PA-98-048: MECHANISMS AND PATHOGENESIS OF PEDIATRIC HIV-1 INFECTION

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MECHANISMS AND PATHOGENESIS OF PEDIATRIC HIV-1 INFECTION Release Date: March 25, 1998 PA NUMBER: PA-98-048 P.T. National Institute of Allergy and Infectious Diseases PURPOSE The Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), invites applications for basic research to study mechanisms of perinatal HIV-1 transmission and pathogenesis of HIV-1 infection in infants and children. The NIAID seeks applications for research studies that utilize advances in virology, immunology, and genetics to address these research areas. Of special interest are those basic research studies that hold promise for improvement of clinical strategies to prevent mother-to-infant transmission of HIV-1 or to treat perinatally infected children in order to prolong and improve the quality of their lives. For applications proposing use of clinical specimens, documented access to an adequate number of samples to address the study hypotheses will be required. Although this Program Announcement is being issued by NIAID, the other components of NIH listed below also have an interest in and support research on the topics covered. o National Institute of Child Health and Human Development o National Institute of Drug Abuse NIDA supports research addressing drug abuse aspects of transmission and pathogenesis in pediatric HIV-1 infection. Applicants may wish to contact each of the NIH components listed in INQUIRIES to find out about other funding opportunities. 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 Program Announcement, Mechanisms and Pathogenesis of Pediatric HIV-1 Infection, is related to the priority areas of HIV infection, immunization and infectious diseases, and maternal and infant health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grant (R01), and small research grant (R03) applications may be submitted in response to this program announcement. Applications for R01 grants may request up to five years of support. NIAID uses R03 grants to support small, highly innovative or pilot projects. Applicants for R03 grants may request up to $50,000 annual direct costs for a period not to exceed three years. Funds and time requested should be appropriate for the research proposed. Applicants for R03 grants must follow the special application guidelines and Terms and Conditions of Award in the NIAID SMALL RESEARCH GRANTS brochure (September 1996), this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/tools/broch.htm Responsibility for the planning, direction, and execution of the proposed research will be solely that of the applicant. RESEARCH OBJECTIVES Background Perinatal Transmission of HIV-1 Mother-to-infant transmission of HIV-1 remains one of the fastest growing aspects in the worldwide pandemic of AIDS. The World Health Organization estimates that presently 1600 babies are infected daily and that 5-10 million children worldwide will be infected by the year 2000. In the United States, the Centers for Disease Control and Prevention estimate that 12,000-14,000 children are currently infected with HIV-1, and approximately 7,000 infants are born annually to HIV- infected women. Recent developments have reduced perinatal HIV-1 transmission rates and altered disease progression in the United States and other developed countries. In February 1994 the results of the AIDS Clinical Trials Group (ACTG) 076 were reported. These findings demonstrated that an intensive regimen of zidovudine (ZDV) given to pregnant women and their infants could reduce the risk of perinatal transmission of HIV-1 by about two-thirds. Since then, increased maternal and infant use of ZDV, according to USPHS guidelines for prevention of perinatal HIV disease, has decreased transmission rates in the U.S. from 20-25% down to 5-10% in most clinical care settings, including among women with more symptomatic HIV-1 disease. However, transmission rates continue to be high in developing countries where the complex regimen such as one used in ACTG 076 cannot be widely applied. Despite the success of the ACTG 076 study using zidovudine to reduce the risk of perinatal transmission, there are still major gaps in our knowledge of the mechanisms of transmission or modes of action of the successful zidovudine regimen. For example, the role of host immunogenetic factors such as possession of the CCR5 chemokine receptor deletion, or certain HLA types, has been related to increased resistance to infection among uninfected adults with repeated exposures to HIV-1. Further research elucidating the role of host immunogenetics in relationship to perinatal HIV-1 transmission is also needed. Likewise, other critical research areas relate to the impact of highly active antiretroviral therapy, the importance of emerging antiretroviral resistance on risk of transmission, and immunologic and virologic factors related to post- partum transmission through breast milk, development of innovative approaches for implementation of successful international perinatal HIV prevention strategies which include nested pathogenesis studies addressing research such as the impact of short course antiretrovirals on breast feeding transmission, maternal and infant viral load or the emergence of drug resistance. Hence, further studies are needed to elucidate the mechanisms of perinatal HIV-1 transmission. Such research might utilize both animal models and nested laboratory studies with samples from clinical perinatal HIV-1 cohort studies. Pathogenesis of Pediatric HIV-1 Disease The pathogenesis of pediatric primary HIV-1 infection appears to differ significantly from adults in that it is characterized by much higher viral load levels, more rapid disease progression, and early central nervous system disease. Such different manifestations may be related in part to immaturity of the infant immune system which results in altered host responses to HIV infection among infants and young children compared to adults. Among HIV-1 infected infants and children, the correlates of HIV disease