Full Text DE-96-003 UNDERLYING MECHANISMS OF ORAL MANIFESTATIONS OF HIV INFECTION NIH GUIDE, Volume 25, Number 1, January 26, 1996 RFA: DE-96-003 P.T. 34 Keywords: AIDS Infectious Diseases/Agents 0705048 National Institute of Dental Research Letter of Intent Receipt Date: March 26, 1996 Application Receipt Date: April 26, 1996 PURPOSE The National Institute of Dental Research (NIDR) invites applications from biomedical and behavioral investigators designed to advance an understanding of the underlying mechanisms i.e., molecular, genetic and behavioral, that result in the development of oral complications associated with HIV-infection and AIDS. The overall goal of this RFA is to encourage research aimed at developing state-of-the art biomedical and behavioral methodologies for the prevention and treatment of these pathologies. Since the current AIDS grant portfolio of the Institute is already supporting a large number of epidemiological studies as well as studies on the basic biology of candida, additional applications on these topics is discouraged. 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, "Underlying Mechanisms of Oral Manifestations of HIV Infection" 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 Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, non-profit and for-profit organizations, public and private, such as universities, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for the First Independent Research Support and Transition Award (FIRST) (R29). Applications from minority and women scientists are encouraged. MECHANISMS OF SUPPORT Support of this program will be through the National Institute of Dental Research. The mechanisms available for support of applications to this RFA include research project grants (R01) and FIRST (R29) awards. FUNDS AVAILABLE The NIDR will allocate approximately $2 million to support projects from this RFA during FY 96. It is anticipated that at least eight awards will be made, provided that applications are of high scientific merit. Applicants may request up to five years of support. Subsequent support will be dependent upon submission by the applicant of a renewal application through established NIH procedures for research grants related to AIDS. Although this program is provided for the financial plans of NIDR, the award of grants pursuant to this RFA is contingent upon availability of funds for this purpose. Policies that govern research grant programs of the National Institutes of Health will prevail. RESEARCH OBJECTIVES Background The AIDS pandemic continues to grow worldwide despite sustained efforts by scientists and health care workers along with the commitment of considerable resources. Progress in minimizing the spread of this public health menace has been slower than anticipated. By the year 2000, the World Health Organization (WHO) estimates that between 30 and 40 million people will be infected with HIV. In the United States, one person dies of AIDS every 8 minutes, and the rate is increasing in women as well as in African American and Hispanic communities. AIDS is a severe T cell immunodeficiency caused by infection with HIV. During the last few years, it was discovered that this RNA virus has a significant rate of mutations, thereby producing various forms of HIV pathogenesis. The major viral form has a tropism for monocytes and CD4+T lymphocytes causing depletion of these cells by direct lysis as well as via several indirect mechanisms that lead to death, defective maturation, and abnormal function of uninfected T cells. The depletion of T cells and acquired alterations in other cell functions result in greatly increased susceptibility to infection by a number of opportunistic microorganisms, including bacteria, fungi and viruses. The NIDR is currently supporting research projects to identify and treat oral pathologies associated with HIV infection and progression to AIDS in all patient groups. The AIDS research program of the NIDR includes studies involving: the prevalence and severity of oral mucosal and gingival lesions; non-infectious oral lesions; the importance of oral fluids as sources of HIV inhibitory factors and non-invasive diagnostic tests for HIV; the etiology, natural history and epidemiology of AIDS; the oral component of the Women~s Interagency HIV study (WIHS); searches for oral diagnostic markers; investigations of the molecular events that transform candida and other oral organisms from non-pathogenic to pathogenic forms; and the development of new therapeutic strategies to combat reoccurrence of candida infections. Other studies include research on oral mucosal immunity, salivary leukocyte protease inhibitor (SLPI), development of synthetic vaccines and drug delivery systems, the use of transgenic mice, and other methods to elucidate the effect of HIV infections on selected tissues. Characterization of inhibitory salivary proteins. As early as the mid-1980s it was recognized that HIV is rarely isolated from saliva. Infectivity of lymphocytes in the presence of saliva is greatly reduced in vitro. These findings were attributed to salivary inhibitory factors. Data from previous and current projects show that inhibitory factors are contained in high and low molecular weight fractions. Inhibitory activity in parotid secretions is associated with four components that bind specifically to recombinant gp120. Major inhibitory activity was found in a 37kDa protein. Partial characterization