Full Text PA-97-105
 
HIV PATHOGENESIS IN WOMEN'S INTERAGENCY HIV STUDY (WIHS)
 
NIH GUIDE, Volume 26, Number 30, September 5, 1997
 
PA NUMBER:  PA-97-105
 
P.T.


Keywords: 

 
National Institute of Allergy and Infectious Diseases
National Institute of Child Health and Human Development
National Institute on Drug Abuse
National Cancer Institute
National Institute of Dental Research
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Neurological Disorders and Stroke
Office of Research on Women's Health
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID),
the  National Institute of Child Health and Human Development
(NICHD), the National Institute on Drug Abuse (NIDA), the National
Cancer Institute (NCI), the National Institute of Dental Research
(NIDR), the National Institute of  Diabetes and Digestive and Kidney
Diseases  (NIDDK),the National Institute of Neurological Disorders
and Stroke (NINDS) and the Office of Research on Women's Health
(ORWH) invite applications for highly focused basic research
integrated with the WOMEN'S INTERAGENCY HIV STUDY (WIHS) scope and
structure.  Applications are expected to utilize the WIHS study
population, a large cohort of HIV-infected women in the U.S., to
formulate specific hypotheses concerning HIV/AIDS pathogenesis in
women. The WIHS cohort is followed in five large metropolitan areas
(New York, Washington DC, Chicago, Los Angeles and San Francisco).
 
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 (PA), "HIV PATHOGENESIS IN WOMEN'S INTERAGENCY HIV STUDY
(WIHS)" is related to the priority area of "HIV Infection" (SAI:
Natural history, transmission, behavior, women, in-vivo
pathogenesis).  Potential applicants may obtain a copy of "Healthy
People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary
Report: Stock No. 017-001-10473) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-0325
(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 or Local
Government, and eligible agencies of the Federal Government.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards.  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 FIRST award (R29)
applications may be submitted in response to this program
announcement.  Applications for R01 grants may request up to five
years of support; applications for R29 grants must request five years
of support.  Responsibility for the planning, direction, and
execution of the proposed research for all applicable mechanisms of
support will be solely that of the applicant.
 
RESEARCH OBJECTIVES
 
A.  Background
 
1.  HIV IN WOMEN.
 
HIV in women is increasing worldwide.  In the U.S., the epidemic
began expanding among women in the late 1980s and the full extent of
the epidemic in this population has yet to be clearly defined.  As of
December 1996, the Centers for Disease Control and Prevention (CDC)
estimated that the cumulative number of AIDS cases in adult and
adolescent women in the U.S. was 85,500, with 20,302 in 1996 alone.
Women now comprise approximately 15% (85,500/581,429) of the total
adult and adolescent AIDS cases, the highest proportion yet reported.
The impact of AIDS is particularly severe in minority populations in
the U.S.  Blacks and Hispanics combined constitute 48% of AIDS cases
among men, but 76% among women.
 
In the U.S., the proportion of women acquiring HIV infection through
sexual contact with HIV-infected men is increasing. In 1996, 40% of
women with AIDS reported acquiring HIV infection through sexual
contact with a man with or at risk for HIV infection, and 34%
reported injecting-drug use as their main exposure category.  AIDS is
now the third leading cause of death for women aged 25 to 44 after
cancer and cardiovascular disease and the leading cause of death for
African-American women in this age group. The increasing mortality
rate for women also affects children: the estimated 80,000
HIV-infected women of childbearing age who were alive in 1992 will
leave about 125,000-150,000 orphans during the 1990s.
 
At the current stage of the HIV/AIDS epidemic, new paradigms have
emerged that will influence the direction of future research on
HIV/AIDS. Some of these paradigms will increasingly apply to women,
as women become a progressively larger fraction of persons with
HIV/AIDS in industrialized countries.  Research areas that are likely
to draw more attention in the near future will include the study of
pathogenicity and transmissibility of different HIV subtypes or
recombinant forms and their interaction with variably susceptible
individuals; the change in the scope of HIV natural history studies
in the era of combination antiretroviral therapy; and the
contribution of such studies to the design of a wide spectrum of
prevention modalities (e.g. prevention of HIV and prevention of
opportunistic infections). In addition, studies of natural history of
HIV-related malignancies and active surveillance of malignancies in
HIV infected and high-risk uninfected women may lead to new screening
and prevention modalities in high-risk populations of women.  Studies
of HIV/AIDS in women can play a unique role in testing new biological
or socio-behavioral hypotheses at the population level and in linking
basic science findings and laboratory methods to epidemiologically
well defined populations and communities.
 
2. WIHS.
 
The Women's Interagency HIV Study (WIHS), a multicenter, prospective
study, was established in August, 1993 to carry out comprehensive
investigations of the impact of HIV infection in women.  This study
has been conducted by NIH in tandem with a similar study coordinated
by the U.S. Centers for Disease Control and Prevention (CDC), the HIV
Epidemiology Research Study (HERS).  In addition to NIAID, several
other NIH institutes currently fund different components of the WIHS.
These Institutes include: the National Institute of Child Health and
Human Development (NICHD), the National Institute on Drug Abuse
(NIDA), the National Cancer Institute (NCI) and the National
Institute of Dental Research (NIDR). The WIHS has interacted with the
community from the outset, by soliciting the community's input to
better identify problems and pursue research opportunities. Community
involvement through the individual WIHS sites and the Community
Advisory Board (CAB) is encouraged to foster women's participation
and understanding of research scope and results.
 