progression have not been well defined. Historically, a high proportion of children (about 15- 20%) have a rapid disease course with AIDS and death within the first 4 years of primary infection. Future pediatric HIV research efforts will continue to focus on the pathogenesis of pediatric HIV infection and factors that impact on disease progression. One important new research area will be to assess the impact of early highly active antiretroviral therapy (HAART) on preservation of CD4 helper cell clones and on the CD8 V-beta repertoire as these relate to pediatric HIV disease progression. Another crucial research area will be to study the role of host immunogenetics and cytokine production in modulating disease progression. In addition, with the widespread use of zidovudine for the prevention of perinatal HIV transmission, there will be increasing numbers of exposed but uninfected infants born to HIV-1 infected women. Studies of host responses (e.g. cytokine production, and CTL responses) to HIV exposure among this growing population of uninfected infants can enhance our understanding of correlates of immunity. Furthermore, late effects of exposure to perinatal antiretrovirals such as potential organ toxicity or cancers are unknown and need further research. Overall, all these emerging research data emphasize the need for coordinated studies to evaluate the interactive role of virologic, immunologic, genetic and clinical factors as they influence both perinatal HIV transmission and pediatric disease progression. Thus, the objectives of this Program Announcement are to 1) encourage state-of- the-art laboratory approaches in the areas of transmission of HIV-1 from mother to infant (or perinatal retroviral transmission in relevant animal models), 2) study pathogenesis of primary infection in infants and factors influencing the course of infection and long-term survival, 3) support innovative implementation strategies for the prevention of perinatal HIV transmission in developing country settings into which basic research studies assessing pathogenesis and mechanisms of transmission are nested, and 4) support studies addressing potential sequelae of perinatal HIV interventions (e.g. late organ toxicities or cancers related to perinatal antiretroviral exposure, impact of short course antiretrovirals for perinatal HIV prevention on emergence of antiretroviral resistance or on viral load) and the impact of HAART on both transmission and disease progression. Research Objectives and Scope The NIAID wishes to support continued laboratory-based research into mechanisms of perinatal HIV-1 transmission and the pathogenesis of pediatric HIV-1 disease. This PA encourages investigators with proposals for basic research studies to collaborate with clinical investigators following HIV-infected children at clinical sites, as well as collaborative research using specimens from multi-site pediatric cohort studies. Research proposals that use animal models to address mechanisms of perinatal transmission or pathogenesis research related to retroviruses are also encouraged. General research areas of interest under this PA include, but are not limited to, assessment of the following: o Mechanisms and timing of perinatal HIV-1 transmission o Maternal and/or infant immunologic, virologic and genetic factors that might influence perinatal HIV-1 transmission o The role of the placenta in facilitating or decreasing risk of transmission including in situ localization of HIV-1, placental immunologic function and cytokine production, and the relationship between virus in the maternal genital tract to infected infants" first HIV-1 isolates o The role of mucosal exposure to HIV-1 as a source of perinatal HIV infection including transmission through breast feeding o Modes of action of successful perinatal pharmacologic or immunotherapy regimens in decreasing perinatal transmission, and potential effects of preventive antiretroviral strategies on timing of infant infection o Impact of implementation of perinatal HIV prevention strategies in developing country settings as assessed by laboratory endpoints (e.g. PCR detection of overall infant infection rates and the proportion of late transmission due to breast feeding, differences in perinatal transmission rates by viral subtype, emergence of antiretroviral resistant strains, impact of short course antiretrovirals on viral load) o HIV-1 viral quasispecies characteristics, viral load patterns, and viral distribution patterns across various body compartments of neonates and young infants (e.g. central nervous system), as well as infant immunologic and immunogenetic responses that may influence disease progression, including identification of early markers of rapid versus more stable disease progression o The impact of HAART begun during the first few months of life, on clinical course, immunologic responses, and viral patterns seen in pediatric HIV primary infection. Assessment of sanctuaries for and persistence of HIV-1 virus among infants treated with HAART o The impact of HAART on timing and emergence of opportunistic infections among HIV-1 infected infants and children including assessment of host lymphocyte functioning, immune proliferative responses, or cytokine production o Host immunogenetic and virologic factors related to long-term nonprogression among children and adolescents o Laboratory studies addressing evidence for or against immunologic responses to HIV-1 among uninfected infants born to HIV infected women, as well as laboratory based studies of infant immune responses to HIV-1 related vaccines o Sequelae (e.g. risk of later cancers, or end organ toxicities) of prophylactic antiretroviral and immune interventions among both infected and uninfected infants and children exposed to perinatal interventions, and animal studies of toxicities related to antiretroviral exposure Laboratory investigations that address the research areas described above or related research topics will be considered responsive to this PA, as will innovative studies addressing perinatal HIV prevention implementation