PAS-00-123: HIV-1 INFECTION AND THE PERIPHERAL NERVOUS SYSTEM

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HIV-1 INFECTION AND THE PERIPHERAL NERVOUS SYSTEM Release Date: July 25, 2000 PA NUMBER: PAS-00-123 National Institute of Neurological Disorders and Stroke National Institute on Deafness and Other Communication Disorders National Institute of Mental Health THIS PA 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 PA. PURPOSE The National Institute of Neurological Disorders and Stroke (NINDS) ,the National Institute of Deafness and Other Communication Disorders (NIDCD), and the National Institute of Mental Health (NIMH) invite investigator- initiated research grant proposals to study the effect of HIV-1 infection on the peripheral nervous system and sensory organs. Although abnormalities of the peripheral nervous system associated with HIV-1 infection are not generally life threatening, they tend to occur relatively early in the course of the disease and contribute significant morbidity. Prompt recognition and effective treatment of these disorders could dramatically improve the quality of life of the patient. RESEARCH OBJECTIVES Background Symptomatic abnormalities of peripheral nerve function are among the most common complications of HIV-1 infection. About one-third of HIV-1 positive individuals develop some form of peripheral neuropathy, frequently relatively early in the course of their disease. Although the use of highly active anti-retroviral therapy (HAART) has been successful in ameliorating the constitutional manifestations of AIDS, there has been no significant impact on the incidence of peripheral neuropathy. In fact, given the increased longevity of patients treated with HAART, one might anticipate that peripheral neuropathy will become more of a clinical problem in the future. The neuropathic syndromes associated with HIV-1 infection are diverse and include both the somatic and autonomic nervous systems. The primary pathological abnormality may be demyelination, both acute and chronic, or axonal degeneration. Either single or multiple nerves may be involved leading to mono-or polyneuropathy. Polyradiculopathy and rare cases of primary ganglioneuronitis have been described. There are multiple etiologies for HIV-1 associated neuropathies. Inflammatory demyelinating polyneuropathy of the Guillain-Barre type, mononeuropathy multiplex, and progressive polyradiculopathy are clearly associated with concomitant infection with cytomegalovirus (CMV). Various nutritional deficiencies, specifically vitamin B12 deficiency, have also been implicated but the evidence is rather weak. Some anti-retroviral agents used in the treatment of HIV infection are known neurotoxins and can produce neuropathies, particularly distal symmetrical polyneuropathy (DSP). However most cases of DSP, which is by far the most common of the HIV-1 associated neuropathies are of unknown etiology. Additional research is required to clarify the diverse etiologies of the peripheral neuropathies associated with HIV-1 infection. Even for those neuropathies in which CMV infection has been definitely implicated, it is not clear if the pathological findings reflect primarily CMV infection per se, invasive HIV-1 infection facilitated by CMV attack upon the immune system, a synergistic interaction of CMV and HIV-1, or a combination of factors. Even a single clinical entity may have more than one etiology. For example, the HIV associated demyelinating neuropathies are associated with CMV infection, but demyelination also occurs occasionally in distal symmetrical neuropathy suggesting that CMV may play a role in at least some cases of DSP. Although the most obvious histological changes in HIV-1 associated neuropathies involve the peripheral nerves, inflammatory infiltrates and neuronal loss have been observed in dorsal root ganglia, as well as degeneration of the gracile tracts in the spinal cord suggesting that a component of the neuropathy may involve the dorsal root ganglionic neurons. The critical importance of the blood brain barrier in controlling the entry of HIV-1, macrophages and/or macrophages into the brain is well-recognized, as well as its role as a barrier to the entry of drugs used in HAART therapy. The blood-spinal cord barrier and the blood-nerve barrier (BNB) may have a similar importance in the development and/or treatment of HIV associated peripheral neuropathies but have been much less well studied. What information is available suggest that the permeability properties of the BNB are quite different from the BBB. For example, large molecules such as horseradish peroxidase can freely cross the blood nerve barrier but not the blood brain barrier. Differences in both normal and abnormal permeability of the BBB and BNB occasioned by HIV-1 infection may explain the large numbers of circulating activated macrophages found in the endoneurium of peripheral nerves, in HIV-1 associative neuropathies, and possibly the neurotoxic effects of antiretroviral agents on the peripheral but not the central nervous systems. Research on these barriers would not only be of basic science interest in defining the normal properties of these barriers, but also could have direct relevance to understanding the pathogenesis of and developing treatments for HIV associated neuropathy. Although HAART therapy has produced dramatic reductions in the systemic viral load and a marked reduction in the incidence of opportunistic infections, and an increase in well-being in the AIDS patients and has become the standard of care for HIV-1 infection in United States, some of the most effective drugs are associated with toxic