MODELS FOR HIV DISEASE AND AIDS-RELATED MALIGNANCIES

Release Date:  January 20, 1999

PA NUMBER:  PA-99-042

P.T.

National Cancer Institute
National Institute of Dental and Craniofacial Research

This Program Announcement (PA) is a reissuance of PA-96-014, which appeared in
the NIH GUIDE, Vol. 25, No.1, January 26, 1996.

PURPOSE

This PA from the National Cancer Institute (NCI) and the National Institute of
Dental and Craniofacial Research (NIDCR) encourages investigator-initiated grant
applications for the development of useful and predictive biochemical, cellular,
in vivo and mathematical models for the preclinical evaluation of new therapies
against HIV and AIDS-related malignancies.  The availability of
well-characterized in vitro and in vivo models would accelerate the pace of
evaluation of different paradigms of disease progression and would facilitate the
discovery of successful treatments, including drugs, vaccines, gene therapy, and
immune modulators.

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, Models for HIV Disease and
AIDS-Related Malignancies, is related to the priority areas of human
immunodeficiency virus/AIDS and cancer. 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),
or at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and nonprofit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government. Applications involving minority institutions are encouraged. 
Foreign institutions may participate in laboratory programs through subcontract
or consortium arrangements. Racial/ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

Research support mechanism for this PA is the investigator-initiated research
project grant (R01).  Collaborative arrangements involving more than one
institution are encouraged, including participation of the pharmaceutical
industry where appropriate.

The level of support is dependent on the receipt of a sufficient number and
diversity of applications of high scientific merit and the availability of funds. 
Although the goal of this PA is to stimulate the development of diverse types of
efficient and predictive biochemical, cellular, in vivo, and mathematical models
for the evaluation of new agents for the treatment of HIV disease and
AIDS-related malignancies, priority will be given to in vivo models if the number
of meritorious applications exceeds funds available.  Because the nature and
scope of the research proposed in response to the PA may vary, it is anticipated
that the sizes of awards will vary also.  The total project period for
applications submitted in response to this PA may not exceed five years.

Awards will be administered under NIH grants policy as stated in the NIH Grants
Policy Statement 10/1/98.

RESEARCH OBJECTIVES

Background

Despite many recent advances in our knowledge of the molecular biology of HIV-1
(human immunodeficiency virus) and HIV-2 and our increased understanding of HIV
pathogenesis in the development of acquired immune deficiency syndrome (AIDS),
no cure has been identified for HIV disease or AIDS-related malignancies,
including Kaposi's sarcoma, high-grade B cell non-Hodgkin's lymphoma, Hodgkin's
disease, Castleman's Disease and anogenital dysplasia and cancer.  As of June
1998, the World Health Organization (WHO) estimated that more than 5.8  million
new cases of AIDS occurred and 2.3 million people died of AIDS worldwide in the
last year.  Nearly 12 million people worldwide have died of AIDS since the
beginning of the epidemic and more than 30 million people are infected and living
with HIV/AIDS as the pandemic continues unabated.

Objectives and Scope

The goal of this PA is to foster the development of useful and predictive
biochemical, cellular, in vivo and mathematical models for the evaluation of new
therapies against HIV disease and AIDS-related malignancies.  New relevant and
cost-effective models are needed for various stages of preclinical therapy
development, including lead discovery, lead optimization, and final evaluation
of the most promising candidates for clinical trial.  While progress has been
made with cell-based and mechanism-based screens, such as those for reverse
transcriptase and proteases, many other suitable targets exist but need to be
employed in assays.  There is an urgent need for simpler, safer, more relevant,
and less expensive in vivo models to assess the in vivo efficacy of potential
therapeutic candidates.  However, exploratory basic research studies on the
mechanism of action of HIV genes, cellular genes involved in HIV gene
replication, and gene products are excluded from this PA.

The research scope encourages applications in the following areas, which are
illustrated by, but not in any way limited to, the examples provided:

o  Biochemical Assays.  Rapid, resource efficient, and cost-effective assays to
block steps in HIV virus replication are encouraged. Models for well-studied
targets such as reverse transcriptase and proteases are not advocated, whereas
models for promising new targets such as the nef protein are encouraged. 
Applicants should consider high volume screens that would accommodate the needs
of combinatorial chemistry programs.  For those AIDS-related cancers in which a
putative cofactor may be involved, such as the Kaposi's Sarcoma-Associated
Herpesvirus (KSHV/HHV-8), Epstein-Barr Virus (EBV) or Human Papilloma Viruses
(HPV), approaches are sought to identify and define the precise role of the
cofactor in the specific malignancy and to exploit this information for
therapeutic advantage.

