Release Date:  July 9, 1998

PA NUMBER: PA-98-091


National Institute of Allergy and Infectious Diseases
National Cancer Institute
National Center for Research Resources
National Institute of Child Health and Human Development
National Institute of Dental Research
National Institute of Diabetes, Digestive and Kidney Diseases
National Institute of Mental Health


This Program Announcement (PA) replaces PA-96-072, Mechanisms of AIDS
Pathogenesis (NIH Guide, Vol. 25, No. 30, September 6, 1996).

The purpose of this PA is to solicit hypothesis-driven in vivo HIV and AIDS
pathogenesis research by collaborative multidisciplinary research teams. In vivo
research includes studies of human clinical or epidemiological cohorts, studies
of animal models, or studies of appropriate specimens from humans or animals.

Often, in vivo research requires an integrated multidisciplinary collaborative
team approach involving state-of-the-art methods and approaches within the
context of animal models and/or well-defined human cohorts or patient samples. 
Collaborative multidisciplinary research teams are defined as two or more
laboratories at the same or different institutions specializing in different
scientific disciplines, e.g., animal models, biochemistry, biophysics, cellular
biology, epidemiology, genetics, immunology, molecular biology, gastroenterology,
cancer virology, cancer biology, neurobiology, and pathology.  Not within the
scope of this PA are support for epidemiology cohorts, therapeutic or vaccine
trials, or proposals from a single laboratory.


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 PA, Mechanisms of AIDS Pathogenesis:
Collaborative Teams, is related to the priority area of HIV infection.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017- 001-10473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC 20402-
9325 (telephone 202-512-1800).


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.


Traditional research project grant (R01) applications may be submitted in
response to this PA.  Applicants may request up to five years of support. 
Responsibility for the planning, direction, and execution of the proposed
research will be solely that of the applicant.  Applicants are strongly
encouraged to coordinate, through the use of consortium arrangements or
subcontracts, integrated approaches with individuals or institutions having
relevant reagents and expertise in their use, demonstrated ability in a
particular area of relevant research, or access to relevant animal or patient


Examples of areas of research requiring multi-laboratory collaborative
multidisciplinary research teams include but are not limited to:

o  Mechanisms of establishment of viral infection, including mucosal transmission

o  Immunological and virological events controlling primary infection

o  Direct and indirect mechanisms of HIV-mediated immunodeficiency; e.g., the
effect of HIV infection on lymphopoiesis, immune regulation, including signaling
ligands, receptors, homing of T cells and their recirculation

o  Host and virological factors modulating latent cellular and tissue reservoirs
of HIV, including compartmentalization of virus

o  Host factors that modulate viral infection and/or disease progression

o  Host and viral factors regulating interspecies transmission of HIV/SIV

o  Mechanisms of protection induced by attenuated viruses

o  Impact of vaccination on viral transmission and/or disease progression

o  Transgenic animal models for HIV induced immunopathogenesis

o  The role of viruses as factors or co-factors in the etiology, biology and
pathogenesis of AIDS-associated malignancies

o  The genetic and molecular mechanisms leading to development of lymphomas or
other malignancies in patients with HIV/AIDS

The most relevant studies are expected to examine molecular and cellular biology,
virology, and immunology within the context of animal models and/or well-defined
human cohorts or patient samples.  Studies examining HIV transmission and
pathogenesis in the context of the gastrointestinal mucosal tissues are also
encouraged.  Investigators are encouraged to minimize the number of new animals
entered into research studies (and related support expenses) by using, whenever
possible, animals in ongoing supported non-human primate research.

Descriptive research that is not structured around a specific hypothesis(es) is
not within the scope of this PA.  For example, natural history epidemiologic
studies in many Division of AIDS (NIAID) supported cohorts are critically
important for collecting information on the cause and course of disease. 
Although the information provided by such studies may provide a foundation for
hypotheses that may be tested in research, this PA is intended to encourage the
next step in research, the testing of these hypotheses.