The rationale for establishing the WIHS in 1993 was to investigate
the clinical, laboratory and psychosocial aspects of HIV infection in
women, in a multi-site, prospective fashion.  The significant
investment needed to develop a complex infrastructure such as exists
in the WIHS requires a period of several years of collaborative
research and cohort follow-up for maximum scientific benefit to
accrue. In addition, changes should be monitored in the natural
history of HIV and associated conditions occurring as a result of
treatment advances and longer survival. The follow-up phase began at
completion of participants' recruitment in November, 1995. A total of
2,641 women (2066 HIV positive and 575 negative), 80% of minority
background, were enrolled.  During the course of the study, progress
in HIV/AIDS research will continue to require flexibility in
modifying goals and adjusting the infrastructure to reflect new
knowledge and new, state-of-the-art methodology.  The achievement of
this goal will be facilitated by the fact that clinical care and
research activities are carried out at the same health facility. This
allows for real-time clinical observation and laboratory testing.
The rapid implementation of new protocols will be especially
dependent on the presence of the following project-wide
characteristics: adequate infrastructure and coordination within the
individual consortia, effective linkage between the study sites,
real-time coordination of activities by the Data Center, and
efficient use of the biological specimens.
 
B.  Research Objective and Scope
 
Applications are invited to conduct studies focused on basic
mechanisms of HIV infection and progression in women. Applications in
response to this Program Announcement may include expansion of
ongoing studies and new studies. In addition, studies may involve all
WIHS sites or may be limited to defined subsets of the WIHS
population, when special requirements exist, such as the need for
more frequent participant visits.  Studies may address, in detail,
biological aspects of HIV infection and how such aspects affect
women's health. Proposed studies should emphasize investigations
predicated upon specific hypotheses.  Applications may focus on
investigations in the specific areas of interest of the collaborating
NIH Institutes, as outlined below.  HIV/AIDS in women is a high
priority for research for ORWH.  ORWH will be pleased to provide
cofunding through the participating institutes in support of
meritorious grant applications, contingent upon the availability of
funds.  Important areas of investigation include, but are not limited
to, the following subjects:
 
NIAID: grant applications in the area of molecular basis of HIV
infection and disease progression in women, including the interplay
of host and viral characteristics; characterization of HIV in
cervico-vaginal mucosa and its relationship with HIV in blood;
virologic and immunologic factors and their relationship with
endocrinologic factors in HIV infected women; cellular and molecular
bases for higher susceptibility of women to HIV transmission via the
mucosal route as compared to men. NICHD: grant applications in the
areas of endocrinologic factors (including both endogenous and common
exogenous hormonal exposures), HIV expression, and disease
progression; interactions between pregnancy and HIV infection; and
fertility-related behaviors among HIV-seropositive women.
 
NIDA: grant applications investigating direct and indirect effect of
drug use and associated co-morbidity; viral and immune factors
influencing the course of HIV-related disease, including correlations
between systemic and genital changes and the role of the female
genital tract as a reservoir of HIV infection.
 
NCI: grant applications in the areas of surveillance of the
prevalence, incidence, and secular trends of all cancers occurring in
the WIHS cohort; the natural history of AIDS-related cancers; the
role of human papillomavirus, Epstein-Barr virus, and Human Herpes
Virus 8 in the etiology of AIDS-associated cancers; and the effects
of viral strain variation, co-infections with multiple viruses, host
genetics, immune perturbations, hormonal changes, and anti-retroviral
treatment on the pathogenesis and clinical epidemiology of
AIDS-related pre-cancerous changes and cancers.
 
NIDR: grant applications investigating the in vivo role and mechanism
of action of oral antiviral factors (salivary and mucosal); the
influence of oral co-infections on HIV infection and disease
pathogenesis; the role of the oral pharyngeal region as a reservoir
of HIV infection; oral diagnostics and therapeutics; the role of host
response in candida infections; characterization of salivary
molecules exhibiting anti-candida activities; and identification of
anti-candida epitopes and construction of bioactive synthetic
peptides.
 
NIDDK: grant applications to elucidate the pathogenesis of AIDS
wasting syndrome (AWS), including the effects of HIV on endocrine and
gastrointestinal function, metabolism, appetite and diet,  physical
activity, and body composition; studies of intercurrent illnesses in
the pathogenesis and natural history of AWS; studies of the
pathogenesis and natural history of endocrine, gastrointestinal and
renal dysfunction in HIV-positive women, including mechanisms of
drug-induced diabetes and hepatic and renal toxicity.
 
NINDS: grant applications investigating the pathogenesis of central
and peripheral nervous system abnormalities caused directly or
indirectly by HIV infection in HIV-positive women. Such research
could include the role of genetic factors, immune status, and
hormonal function in women at risk for AIDS-related neurological
disorders.
 