o  Cell Culture Assays.  It is desirable that new cell culture models be
developed for HIV replication and AIDS-related malignancies that more closely
simulate the in vivo state.  For example, models that mimic the three
dimensional, multicellular environment or those based on single cycle replication
kinetics would be of utility.  For AIDS-related cancers, cell culture systems
predictive of in vivo events that allow for studies of the mechanism(s) of action
of specific cofactors and that would be useful for evaluating potential therapies
are highly encouraged.

o  In Vivo Models.  Models that reflect the current state of knowledge of HIV
pathogenesis and are simpler, safer, more relevant and less expensive than
currently available models are urgently needed for the evaluation of therapies
for HIV disease and AIDS-related malignancies.  Novel approaches using transgenic
and gene knockout animals are especially encouraged.  Although the use of small
animals such as mice is most practical because of their availability and low
cost, other animal models may be proposed. However, non-lentivirus, retroviral
animal models are not encouraged.  For the models of both HIV disease and
AIDS-related malignancies, the development of valid surrogate endpoints for
survival is favored in the interest of conserving resources and reducing assay
time and animal discomfort.

o  Mathematical Models.  Refinement of mathematical models for viral levels,
CD4+T cell counts, etc. that can be used as predictors of therapeutic efficacy
and/or viral resistance and in conjunction with clinical studies will be
considered.  New paradigms of HIV pathogenesis that can provide alternative
treatment strategies are encouraged.

Applicants are reminded to provide a rationale for their model; to justify and
demonstrate its potential utility over existing models, if applicable; to provide
a research plan involving a testable hypothesis; and to use the model to
demonstrate its utility.  Relevance to the in vivo disease state, reproducibility
using appropriate statistical analysis, and other important parameters of the
assay should be documented.

Although the intent of this PA is to restrict studies to those that are
preclinical in nature, clinical specimens may be used whenever required for the
appropriate development of in vitro and animal models.

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 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994, available at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not94-105.html.

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRES.  Program staff may also provide additional relevant information
concerning the policy.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRES.  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.
4/98) and will be accepted at the standard application deadlines as indicated in
the application kit.  Receipt dates for applications for AIDS-related research
are January 2, May 1, and September 1.  Application kits are available at most
institutional offices of sponsored research and may be obtained from 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: grantsinfo@nih.gov.  Application kits are also available on the Internet
at:  http://www.nih.gov/grants/forms.htm

Applicants planning to submit an investigator-initiated new (type 1), competing
continuation (type 2), competing supplement, or any amended/revised version of
the preceding grant application types requesting $500,000 or more in direct costs
for any year are advised that they must contact Institute/Center program staff
before submitting the application, while plans for the study are being developed. 
Furthermore, the applicant must obtain agreement from the Institute that it will
accept the application for consideration for award.  Finally, the applicant must
identify, in a cover letter sent with the application, the staff member (and
Institute) who agreed to accept assignment of the application.  This policy
requires an applicant to obtain agreement for acceptance from both for any such
application and any such subsequent amendment.  Refer to the NIH Guide for Grants
and Contracts, March 20, 1998 at: http://www.nih.gov/grants/guide/notice-files/not98-030.html.

The title and number of this Program Announcement must be typed on line 2 of the
face page of the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and five identical, signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC-7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications that are complete will be evaluated for scientific and
technical merit by study sections of the Center for Scientific Review, NIH, in
accordance with 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

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 analysis
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 methods? 
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,
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.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions:
Quality of the proposed project as determined by peer review, availability of
funds, and program priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Mary K. Wolpert
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 841, MSC 7456
Bethesda, MD  20892-7456
Telephone:  (301) 496-8783
FAX:  (301) 402-5200
Email:  mw8u@nih.gov

Dr. Kenneth J. Cremer
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Room 540, MSC 7398
Bethesda, MD  20892-7398
Telephone:  (301) 496-6085
FAX:  (301) 496-2025
Email:  kc47i@nih.gov

Dennis F. Mangan, Ph.D.
Division of Extramural Research,
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-32F, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-2421
FAX:  (301) 480-8318
Email:  Dennis.Mangan@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Michelle Burr
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Suite 243, MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, Ext. 231
FAX:  (301) 496-8601
Email:  mb94r@nih.gov

Mr. Kevin Crist
Division of Extramural Research
National Institute of Dental and Craniofacial Research
Natcher Building, Room 4AS-44
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email:  Kevin.Crist@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.399 - Cancer Cause and Prevention Research, 93.395 - Cancer Treatment Research
and No. 93.121 - Oral Diseases and Disorders Research Awards.  Awards are made
under authorization of the Public Health Service Act, Title IV, Part A (Public
Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered
under HHS policies and grant regulations.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health Systems
Agency review.

The Public Health Service (PHS) strongly encourages all grant 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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