Full Text AA-97-002
NIH GUIDE, Volume 25, Number 41, November 29, 1996
RFA:  AA-97-002
P.T. 44


National Institute on Alcohol Abuse and Alcoholism
Letter of Intent Receipt Date:  March 21, 1997
Application Receipt Date:  April 24, 1997
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
seeking applications to support human immunodeficiency virus
(HIV)-related biomedical alcohol research. Investigations into the
biologic determinants of HIV disease have begun to yield
interventions that can transform HIV disease from a fatal condition
to a chronic, manageable disease syndrome.  As understanding of the
pandemic progresses, and as HIV/AIDS research becomes more focused,
it is becoming increasing apparent that cofactors such as alcohol
consumption may play an important role in sexual transmission,
susceptibility to infection, and progression of HIV disease.  Alcohol
has been suggested as a cofactor in HIV disease (Crum, et al.;
Alcoholism Clin Exp Res 20:364-371, 1996) and recent evidence
demonstrated additive effects of alcohol abuse and HIV infection on
brain function (Fein, et al.; Biological Psychiatry 37:183-195,
1995).  However, there is no conclusive evidence that acute or
chronic alcohol consumption increases susceptibility to HIV infection
or accelerates AIDS progression. Strain variations of HIV, individual
differences in susceptibility, and long incubation time following
seroconversion are some of the difficulties in studying disease
progression.  Whether alcohol consumption increases susceptibility to
opportunistic infections in HIV+ patients and whether alcohol-induced
immunosuppression is associated with stimulation, expansion, and
perpetuation of disease are important questions to be answered.
The purpose of this Request for Applications (RFA) is to solicit
applications to study two of the most important questions in
alcohol-AIDS research:
1.  Does alcohol consumption modulate host susceptibility to HIV
2.  Does alcohol consumption accelerate progression of AIDS or
predispose to new complications of HIV infection?
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 RFA,
Biomedical Research on Alcohol and AIDS, is related to the priority
area of AIDS prevention.  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).
Applications may be submitted by domestic and foreign, for-profit and
non-profit, public and private organizations, 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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Research project grant
applications (R01) from foreign institutions are limited to three
Research support may be obtained through applications for a regular
research project grant (R01) or FIRST (R29) award.  Applications are
also encouraged for exploratory/developmental grants (R21), which are
limited to two years for up to $70,000 per year for direct costs.
Applicants may also submit applications for Investigator-Initiated
Interactive Research Project Grants (IRPGs).  Interactive Research
Project Grants require the coordinated submission of related research
project grant (R01) and, to a limited extent FIRST Award (R29)
applications from investigators who wish to collaborate on research,
but do not require extensive shared physical resources.  These
applications must share a common theme and describe the objectives
and scientific importance of the interchange of, for example, ideas,
data, and materials among the collaborating investigators.  A minimum
of two independent investigators with related research objectives may
submit concurrent, collaborative, cross-referenced individual R01 and
R29 applications. Applicants may be from one or several institutions.
Further information on the IRPG mechanism is available in program
announcement PA-96-001, NIH Guide for Grants and Contracts, Vol. 24,
No. 35, October 6, 1995.
Potential applicants for FIRST Awards and Exploratory/Developmental
Grants may obtain copies of the specific announcements for these
programs from the NIAAA Home Page at HTTP://WWW.NIAAA.NIH.GOV or from
the Office of Scientific Affairs, NIAAA, Willco Building, Suite 409,
6000 Executive Boulevard MSC 7003, Bethesda, Maryland 20892-7003,
telephone: 301-443-4375 or FAX 301-443-6077.  Further information on
these and other grant mechanisms may be obtained from the program
staff listed under INQUIRIES.
It is estimated that up to $2.0 million will be available to fund
approximately twelve grants under this RFA.  This level of support is
dependent on the receipt of sufficient number of applications of high
scientific merit.  Although this program is provided for in the
financial plan of the NIAAA, the award of grants pursuant to this RFA
is also contingent upon the availability of funds for this purpose.
The earliest possible award date is September 30, 1997.