Clinical trials and recruitment or retention of cohorts are not encouraged under
this PA.  However, identified costs for patient visits, sample storage and
handling specific to the applicant's proposed research are appropriate.  Proposed
analyses of samples acquired from epidemiologic or clinical trials are also
appropriate.  Investigators are encouraged to use existing supported
epidemiologic or clinical cohorts instead of requesting funds to support or
establish additional cohorts.  Applicants are responsible for establishing
collaborative arrangements.  Program staff listed under INQUIRIES may be able to
assist in forming collaborations and suggesting relevant cohorts or reagent


Awardees will be invited to attend a meeting to present the progress of the work
funded under this program.  Details of this meeting will be provided post-award. 
Thus, applicants should include in their budget request funds for the PI to
attend one two-day meeting per year in the Washington, DC area.


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 the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.


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 ethical 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:

Investigators may obtain copies from these sources or from the Program Contact
person listed under INQUIRIES who may also provide additional relevant
information concerning the policy.


Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted on 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 Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email:

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 item 2.

Applications including nonhuman primate resources at the Regional Primate
Research Centers (RPRC), must follow the procedures for accessing a RPRC resource
published in the NIH Guide for Grants and Contracts, Vol. 25, No. 2, January 17,
1997.  Briefly, applications must contain a letter from the relevant RPRC
director confirming the availability of the center resources.  Also, the
application should provide details of any collaborative research arrangements
with RPRC-based investigators.  For further information contact the NCRR person
listed under INQUIRIES.

The completed, signed original and five legible, single-sided copies of the
application and five copies of appendices must be sent or delivered to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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, March 20, 1998.

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


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.  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.

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

2.  Approach.  Are the conceptual framework, design, collaborative arrangements,
methods, subjects and materials appropriate to accomplish goals of the proposed
work?  Does the applicant acknowledge potential problem areas and consider
alternative strategies?

3.  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?

4.  Investigator.  Considering their respective backgrounds and proposed roles,
are the proposed personnel qualified to perform the study?

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?

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders,
minorities and their subgroups, and children 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.


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 program announcement, and availability of


Written and telephone inquiries are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Inquiries regarding programmatic issues may be directed to:

Opendra K. Sharma, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C04 - MSC 7620
Bethesda, MD  20892-7620
Telephone:  (301) 496-9041
FAX:  (301) 402-3211

Kenneth J. Cremer, Ph.D.
Division of Cancer Biology
National Cancer Institute
Executive Plaza North 540 - MSC 7398
Bethesda, MD  20892-7398
Telephone:  (301) 496-6085
FAX:  (301) 496-2025

Jerry A. Robinson, Ph.D.
Regional Primate Research Centers and AIDS Models Programs
National Center for Research Resources
6705 Rockledge Drive, Suite 6030 - MSC 7965
Bethesda, MD  20892-7965
Telephone:  (301) 435-0744
FAX:  (301) 480-3819

Anne Willoughby, M.D., M.P.H.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11 - MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-7339
FAX:  (301) 496-8678

Eleni Kousvelari, D.D.S., D. Sc.
Division of Extramural Research
National Institute of Dental Research
Building 45, Room 4AN-18A
Bethesda, MD  20892-6402
Telephone:  (301) 594-2427
FAX:  (301) 480-8318

Thomas F. Kresina, Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes, Digestive and Kidney Diseases
Building 45 , Room 6AN-12A
Bethesda, MD  20892-6600
Telephone:  (301) 594-8871
FAX:  (301) 480-8300

Dianne M. Rausch, Ph.D.
Office of AIDS Research
National Institute of Mental Health
5600 Fishers Lane, Room 18-101
Rockville, MD  20857
Telephone:  (301) 443-6100
FAX:  (301) 443-9719

Direct inquiries regarding fiscal matters to:

Ms. Jackie Johnson
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C16 - MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 402-5936
FAX:  (301) 480-3780


This program is described in the Catalog of Federal Domestic Assistance No.
93.856, 93.855, 93.242, and 93.121.  Awards are made under authorization of the
Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended.  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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