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 รพ 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) 435-0714,
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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