IMPACT OF HIV VARIATION ON IMMUNOLOGICAL RECOGNITION

NIH Guide, Volume 26, Number 38, November 21, 1997

PA NUMBER:  PA-98-011

P.T.

National Institute of Allergy and Infectious Diseases

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), National
Institutes of Health (NIH), invites applications through this Program
Announcement (PA) to support research to address the impact of HIV variation on
immunological recognition.  The objective is to foster investigations to provide
information that will ultimately be useful for identifying the strain(s) of HIV
that should be used for vaccine development.  Increased understanding of the
mechanism of HIV neutralization, identification of neutralization immunotypes,
and understanding of the impact of viral variation on CTL recognition is sought.

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 PA, Impact of HIV-1 Variation on
Immunological Recognition, is related to the priority area(s) of immunization and
infectious diseases; HIV infection; sexually transmitted diseases.  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

Applications may be submitted by 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. 
Domestic and foreign institutions are eligible to apply for R01 grants.  Foreign
institutions are not eligible for 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.  Applicants for the FIRST
award must comply with the NIH Guidelines for FIRST awards and the Just-in-Time
procedures announced in the NIH Guide, Vol. 25, No. 10, March 29, 1996. 
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

Background

Antigenic variability of HIV has been identified as a major obstacle to AIDS
vaccine development.  The rapidly changing structure of HIV-1 envelope proteins
may necessitate a series of AIDS vaccines tailored for the virus strain(s)
prominent in a geographic area even though they change as the virus evolves with
time.  This genetic heterogeneity is reflected in changes in susceptibility to
neutralization by given antisera or monoclonal antibodies, and may also affect
immune recognition of the virus by T-cells.  However, studies have also shown
that there are conserved neutralization and cytotoxic T-lymphocyte epitopes
shared by diverse isolates even across clades, suggesting the possibility that
broadly cross-reactive vaccines could be developed.  To study the potential
impact of HIV variation on vaccine efficacy, the Division of AIDS has supported
an HIV Variation Program consisting of two laboratories, one for genetic cloning
and sequencing and another for isolation and neutralization analysis.  Utilizing
HIV isolates and blood samples derived from sites around the U.S. and the world,
it has been shown that HIV-1 contains both type-specific and broadly cross-
reactive neutralization epitopes.  However, two developments have altered the
kind of research that is now required to understand antigenic variation.  First,
the identification of co-receptors for HIV infection has significantly altered
and advanced our concepts of blocking HIV infection with antibody and other
humoral factors.  Second, the greater realization of the potential role of CTL
in protection widens the scope of antigenic variation to include T-cell epitopes. 
While the isolation/neutralization arm of the Variation Program was previously
carried out under the contract mechanism, it is felt that future work on this
theme, which remains essential to the design of an efficacious vaccine, would
more effectively be carried out through investigator-initiated research.

Research Objectives and Scope

This initiative will fund basic research to explore the impact of variation on
both humoral and cellular immune recognition.

Examples of areas of research that examine the impact of HIV variation on immune
recognition include, but are not limited to, the following:

o  Studies of humoral immune recognition designed to identify the specificity of 
the neutralizing components present [a] in high-titer HIV-1 (+) sera, and [b] in
broadly cross-reactive HIV-1 (+) sera;

o  Studies to determine the epitopes and conformation of the HIV-1 antigen(s)
needed to induce a high-titer and/or broadly cross-reactive neutralizing
response;

o  Studies designed to determine if neutralization immunotypes exist for HIV, and
to identify isolates representing each immunotype;

o  Analysis of the degree of conservation of CTL epitopes required to allow CTL
from individuals infected with one clade of HIV to lyse MHC-matched cells
infected with HIV of another clade;

o  Analysis of HIV T-cell epitopes recognized in different HIV clades by
individuals of different HLA types, especially from international populations.

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 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 for PHS 398 (rev. 5/95)
and will be accepted on the standard application AIDS deadlines as indicated in
the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Office of Extramural
Outreach and Information Resources, 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 (formerly 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 award
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 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
Center for Scientific Review (CSR).  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 CSR, 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 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

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 and eligibility) issues may be
directed to:

James A. Bradac, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A32
Bethesda, MD  20892-7640
Telephone:  (301) 402-0121
FAX:  (301) 402-3684
Email:  jb68k@nih.gov

Direct inquiries regarding fiscal matters to:

Dianne E. Tingley, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C04
Bethesda, MD  20892-7610
Telephone:  (301) 496-8206
FAX:  (301) 402-2638
Email:  dt15g@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 Citation is (No. 93.855 - Immunology, Allergy, and Transplantation
Research [or] No. 93.856 - Microbiology and Infectious Disease Research [or] both
of the preceding.  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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