MODELS FOR HIV DISEASE AND AIDS-RELATED MALIGNANCIES

Release Date:  May 16, 2001
 
PA NUMBER:  PA-01-094 (see replacement PA-04-157)
 
National Cancer Institute

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

This Program Announcement (PA) replaces PA-99-042, which was published in NIH 
Guide Volume 25, Number 1, January 29, 1999.
 
PURPOSE

The purpose of the this Program Announcement (PA) is to encourage 
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.

This PA will expire on September 3, 2003 unless reissued.  NIH Grants policies 
apply to these awards.

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 is available for HIV associated 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 December 2000, the World Health Organization (WHO) estimated 
that more than 5.3 million new cases of AIDS occurred and 3.0 million people 
died of AIDS worldwide in the last year.  More than 21.8 million people 
worldwide have died of AIDS since the beginning of the epidemic and more than 
36 million people are infected and living with HIV/AIDS as the pandemic 
continues unabated.

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 HIV reverse transcriptase and proteases are not 
advocated, whereas models for promising new targets such as the nef or other 
HIV proteins 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 viral factors of 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 viral associated 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.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of Health 
(NIH) research project grant (R01) mechanism and the exploratory/developmental 
grant (R21) mechanisms.  Applicants will be responsible for the planning, 
direction, and execution of the proposed project.  All PHS and NIH grants 
policies will apply to applications received and awards made in response to 
this PA..  The R21 mechanism supports pilot projects or feasibility studies.  
Accordingly, a sound rationale and a well designed research plan but not 
preliminary data are required.  The R01 supports more advanced projects.  
Responsibility for the planning, direction, and execution of the proposed 
research for all applicable mechanisms of support will be solely that of the 
applicant.   Applicants for the R21 grant mechanism may request up to $100,000 
direct costs (four budget modules) per year unless the application includes 
consortium costs, in which case the limit is $125,000 direct costs (five 
budget modules) per year.  For R21 grants, support may not exceed two years.  
Though the size of award may vary with the scope of research proposed, it is 
expected that R21 applications will stay within the budgetary guidelines for 
an exploratory/developmental project.  The R21 grants are non-renewable, and 
competitive continuation of projects developed under this program will be 
through the R01 research grant mechanism.  Applications for the R01 grant 
mechanism may not exceed five years.

This PA is one-time solicitation.  Future unsolicited competing continuation 
applications will compete with all investigator-initiated applications and be 
reviewed according to the customary
peer review procedures.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

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 governments, and eligible 
agencies of the Federal government.  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.

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

Direct inquiries regarding programmatic issues to:

Dr. Kenneth Cremer
Biological Carcinogenesis Branch
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Room 5016
Bethesda, MD  20892-7398
Telephone:  301 496-6085
FAX:  301-496-2025
Email:  cremerk@mail.nih.gov or kc47i@nih.gov

Dr. Mary Wolpert
Developmental Therapeutics Program
Division of Cancer Treatment and Diagnosis
National Cancer Institute
Executive Plaza North, Room 8153
Bethesda, MD  20892-7456
Telephone:  301 496-8783
FAX:  301-402-5200
Email:  wolpertm@mail.nih.gov or mw8u@nih.gov

Direct inquiries regarding fiscal matters to:
 
Ms. Eileen Natoli
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd, Suite 243, MSC 7150
Bethesda, MD  20892-7150
Telephone: (301) 496-8791
FAX:  301-496-8601
Email:  natoliea@gab.nci.nih.gov

Mr. Bill Wells
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd, Suite, 243 MSC 7150
Bethesda, MD  20892-7150
Telephone: (301) 496-8796
FAX:  301-496-8601
Email:  ww14j@nih.gov or wellsw@gab.nci.nih.gov

APPLICATION PROCEDURES  

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff. The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.  Applications 
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.  Applications 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 
301/435-0714, email:  grantsinfo@nih.gov.  The title and number of the PA must be 
typed on line 2 of the face page of the application form and the YES box must 
be marked.  For those applicants with Internet access, the 398 kit may be found 
at: http://grants.nih.gov/grants/forms.htm.  

Applicants are strongly encouraged to call the program contacts listed in 
INQUIRIES above with any questions regarding the adherence to the guidelines 
of their proposed project to the goals of this PA.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT 

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to 
a total direct cost request of $250,000 per year for R01 and, up to a total 
direct cost request of $100,000 per year ($125,000 if there are 
consortium/contractual Cost) for R21. Applications that request more than 
$250,000 direct costs for an R01 in any year must follow the traditional PHS 
398 application instructions.  The total direct costs must be requested in 
accordance with the program guidelines and the modifications made to the 
standard PHS 398 application instructions described below:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities 
and Administrative (F&A) costs] for the initial budget period.  Items 8a and 
8b should be completed indicating the Direct and Total Costs for the entire 
proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398.  It is not required and will not be accepted with the 
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION -  Prepare a Modular Grant Budget Narrative 
page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages). At the top of the page, enter the total direct costs requested for 
each year.  This is not a form page.

o  Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the nearest 
$1,000. List the individuals/organizations with whom consortium or contractual 
arrangements have been made, the percent effort of all personnel, and the role 
on the project. Indicate whether the collaborating institution is domestic or 
foreign.  The total cost for a consortium/contractual arrangement is included 
in the overall requested modular direct cost amount. Include the Letter of 
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual"s qualifications for a specific 
role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three pages 
may be used for each person.  A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years,
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST -  This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the type 
of agreement and the date. All appropriate exclusions must be applied in the 
calculation of the F&A costs for the initial budget period and all future 
budget years.

The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review.

Submit a signed, typewritten original of the application, including the 
checklist, and five signed, exact, single-sided 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 will be evaluated for scientific and technical merit 
by an appropriate scientific review group convened 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

The five criteria to be used in the evaluation of grant applications are 
listed below.
 
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.
  
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 analyzes 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  

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?  

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?  

The initial review group will also examine: the adequacy of plans to include 
both genders and 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
 
This section must describe the factors, including the scientific and technical 
merit reflected in the priority score or percentile, that will be used to make 
award decisions.  PAs can apply other criteria such as the geographical 
location of the applicant organization.  The most common award criteria are:  
scientific merit as determined by peer review, availability of funds, and 
programmatic priorities.

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 indicating 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 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000  (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-
048.html), a complete copy of the updated Guidelines is available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable, and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.
  
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 clear and compelling 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://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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

REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS

All investigators proposing research involving human subjects should read the 
NIH policy on education in the protection of human research participants now 
required for all investigators, which is published in the NIH Guide for Grants 
and Contracts, June 5, 2000 (Revised August 25, 2000), available at the 
following URL address:  http://grants.nih.gov/grants/guide/notice-files/NOT-
OD-00-039.html.  A continuing education program in the protection of human 
participants in research is now available online at http://cme.nci.nih.gov/.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site. 

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS led national 
activity for setting priority areas. This PA, Models for HIV Disease and AIDS-
Related Malignancies, is related to priority area of human immunodeficiency 
virus/AIDS and cancer  Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.health.gov/healthypeople/.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.399 – Cancer Cause and Prevention Research and 93.395 – Cancer Treatment 
Research.  Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92. This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The 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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