of this latter protein suggests that it may be the parotid-specific basic proline-rich protein, PS1. Factors unique to submandibular/sublingual secretions, such as mucins, appear to function in viral particle entrapment. Evidence suggests that in whole saliva at least two mechanisms, aggregation and agglutination, may be responsible for inhibition of HIV infectivity. Recently, SLPI has been reported to exhibit inhibition of HIV infectivity in vitro at physiological concentrations. In addition, data from current projects indicate that saliva contains low molecular weight molecules called histatins with anti-candida activity. Histatins have shown to be reduced in saliva of HIV infected persons. One of the goals of this RFA is to develop methods to enhance the biological activity of the salivary proteins with anti-candida and anti-HIV activities in the oral cavity as a way to increase the host~s defense capabilities. To fulfill this goal, additional research is needed to isolate and characterize the genes and protein structures of the salivary proteins which serve as candidates to exhibit anti-candida and anti- HIV activities. Molecular mechanisms underlying HIV-associated immunosuppression. The oral complications of HIV infection have been considered an initial manifestation of infection in high-risk patients for HIV as well as an important marker for the disease progression. The oral lesions manifested by HIV infection may be associated with specific pathogens, including fungi, bacteria and viruses. NIDR has initiated a number of studies of the elucidation of AIDS-related opportunistic infections particularly involving candida as an AIDS-related pathogen.The goals of these studies were to elucidate the basic biology and pathogenic mechanisms of candida species. However, it is becoming clear that oral candidiasis, hairy leukoplakia (Epstein-Barr virus, EBV) and reactivation of human cytomegalovirus (HCMV), herpes simplex virus (HSV) and human papillomavirus (HPV) are manifestations within a complex series of inflammatory and immune responses to HIV infection. Additional research is needed to elucidate the molecular mechanisms by which HIV or HIV-associated immunosupression might affect the phenotypic variability and pathogenesis of candida and the reactivation of HCMV, HSV, HPV and EBV. Mechanisms of retrovirus infection in exocrine tissue. Early in the AIDS pandemic it appeared that HIV-infected persons may have shared clinical symptoms of salivary gland dysfunction with patients with autoimmune disease. HIV associated salivary gland disease is defined as the presence of enlargement of the major salivary glands and diminished salivary function in some HIV infected individuals. It has a number of similarities as well as differences from Sjogren~s syndrome (SS). For example, SS patients often exhibit polyclonal gammopathy which is also present in AIDS. T cell defects and autoantibodies occur in both SS and AIDS patients, however, CD4+T cells are the predominant infiltrating cells in SS, whereas CD8+T cells dominate the salivary infiltrate in HIV-associated salivary gland disease. This manifestation of HIV infection seems to reflect host immune response associated with the salivary glands and lungs. In view of the considerable clinical overlap between SS and AIDS, at least at the early stage of infection, minor salivary gland biopsies from both patient groups can be used to elucidate the mechanisms of retrovirus interactions with exocrine tissues along with their differences and/or similarities with autoimmune disease. Thus, not only is the study of the role of HIV infection in salivary gland function important in its own right but it also could offer an excellent model system to study the progression of the disease in exocrine glands. Oral mucosal immunity and HIV infection. Increases in oral infections associated with HIV infection provide opportunities to investigate the oral mucosal immune responses that provide protection against HIV-associated opportunistic infections in the mouth. The mucosal immune system is generally characterized by the predominance of IgA in external secretions, and in IgA producing plasmacytes in tissues underlying mucosal epithelium as well as within certain excretory glands, i. e., salivary glands. In the oral cavity, secretory IgA is synthesized by the major and minor salivary glands. It has been shown that IgA-committed cells travel from gastrointestinal and other lymphoid tissues (GALT) to glandular mucosal tissues such as salivary, lachrymal and mammary glands. These cells also go from GALT to the lamina propria of small intestine, bronchiae and vagina, thus establishing the mucosal immune network. Secretory IgA (SIgA) is believed to neutralize some types of viruses more effectively than serum IgA. Its polymeric structure, its presence in mucus secretions, and its resistance to proteolytic degradation are often described as factors which may contribute to a more effective neutralizing ability. It has been shown that as HIV infection advances, there are variations in serum IgA and SIgA levels. Total non-specific SIgA levels often decline while, total non-specific serum IgA levels often increase dramatically. This is suggestive of selective deregulation of IgA production and transport. Changes in IgA modulation may be reflective of alterations in mucosal immunity induced by HIV. The mechanisms responsible for the regulation of serum IgA and SIgA