ORWH: co-sponsor of this program announcement.  As such, ORWH will be
providing partial funding to selected grants awarded by the
Institutes identified above contingent upon the availability of
funds.
 
In addition to addressing the aspects described above in the main
study population (approximately 2000 HIV seropositive women), focused
studies may be conducted in the approximately 500 HIV seronegative
women who are currently under active follow-up.  Using the WIHS
infrastructure and through the rapid identification and enrollment of
recent seroconverters, such studies may investigate events during
early HIV infection in women and may address questions such as the
genetic basis for HIV exposure without infection and its relationship
with high-risk behavior (sexual or drug-related).  By investigating
the dynamics of initial HIV infection, these studies may provide
critical background knowledge for the design of clinical trials in
patients with primary HIV disease.  HIV uninfected women may also be
enrolled in studies investigating the role of hormonal factors and
contraceptive use on susceptibility to HIV infection.
 
C.  Research Structure.
 
BIOLOGICAL SPECIMENS.
 
Scientific questions addressed by studies submitted under this
Program Announcement may utilize biological specimens already
collected and banked or specimens to be prospectively collected.
Stringent monitoring of specimen utilization will occur throughout
the study duration to permit specimen use by a broad number of
investigators. Use of WIHS specimens will be restricted to the use
stated in the grant. To address any peer review's concerns regarding
specimen access, applicants are advised to provide documentation of
the establishment of  a collaboration with the WIHS investigators.
Inquiries on this matter should be directed to the Program staff of
the participating NIH Institutes.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS.
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43). All investigators proposing research involving human
subjects should read the "NIH Guidelines For Inclusion of Women and
Minorities as Subjects in Clinical Research", which have been
published in the Federal Register of March 9, 1994 (FR 59
14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume
23, Number 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.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted on the standard deadlines for
AIDS applications 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 Resources, National Institutes of Health, 6701
Rockledge Drive MSC 7910, Bethesda, MD 20892-7910, telephone
(301)710-0267, e-mail: [email protected].
 
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 original application and five legible, single-sided
copies of the application must be sent to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)
 
FIRST (R29) award applications must include at least three sealed
letters of reference attached to the face page of the original
application.  FIRST applications submitted without the required
number of reference letters will be considered incomplete and will be
returned without review.
 
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 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
 
Applications will be assigned on the basis of the established PHS
referral guidelines. Upon receipt, applications will be reviewed for
completeness by the NIH Division of Research Grants, NIH. Incomplete
applications will be returned to the applicant without further
consideration.
 
R01 and R29 applications will be reviewed for scientific and
technical merit by the Division of Research Grants, 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 applications
under review, will be discussed, assigned a priority score, and
receive a second level review by the appropriate national advisory
council or board.
 
REVIEW CRITERIA
 
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? Is there a
comprehensive use of the WIHS cohort of women, the WIHS database and
the WIHS-originated specimen bank?
 
Innovation:  Does the project employ novel concepts, approaches or
methods?  Are the aims original and innovative?  Does the project
challenge existing paradigms or develop new methodologies or
technologies?
 
Investigator:  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? Is there an optimal level of
integration with the current WIHS activities and investigators?
 
Budget:  Is the requested budget and estimation of time to completion
of the project  appropriate for the proposed research?
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
 
AWARD CRITERIA.
 
Applications will compete for available funds with all other
favorably recommended applications. 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 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.
Inquiries regarding programmatic (research scope, eligibility and
responsiveness) issues may be directed to:
 
NIAID:
Paolo Miotti, M.D., M.P.H.
Telephone:  (301) 496-9176
FAX:  (301) 402-3211
e-mail:  [email protected]
 
NICHD:
David Burns, M.D., M.P.H.
Telephone:  (301) 496-7339
FAX:  (301) 496-8678
e-mail:  [email protected]
 
NIDA:
Katherine Davenny, Ph.D.
Telephone:  (301) 443-1801
FAX:  (301) 443-2317
e-mail:  [email protected]
 
NCI:
Sandra Melnick, Dr.P.H.
Telephone:  (301) 435-4914
FAX:  (301) 402-4279
e-mail:  [email protected]
 
NIDR:
Maryann Redford, D.D.S., M.P.H.
Telephone:  (301) 544-5588
FAX:(301) 480-8254
e-mail:  [email protected]
 
NIDDK:
Judith Fradkin, M.D.
Telephone:  (301) 594-8814
FAX:  (301) 480-3503
e-mail:  [email protected]
 
NINDS:
A.P. Kerza-Kwiatecki, PhD.
Telephone:  (301) 496-1431
FAX:  (301) 402-2060
e-mail:  [email protected]
 
ORWH:
Joyce Rudick
Telephone:  (301) 402-1770
FAX:  (301) 402-1798
e-mail:  [email protected]
 
Direct inquiries regarding fiscal matters to:
 
Ms. Ann Devine
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C23
6003 Executive Blvd.
Bethesda, MD  20892
Telephone:  (301) 402-5601
 
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 No. 93.855 -
Immunology, Allergy, and Transplantation Research and No. 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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