strategies in developing countries which include laboratory studies assessing mechanisms of transmission and pathogenesis. Collaborations between basic laboratory researchers and clinical investigators who follow perinatal or pediatric HIV cohorts are strongly encouraged under this PA. It is anticipated that clinical specimens required for the proposed laboratory studies could be obtained from a variety of sources including ongoing animal studies investigating perinatal transmission of retroviruses, perinatal or pediatric HIV cohorts followed at specific clinical sites, ongoing multi-site epidemiologic studies, as well as clinical trials both in the U.S. and in international settings. Program Staff at DAIDS can offer assistance to laboratory-based investigators wishing to contact clinical investigators with relevant specimens from perinatal or pediatric HIV cohorts. Contact the DAIDS Program Officer listed under INQUIRIES for further assistance. Note: This PA is not intended for direct conduct of clinical trials, patient care, or maintenance of natural history cohorts, but it can help support innovative implementation studies of perinatal HIV prevention studies in developing countries that include basic laboratory research addressing pathogenesis and mechanisms of transmission. Availability of adequate numbers of clinical samples or animal resources to address the study hypotheses must be documented in the application. Studies of mother-to-infant transmission may, by their nature, include women but not men as study subjects. The gender of their infants will be unknown to the investigator in studies beginning during pregnancy. If the population of HIV- infected women available for study is limited to, or primarily composed of, one racial or ethnic group, investigators should explain the circumstances in the application and address potential ways to overcome this limitation. 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 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 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 Dr. Fowler (listed under INQUIRIES). Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted on the standard AIDS 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 Division of Extramural Outreach and Information, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@od.nih.gov. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES". The PA number and the PA title must also be typed in section 2. The completed, signed original and five legible, single-sided copies of the application and five copies of appendices must be sent or delivered to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) R03 Applicants. Applicants for small research (R03) grants are to follow the application guidelines in the NIAID SMALL RESEARCH GRANTS brochure (September 1996), which is available from the program staff listed under INQUIRIES and via the WWW at: http://www.niaid.nih.gov/ncn/tools/broch.htm R03 applications that do not conform to the instructions in the brochure will be returned to the applicant without review. ALL APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL DIRECT COSTS. The NIH Policy Update on Acceptance for Review of Unsolicited Applications that Request More Than $500,000 Direct Cost for Any One Year applies to applications in response to this PA. The Policy Update was published in the NIH Guide for Grants and Contracts, Volume 25, No. 14, May 3, 1996, and became effective June 1, 1996. Potential applicants must contact the appropriate program staff listed in INQUIRIES below to initiate clearance processes for acceptance of their applications if ANNUAL DIRECT COSTS EXCEED $500,000 FOR ANY ONE YEAR. 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. 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 NIH Center for Scientific Review. Incomplete applications will be returned to the applicant without further consideration. R01 applications will be reviewed for scientific and technical merit by study sections of the Center for Scientific Review, NIH, in accordance with the standard NIH peer review procedures. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. R03 applications that are complete and responsive to this PA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID. 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. 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? 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, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance among research areas of the program announcement, and availability of funds. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. The NIAID brochure on "NIAID Small Research Grants" can be found on the WWW at http://www.niaid.nih.gov/ncn/tools/broch.htm Inquiries regarding the brochure or programmatic (research scope and eligibility) issues may be directed to: Mary Glenn Fowler, MD, MPH Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2A09 Bethesda, MD 20892 Telephone: (301) 496-6178 FAX: (301) 402-3684 Email: mf25c@nih.gov Direct inquiries regarding fiscal matters to: Jane Unsworth Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B25 Bethesda, MD 20892-7610 Telephone: (301) 402-6824 FAX: (301) 480-3780 Email: ju3a@nih.gov Direct inquiries about the related research interests of other NIH Institutes and Centers to: Anne Willoughby, MD, MPH Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11, MSC 7510 Rockville, MD 20892-7510 FAX: (301) 496 8678 Telephone: (301) 496 7339 Email: WILLOUGA@HD01.NICHD.NIH.GOV Katherine Davenny, Research Epidemiologist Division of Clinical Research National Institute on Drug Abuse 5600 Fishers Lane, Room 10A-08 Rockville, MD 20857 FAX: (301) 596-6566 Telephone: (301) 443-1801 Email: KD25H@NIH.GOV AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citations are 93.855 - Immunology, Allergy, and Transplantation Research and 93.856 - Microbiology and Infectious Disease Research. Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems review. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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