in HIV infection need further investigation. Cytokines are responsible for switching of IgA isotypes as well as migration of IgA producing cells to the lamina propria. Correlation of cytokine profiles and levels in the oral tissues of HIV infected and healthy persons may provide information on the role of cytokines on the deregulation of IgA production and transport. Behavioral research on oral manifestations of HIV infection. Epidemiological studies have indicated that AIDS can be prevented with changes in lifestyle or behaviors which limit transmission of the virus. Behaviors engaged in by patients and health care providers also influence the detection, prevention, and treatment of oral manifestations of HIV infection. Since oral manifestations of HIV infection tend to occur early, access to health care providing accurate detection of oral changes associated HIV infection, could lead to earlier referral to appropriate health care providers and possibly improve therapeutic outcomes. Few studies have determined behavioral/educational strategies to enhance early detection of oral indicators of HIV infection manifestations, or have assessed specific factors impeding oral self-examination or professionals~ detection of HIV-associated oral changes. Behavioral studies in these areas are encouraged. Similarly, few studies have assessed the effects of oral manifestations of HIV infection on patients~ adherence to therapeutic regimens, quality of life, functional status, pain experience, and rehabilitation. Assessing the effects of HIV-related oral changes and specific oral therapies on functional outcome measures could contribute valuable insights on preventive or therapeutic strategies yielding outcomes which directly and demonstrably benefit the HIV patient. Research Objectives and Scope The goal of this RFA is to encourage basic research into the mechanisms of HIV infection and subsequent pathogenesis to understand the oral complications associated with AIDS. In addition, critical studies are needed to develop strategies for biomedical and behavioral approaches to prevent and reduce the severity of these pathologies. The oral cavity presents an excellent model for investigations on the pathological effects of HIV because of frequent manifestations of HIV infection in the mouth, easy access for specimen collection, a reflection in the oral cavity of alterations in the immune function at distant mucosal sites, and availability of information about the effects of viruses, particularly through infectious changes, on the mucosal immune system. This RFA is intended to stimulate further scientific investigations on the underlying molecular and genetic mechanisms that allow the development of oral complications associated with HIV-infection and AIDS as well as to develop state-of-the-art methodologies for the prevention and treatment of these pathologies. Some recommended research topics are provided as examples and are not intended to be inclusive or restrictive: o determination of genes and protein structures and elucidation of the molecular mechanisms of action of the salivary inhibitory components; o use of NMR spectroscopy, X-ray crystallography and computer programs to model biologically active peptide regions that have implications for anti-candida and anti-HIV activities; o construction of bioactive synthetic peptides and recombinant proteins of the salivary proteins that have been identified as having anti-candida and anti-HIV activities and development of systems for their delivery; o identification and elucidation of the molecular changes induced in the oral environment by HIV that can affect the phenotypic variability of candida and the reactivation of HCMV, HSV, HPV and EBV; o examination of the changes in the minor salivary glands and elucidation of the mechanisms underlie salivary gland pathogenesis in HIV-infected individuals (particularly, the mechanisms leading to the CD8+ T cell infiltrate in HIV-infected individuals as well as studies in understanding the function(s) of these lymphocytes in salivary gland injury); o delineation of the mechanisms of oral genetic factors that mediate resistance or sensitivity to infection and influence disease progression (e.g. HLA-controlled immune responses to HIV and self antigens; HIV modulated cytokine responses); o use of immune deficient mice as a model to analyze host-virus interactions on mucosal surfaces and in the salivary glands and to outline the specific immune mechanisms that are important for inherited or acquired resistance to oral infections or to salivary gland pathologies; o development and use of existing innovative and highly sensitive molecular techniques such as in situ PCR, mimic PCR, flow cytometry and ELISPOT, to examine changes in cytokines, other immune regulators and cellular levels of immunoglobulins in saliva and in oral biopsies; o examination of the local (oral) immune responses in HIV- seropositive and HIV-seronegative individuals by making use of saliva, oral biopsies (e.g., minor salivary glands, mucosal cells) which are easy to sample and represent a unique aspect in monitoring diseases at the site of the tissue under attack and comparisons with other mucosal sites; o quantitation of salivary SIgA, serum IgA and cytokine levels at the different stages of HIV infection and correlation with the pathogenesis of oral manifestations of HIV infection; o development of recombinant methodologies and adjuvants for the enhancement of SIgA in saliva; o development and evaluation of strategies for influencing members of high-risk groups, patients, and health care providers to adopt behaviors which improve early detection, prevention and treatment of oral manifestations of HIV infection, thus contributing to the early detection, prevention, and treatment of HIV infection; and o development of knowledge providing the basis for improving quality of life, adherence to treatment protocols and functional and health outcomes in patients with oral manifestations of HIV infection. 