Chronic and acute alcohol consumption has been demonstrated to be
immunosuppressive, to decrease host defense against infection, and to
increase viral replication.  Given the frequency of alcohol
consumption (to moderate and excessive extents), alcohol drinking has
the potential to influence the severity and course of disease.
Sophisticated molecular and cellular biology methodologies are
revealing the detailed cellular processes responsible for virus
growth and escape from host defense systems, and alcohol/AIDS
researchers are beginning to define mechanisms of ethanol-induced
immune impairments.  However, basic questions such as whether alcohol
consumption can modulate susceptibility to HIV infection remain
unanswered.  Although alcoholics have been reported to be at higher
risk for HIV infection because of associated intravenous drug use,
recent studies on HIV seropositivity rates in alcoholics without a
history of intravenous drug use reported significant rates of HIV
infection ranging from 4.5 percent (Schleiffer, et al.;  Alcohol Clin
Exp Res 20:75-80, 1996) to 11.4 percent (Lee, et al.; Am J Addiction
1:85-88, 1992 ).   Behavioral studies in adolescents, gay men, and
alcoholics in treatment settings indicate a substantial correlation
between alcohol consumption and risky sexual behavior which can
result in increased frequency of exposure to HIV.  However,
regardless of the route of primary HIV infection, once infected,
whether alcohol consumption can accelerate the clinical course of the
disease is a second critical question that remains unanswered.
Although progress in alcohol/AIDS research has been significant, many
areas require further investigation.
Strategies to study the effects of alcohol consumption on modulating
host susceptibility to primary HIV infection may include
investigations on:
o  HIV infectivity on host immune function including studies on
immune activation, suppression, and differentiation, and alteration
of cytokine production by lymphocytes, monocytes/ macrophages,
dendritic cells, and neural cells;
o  HIV factors including studies on early replication events such as
attachment, uncoating and reverse transcription;
o  Host organ systems that may alter HIV infectivity and/or
replication characteristics including studies on mucosal integrity,
mucosal immunity, inflammation, microflora, and viral uptake; and
o  Other host factors that may alter HIV infectivity including
studies on nutritional consequences, changes in regional immunity,
and interactions with underlying disease, e.g., alcoholic liver
disease and alcoholic neurologic disease, and other sexually
transmitted diseases.
Strategies to elucidate the effects of alcohol consumption on
acceleration of progression of HIV disease or on predisposition to
new complications of HIV infection may include studies on:
o  HIV-infected cells including studies on upregulation of HIV gene
expression and replication in permissive cells, and in activated
versus resting CD4+ cells; cytopathogenic effects; cell-to-cell
transmission; and differences in HIV phenotype;
o  Host immune mechanisms directed against HIV including studies on
whether ethanol enhances the acquisition of Th2-like state by T cells
from HIV+ patients or enhances the immunodeficient state in animal
models of ethanol consumption and AIDS;
o  Host immunosuppression as a consequence of HIV infection including
studies on localized and systemic opportunistic infections; cancer
development, progression, and metastasis; and
o  HIV-specific complications including studies on the
neuropathogenesis and pathogenic processes involved in HIV wasting,
neuropathy, encephalopathy, and enteropathy; studies that evaluate
whether ethanol alters efficacy of AIDS treatment strategies,
especially by interfering with drug absorption and altered hepatic
drug metabolism; and whether ethanol increases toxicity of AIDS
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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.
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 20, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
Prospective applicants are asked to submit, by March 21, 1997, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number of title of the RFA in response to which
the application may be submitted.  Although a letter of intent is not
required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows NIAAA
staff to estimate the potential review workload and avoid conflict of
interest in the review.
The letter of intent is to be sent to:
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 409
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
FAX:  (301) 443-6077
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and may be obtained
from the Grants Information Office, 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@odrockm1.od.nih.gov.