neuropathies, which in some cases are sufficiently serious so as to require discontinuation or suboptimal modification of HAART therapy. The development of effective drugs without neurotoxic effects, resulting from research on the mechanisms of the HAART-induced neuropathies, would be a major advance in the treatment of HIV-1 infection. Sensory impairments are frequent complaints associated with HIV infection. Complaints include sensorineural hearing loss, smell and taste distortions, and other problems. For example, ear disease affects up to one-third of HIV- infected patients and otitis media is a frequent finding. Research is needed to assess whether sensory effects are the result of direct HIV infection, secondary opportunistic infections, or possibly neurotoxic effects of HIV drug treatment on the sensory organs. A serious outcome of HIV induced neuropathy is chronic pain. The impact of chronic pain on mental health outcomes is an area of significant interest to NIMH. Chronic pain may result in depression, anxiety, and substance abuse. In addition, studies of the approaches used for coping with HIV induced neuropathic pain is also encouraged. Examples of relevant research include, but are not limited to, the following: 1. Studies of the blood-nerve barrier (BNB) under normal and pathological conditions associated with HIV-1 infection including permeability of the barrier to HIV-1 virus, circulating macrophages, or neurotoxic agents produced systemically by activated macrophages. Such studies might include investigation of the role of the vasculitis produced by inflammation and/or HIV-1 infection of the endothelial cells of the endoneurial blood capillaries in compromising the integrity of the BNB or the blood supply to nerve fibers. 2. Study of the properties of the blood-spinal cord barrier under normal and pathological conditions associated with HIV-1 infection (as opposed to the blood-brain barrier) including the ability of the barrier to pass virus, macrophages, or cytotoxic materials. 3. Studies of the etiology of distal symmetrical polyneuropathy (DSP) including the relative importance of direct HIV-1 infection of peripheral axons and neurotoxic effects of substances such as cytokines produced by activated macrophages. 4. Studies of the pathogenesis of the demyelinating HIV-1 associated neuropathies including the role of activated resident and circulating macrophages in producing demyelination either by directly attacking myelin or by elaborating cytotoxic or demyelinating substances. 5. Study of the role, in producing demyelination, of molecular mimicry resulting from homology of segments of HIV-1 genes and protein products with sequences in the myelin protein. 6. Study of the relative roles of HIV-1 and macrophages in producing dorsal root ganglion cell damage and/or damage to the long sensory tracts in the spinal cord. 7. Study of the differential effect which HIV-1 infection and/or therapeutic agents might have on small and large fiber function in peripheral sensory nerves. 8. Study of morphological changes, associated with HIV-1 infection, which occur in the distal terminals of nociceptive fibers and in the peripheral sensory organs. 9. Study of the ability of drugs used in HAART therapy to pass the blood- nerve barrier (BNB) in sufficient concentrations to be effective. 10. Study of the mechanisms of the neurotoxic effects produced by drugs commonly used in HAART therapy and the development of less toxic agents. 11. Studies of the relative importance of direct CMV infection of the peripheral nervous system as opposed to synergistic interaction of CMV with HIV-1 to produce elaboration of neurotoxic materials. 12. Studies of the ability of agents such as gancyclovir, acyclovir, or foscarnet, used to treat CMV infection to pass the blood-nerve barrier in sufficient concentration to be effective in the treatment of those peripheral neuropathies associated with CMV infection. 13. Development of animal model of HIV associated peripheral neuropathy. 14. Studies of maladaptive responses to HIV associated neuropathic pain. Maladaptive responses may lead to comorbid conditions such as depression, anxiety, and substance abuse. 15. Study of adaptive responses, such as unique coping strategies for dealing with HIV induced neuropathic pain. 16. Studies of the effects of nucleoside analogs and protease inhibitors used as essential components of medications to treat HIV infection on taste quality perception that significantly impact on patient compliance, diet and nutrition. Possible peripheral causes of altered taste quality perception are changes in the sensitivity of select populations of taste receptors and concomitant changes in the response profiles of gustatory afferent fibers, HIV-mediated changes in the peripheral trigeminal system, and changes in the oral environment as a consequence of compromised autonomic nervous system function. 17. Studies on the neurotoxic effects of HIV medications on the peripheral sensory organs. Investigators also may obtain copies of these from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. MECHANISM OF SUPPORT The mechanism of support will be the individual research project (R01). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total requested project period for an application submitted in response to this announcement may not exceed five years. Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated that the size of an award will vary also. Collaborative efforts between research sites are acceptable. The NIDCD, NINDS, and NIMH may administratively limit the duration and the budget level of an award. Standard receipt dates for AIDS applications will be used. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The estimated total funds (direct and F&A costs) available for the support for all awards made under this PA will be $4.0 Million in FY 2001 or over multiple years. Although this program is provided for in the financial plans of the NIDCD, NIMH and the NINDS, awards pursuant to this PA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non- profit organizations, public and private institutions, 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. INQUIRIES Written and telephone inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: A.P. Kerza-Kwiatecki, Ph.D. Program Director Neural Environment Team National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2115 Bethesda, MD 20892-9521 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: ak45w@nih.gov Julianna Gulya, MD Director, Clinical Trials Program National Institute on Deafness and Other Communication Disorders Executive Plaza South, 400D-7, MSC 7180 6120 Executive Blvd Bethesda, Maryland 20892-7180 Telephone: 301-435-4085 Fax: 301-402-6251 E-mail: julie gulya@nih.gov Dianne Rausch, Ph.D Center for Mental Health Research on AIDS National Institute of Mental Health 6001 Executive Blvd, Room 6209, MSC 9619 Bethesda, MD 20892-9619 Telephone: (301)-443-7281 Fax: (301) 443-9719 Email: dr89b@nih.gov Ms. Sharon Hunt Chief, Grants Management Branch National Institutes on Deafness and Other Communication Disorders EPS, 400-B, MSC 7180 Bethesda, Maryland 20892-7180 Telephone: 301-402-0909 FAX: 301-402-1758 e-mail: SH79F@nih.gov Direct inquiries regarding fiscal matters to: Dianna Jessee Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3290 Bethesda, MD 20892-9537 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: dj35j@nih.gov Diana S. Trunnell Grants Management Branch National Institute of Mental Health 6001 Executive Blvd, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2805 Fax: (301) 443-6885 Email: Diana Trunnell@nih.gov APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application 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) 435-0714, email: Grantsinfo@nih.gov For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the PA number (PAS-00-123) and the title of this PA HIV-1 INFECTION AND THE PERIPHERAL NERVOUS SYSTEM must be entered. If the application submitted in response to this PA is substantially similar to a grant application already submitted to the NIH for review, but that has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application that is essentially identical to one that has already been reviewed cannot be submitted in response to this PA. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html 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 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and 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 $250,000) 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 the 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 telephone 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, including the checklist, and five signed, exact, single-sided photocopies, and five sets of appendix material in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040 - MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express mail or courier service) 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the NIH Center for Scientific Review (CSR) and will be assigned on the basis of established referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique, and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by a national advisory council or board. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. To put those criteria in context, the following information is contained in instructions to the peer reviewers. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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. 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 method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 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)? 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 group will also examine: the appropriateness of proposed project 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, adequacy of plans for including children as appropriate for the scientific goals of the research, the reasonableness of the proposed budget and duration in relations to the proposed research, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. 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 are provided that inclusion is inappropriate with respect to the health of the subjects of 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 the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or from program staff listed in INQUIRIES below who may also provide additional relevant information concerning the policy. 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 ethnical 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 URLs IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in a NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This PA, HIV-1 INFECTION AND THE PERIPHERAL NERVOUS SYSTEM , is related to the priority area of hypothesis-driven studies of nervous system disease. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.173 for NIDCD , No. 93.853 for NINDS, and 93.242 for NIMH. Awards are made under authorization of sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 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 Public Health Service 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 for 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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