but also new opportunities for other primate models and viral strains as well as the creation of transgenic animals should be explored. o Conduct studies to compare bronchial, vaginal, rectal and oral mucosal sites to characterize unique and common immunological parameters relevant to HIV infection. Explore the presence of chemokine receptors and their ligands in these sites, and examine the mechanisms by which M cells and dendritic cells contribute to the internalization of the virus and to the viral selection process. o Delineate aspects of tonsils and their function contributing to initial HIV infection, their status as viral reservoirs, induction of virus production and as therapeutic targets. o Explore the role of cytokines on the dysregulation of IgA production and transport; characterize the properties of salivary IgA antibodies in HIV infected people, and the role alterations in salivary cytokines have on those events, as well as the potential for intracellular formation of IgA anti-HIV/HIV complexes. Design epidemiological investigations to examine the relative risk of oral transmission of HIV and identify factors [e. g., oral lesions, sexually transmitted diseases (STDs), social mixing and level of seroprevalence, different types of substance abuse] which increase risks of transmission during oral sex. o Conduct studies to examine socio-behavioral factors (e.g., patterns and/or characteristics of oral-genital sexual behavior) related to oral transmission; design effective behavioral approaches including protective strategies to reduce the risk of possible HIV transmission through the oral cavity. o Assess the effectiveness and acceptability of protective strategies for eliminating or reducing risks of oral HIV transmission among population subgroups; identify effective strategies for disseminating information on risks and protective behaviors to health professionals and high risk population subgroups. o Develop more sensitive and specific oral HIV diagnostic tests; delineate the mechanisms of action of antiviral molecules in saliva including mucosal peptides (i.e., defensins, magainins), secretory leukocyte protease inhibitor (SLPI) and thrombospondin-1; design therapeutic strategies based on these molecules to block HIV-1 infection; develop novel drug delivery systems that would target the oral- nasal-pharyngeal region. o Identify compartments harboring HIV in breast milk; elucidate the portal of HIV transmission in breast feeding; identify potential innate maternal and neonatal antiviral molecules (i.e., antibodies, chemokines, SLPI) which may account for protection in the infants who do not get infected, and may provide important insight into mechanisms to augment defense against HIV infection. o Examine the role of opportunistic pathogens (e.g. Candida, HHV8, EBV, HPV) in facilitating HIV transmission/infection, pathogenesis and associated oral manifestations. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. LETTER OF INTENT Prospective applicants are asked to submit, by February 1, 1998 a letter of intent that includes a descriptive title of the proposed research, the name, mailing address, FAX, email address, and telephone number of the Principal Investigator and the identities of other key personnel and participating institutions and departments, 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 is helpful in planning for the timely review of the applications. It helps NIDR staff to estimate the potential review workload and to avoid possible conflicts of interest in the review. The letter of intent is to be addressed to Dr. Eleni Kousvelari at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@od.nih.gov. The forms are also available on the NIH World Wide Web Home Page at https://grants.nih.gov/grants/funding/phs398/phs398.html. The RFA label available in the PHS 398 application form kit must be affixed to the bottom of the face page of the original and the original must be placed on top of the entire package. 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, in order to identify the application as a response to this RFA, the RFA title ("Role of Oral Environment in HIV Transmission and Pathogenesis") and number, DE-98-007 must be typed in item 2 of the face page of the application form and the YES box must be checked. The instructions accompanying Form PHS 398 must be followed as far as possible. Applicants from institutions that have a General Clinical Research Centers (GCRC) funded by the NIH National Center for Research Resources may wish to identify the Center as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC Program Director must be included in the application material. Submit a signed, typewritten original of the application, including a cover letter, the checklist and three signed photocopies in one package to: CENTER FOR SCIENTIFIC REVIEW (formerly 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 also be sent to: Dr. H. George Hausch Division of Extramural Research National Institute of Dental Research Building 45, Room 4AN-38D Bethesda, MD 20892-6402 Applications must be received by March 12, 1998. If an application is received after that date, it will be returned to the applicant without review. REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR), NIH. Incomplete 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 a special emphasis panel convened by the Scientific Review Section, NIDR. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. 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 review, comments on the following aspects of the application will be made 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 the assignment of the overall score. 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? 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? Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Investigator and Team: 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? Are multidisciplinary expertise required to address the study questions represented on the team? Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review will also examine the appropriateness of proposed budget and duration, the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA The earliest anticipated date of award is September, 1998. Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total cost of the proposed project and the availability of funds will be considered by the NIDR and NIMH staff, the National Advisory Dental Research Council and the National Advisory Mental Health Council in making funding recommendations. In addition, the NIDR and NIMH value complementary funding from other public and private sources including foundations and industrial concerns. In circumstances in which applications have similar scientific merit, but vary in cost-competitiveness, the NIDR and NIMH are likely to select the more cost-competitive for funding. INQUIRIES Written, email and telephone 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: Eleni Kousvelari, D.D.S., MSc., DSc. Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN 18A Bethesda, MD 20892-6402 Telephone: (301) 594-2427 FAX: (301) 480-8318 Email: kousvelari@de45.nidr.nih.gov Willo Pequegnat, Ph.D. Office on AIDS National Institute of Mental Health Parklawn Building, Room 18-101 Rockville, MD 20857 Telephone: (301) 443-9700 FAX: (301) 443-9719 Email: WPEQUEGN@NIH.GOV Direct inquiries regarding grants management issues to: Mr. Martin R. Rubinstein Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN 44A Bethesda, MD 20892-6402 Telephone: (301) 594-4800 FAX: (301) 480-8301 Email: Martin.Rubinstein@nih.gov Diana S. Trunnell Grants Management Branch National Institute of Mental Health Parklawn Building, Room 7C-08 Rockville, MD 20857 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov Schedule Letter of Intent Receipt Date: February 1, 1998 Application Receipt Date: March 12, 1998 Scientific Review Date: May-June 1998 Advisory Council Date: August 1998 Earliest Award Date: September 1998 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.121 and 93.242. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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.
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files. |