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 minorities in study populations which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or 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 March 26, 1996, a letter of intent. This should include the number and title of this RFA, a descriptive title of the proposed research, the name, addresses, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, the number of the RFA DE-96-003, and the title "Underlying Mechanisms of Oral Manifestations of HIV Infection." 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 allows 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 Prospective applicants are encouraged to communicate with program and grants management staff of the NIDR's Division of Extramural Research as early as possible in the planning phase of application preparation. Advice and suggestions by staff may materially assist applicants to ensure that the objectives and structure and the budget format are acceptable. Applications must be prepared on form PHS 398 (Rev. 5/95). An Application for a PHS Grant is available at most institutional business or grants and contracts offices and may be obtained from the Office of Grants Information, Division of Research Grants (DRG), National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892 (Telephone: 301-710-0267). 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 "Underlying Mechanisms of Oral Manifestations of HIV Infection." "DE-96-003" must be typed in item 2 of the face page of the application form and the YES box must be checked. Applications of 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. Applicants from institutions which 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. In such a case, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. Submit a signed, typewritten original of the application, including a cover letter (if appropriate), the checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health 6701 Rockledge Drive, Room 1040 Bethesda, MD 20892 (use 20817 for Federal Express) 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 Natcher Building, Room 4AN-38D Bethesda, MD 20892-6402 Applications must be received by April 26 , 1996. If an application is received after that date, it will be returned to the applicant without review. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by the NIDR. Incomplete applications will be returned to the applicant without further consideration. If NIDR staff find that the application is not responsive to the RFA, it will be returned without further consideration. Remaining applications may be subjected to a streamlined review process by a special grants review committee convened by the NIDR Scientific Review Office, to determine their scientific merit relative to other applications received in response to the RFA. The NIDR will withdraw applications judged to be in the bottom tier of applications. Applications determined to be competitive will be evaluated for scientific and technical merit by the review committee. Secondary review of the applications will be conducted by the National Advisory Dental Research Council. Major factors to be considered in the evaluation of the applications include: o the extent to which research project will broaden and strengthen the scientific base underlying the national capability to improve oral health; o the scientific merit of the proposed research project, including its significance, originality, feasibility, and experimental design; o qualifications and research experiences of the Principal Investigator and staff, particularly but not exclusively in the area of the proposed research; o the scientific/technical merit and justification for requested resources; and o the ability to recruit individuals from appropriate study populations (i.e., women, subpopulations of minorities and disabled individuals) as defined by the NIH guidelines along with provisions for their protection from research risks and the humane treatment of animal research subjects that may be used. AWARD CRITERIA The earliest anticipated date of award is September 30, 1996. 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 staff and the National Advisory Dental Research Council in making funding recommendations. In addition, the NIDR appreciates the value of 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 is likely to select the more cost-competitive application for funding. INQUIRIES Written 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: Dr. Eleni Kousvelari 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 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 Email: Martin.Rubinstein@NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93. 121. 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 Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. 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. |