The RFA label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review.  In addition, the RFA title and number must be typed on
line 2 of the face page of the application form and the YES box must
be marked. Applications for support mechanisms other than R01 (i.e.,
an R29) must cite the relevant program announcement on line 2 in
addition to listing the current RFA.  Applications for FIRST awards
(R29) must include at least three sealed letters of reference
attached to the face page of the original application.  FIRST award
(R29) applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.  Page limits and limits on size of type are strictly
enforced.  Non-conforming applications will be returned without being
Submit a signed, typewritten original of the application, including
the checklist and three signed photocopies in one package to:
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
At the time of submission, two additional copies of the application
must also be sent to:
RFA AA-97-002
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Room 409
6000 Executive Boulevard, MSC 7003
Bethesda, MD  20892-7003
Rockville, MD  20852 (for express/courier service)
Failure to forward the above two applications to the NIAAA at the
above address may
delay consideration of an application such that it may not be
received in time for FY
1997 funding consideration.
Applications must be received by April 24, 1997.  If an application
is received after
that date, it will be returned to the applicant without review.  The
Division of
Research Grants (DRG) will not accept any application in response to
this RFA that is
essentially the same as one currently pending initial review, unless
the applicant
withdraws the pending application.  The DRG will not accept any
application that is
essentially the same as one already reviewed.  This does not preclude
the submission of
substantial revisions of applications already reviewed, but such
applications must
include an introduction addressing the previous critique and must be
prepared in the
format of a revised application.
Upon receipt, applications will be reviewed for completeness by the
DRG and for responsiveness by the NIAAA.  Incomplete applications
will be returned to the applicant without further consideration.  If
the application is not responsive to the RFA, the DRG staff may
contact the applicant to determine whether to return the application
to the  applicant or submit it for review in competition with
unsolicited applications at the next review cycle.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the Institute in accordance with the review
criteria stated below. As part of the initial merit review, a
streamlined review process may be used by the initial review group in
which applications may or may not be discussed based on their
scientific merit relative to other applications received in response
to the RFA.  Applications that are fully discussed will be assigned a
priority score.  Applications that are not discussed will be
withdrawn from further considerations and the Principal Investigator
and the official signing for the applicant organization will be
notified.  The second level of review will be provided by the
National Advisory Council on Alcohol Abuse and Alcoholism.
Review Criteria
Criteria to be used in the scientific and technical merit review of
the research grant applications will include the following:
1. The scientific, technical, or medical significance and originality
of the proposed research and its relevance to the goals of this RFA.
2. The appropriateness and adequacy of the experimental approach and
methodology, including adequacy of quality control methods, proposed
to carry out the research.
3. The adequacy of the qualifications (including level of education
and training) and relevant research experience of the principal
investigator and key research personnel.
4. The availability of adequate facilities, general environment for
the conduct of the proposed research, other resources, and
collaborative arrangements necessary for the research.
5. The reasonableness of budget estimates and duration for the
proposed research.
6. When applicable, adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific
goals of the research.  Plans for the recruitment and retention of
these subjects will also be evaluated.
When applicable, the initial review group will also examine the
provisions for the protection of human and animal subjects and the
safety of the research environment.
The review criteria for Exploratory/Developmental Grants (R21) and
FIRST Awards (R29) are contained in their program announcements.
Applications recommended for approval by the National Advisory
Council on Alcohol Abuse and Alcoholism will be considered for
funding on the basis of the overall scientific and technical merit of
the application as determined by peer review, NIAAA programmatic
needs and balance, and the availability of funds.
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Leslie Isaki, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard  MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4224
FAX:  (301) 594-0673
Email:  lisaki@willco.niaaa.nih.gov
Direct inquiries regarding fiscal matters to:
Linda Hilley
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4703
FAX:  (301) 443-3891
Email:  lhilley@willco.niaaa.nih.gov
This program is described in the Catalog of Federal Domestic
Assistance, No. 93.273. Awards are made under the authorization of
the Public Health Service Act, Sections 301 and 464H, and
administered under the PHS policies and Federal Regulations at Title
42 CFR Part 52, "Grants for Research Projects;" Title 45 CFR Parts 74
and 92, "Administration of Grants;" and 45 CFR Part 46, "Protections
of Human Subjects."  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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