Full Text AI-94-010

MULTICENTER AIDS COHORT STUDY PATHOGENESIS RESEARCH LABORATORY

NIH GUIDE, Volume 23, Number 11, March 18, 1994

RFA:  AI-94-010

P.T. 34

Keywords: 
  AIDS 
  Pathogenesis 
  Biology, Molecular 
  Immunology 
  Genetics 
  Viral Studies (Virology) 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  April 1, 1994
Application Receipt Date:  June 15, 1994

PURPOSE

The Vaccine Trials and Epidemiology Branch (VTEB) of the Division of
AIDS (DAIDS), National Institute of Allergy and Infectious Diseases
(NIAID), administers major, prospective studies of HIV infection and
disease in large, multicenter cohort studies.  The largest and
longest-running of these studies is the Multicenter AIDS Cohort Study
(MACS).  The MACS was created in 1983 as a study of HIV infection in
homosexual and bisexual men; over 5,500 men have participated in the
MACS since the initial 1984 enrollment.  The National Cancer
Institute co-funds MACS studies of malignancy in HIV infection.  The
purpose of this Request for Applications (RFA) is to fund a
laboratory or a consortium of laboratories to study the immunologic,
virologic, and other biologic determinants of disease progression and
factors that mitigate HIV-mediated immune system destruction among
participants in the MACS.  The work to be accomplished requires
diverse expertise in HIV virology, immunology, genetics, and
molecular biology that must be applied in a highly coordinated manner
to adequately address the issues of interest.  Therefore, proposed
studies should utilize an interdisciplinary approach in which the
research plans are well integrated and are based on appropriate
collaborations.

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 RFA,
MACS Pathogenesis Research Laboratory, 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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic non-profit and for-profit
research institutions, public and private organizations such as
universities, colleges, hospitals, laboratories, units of State or
local governments, and eligible agencies of the Federal government.
Foreign organizations are not eligible to apply.  Domestic
applications may not include international components.  Applications
from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Successful applicants funded under this RFA will be supported through
a National Institutes of Health (NIH) Cooperative Agreement (U01).
Cooperative agreements are grants awarded to institutions when it is
desired to encourage investigator-initiated research in areas of
special importance to the NIH.  It is an "assistance" mechanism,
rather than an "acquisition" mechanism, in which substantial NIH
scientific and/or programmatic involvement with the awardee is
anticipated during performance of the activity.  Under the
cooperative agreement, the NIH will support and/or stimulate the
recipient's activity by working jointly with the awardee in a partner
role; the NIH will not assume direction, prime responsibility, or a
dominant role in the activity.  The advantage of the cooperative
agreement funding mechanism for this RFA is to ensure coordination of
use of valuable research specimens and data derived from the MACS.
This coordination is critical due to the finite and irreplaceable
nature of the resource of MACS specimens, and the need to do diverse
studies on the same samples.  Details of the responsibilities,
relationships, and governance of the study to be funded under this
cooperative agreement are discussed later in this document under the
section "Terms and Conditions of Award."

The NIAID intends to award one or two Cooperative Agreements for
laboratory studies on the pathogenesis of HIV/AIDS in MACS
participants.  A collaborative and innovative interdisciplinary
approach to address the full spectrum of research objectives is
essential.  Therefore, applicants are encouraged to coordinate,
through the use of consortium arrangements or subcontracts,
integrated approaches with individuals or institutions having
relevant and demonstrated ability in immunologic, virologic, genetic,
and other molecular biologic techniques necessary to address the
stated objectives.

This RFA solicitation represents a single competition with a
specified deadline for receipt of applications.  The anticipated
award date is April 1, 1995.  Awards will be made for a twelve month
budget period within a total project period not to exceed four years.
Funding beyond the first and subsequent years of the award will be
contingent upon satisfactory performance during the preceding years
and upon the availability of funds for this purpose.  Reissuance of
this RFA will be dependent on the state of science and findings at
the completion of the grant period.

FUNDS AVAILABLE

Approximately $800,000 will be available for funding the total costs,
both direct and indirect, for the initial year of awards made
pursuant to this RFA.  The NIAID anticipates making one or two awards
as a result of this RFA.  The issuance of the final award or awards
will be dependent upon receipt of applications of high scientific
merit that cover the range of scientific objectives in a
comprehensive fashion, and upon the availability of funds.

RESEARCH OBJECTIVES

Background

The ongoing Multicenter AIDS Cohort Study (MACS), which includes four
clinical centers and a data center, is supported by VTEB, CRP, DAIDS,
NIAID.  Studies of HIV-related malignancy in the MACS are co-funded
by the NCI.  MACS clinical centers are located at Johns Hopkins
University, Baltimore, MD; the University of Pittsburgh, Pittsburgh,
PA; the Howard Brown Memorial Clinic/Northwestern University,
Chicago, IL; and the University of California at Los Angeles in Los
Angeles, CA.  The Center for the Analysis and Management of MACS Data
(CAMACS) is located at Johns Hopkins University in Baltimore, MD.

The MACS was created in 1983 as a study of HIV infection in
homosexual and bisexual men; over 5,500 men have been enrolled in the
MACS since 1984.  The remarkable dedication of MACS participants and
MACS site study staff has resulted in a high retention rate with a
loss to follow-up of approximately 20 percent among HIV-infected men
after ten years.

Because of the continuing unique scientific contributions of this
large prospective, multi-site cohort study, the NIAID intends to
renew support for the MACS clinical centers and data center to follow
and study selected MACS participants for clinical and laboratory
outcomes and to collect specimens for pathogenesis research.  The
selected participants to be followed will include:  (1) all
HIV-seropositive men who were enrolled in the study as seroprevalent
cases or who have seroconverted while in the study, (2)
HIV-seronegative men at high risk of HIV acquisition based on
behavioral assessments, and (3) a matched subset of HIV-seronegative
men who are at lower risk of HIV infection.  The NIAID currently
plans to follow these MACS participants from the present time through
at least 1999.

The MACS research infrastructure offers a unique focus for study of
HIV pathogenesis including:

1.  A ten year prospective cohort study with well documented
longitudinal clinical and laboratory outcomes data of HIV infection
and disease.

2.  A repository of clinical specimens of serum, plasma, and PBMCs
that cover the natural history of HIV infection and disease.

3.  Extensive clinical, epidemiologic, and statistical expertise
within the MACS infrastructure that will be available to assist in
the design and analysis of the laboratory studies.

Approximately 1,800 men were found to be HIV-seropositive upon
initial enrollment in 1984-1985; an additional 350 HIV- seropositive
men were enrolled from 1987-1991.  Over 450 of the seronegative men
have seroconverted while being followed in the MACS.  Approximately
seventy men have displayed no CD4+ cell loss despite at least nine
years of HIV infection (and without receipt of antiretroviral
therapy).  On the other end of the spectrum, at least twenty men have
rapidly developed immunodeficiency disease, developing AIDS within
three years of documented seroconversion.  Other potentially
important variants from the classical pattern of HIV-mediated CD4+
cell decline have been documented among HIV-infected MACS
participants, including persons remaining clinically stable for long
periods despite very low CD4+ cell counts.  Additionally, the MACS
follows at least 250 men who did not become infected with HIV despite
a history of high-risk sexual behavior.

MACS participants are followed at the clinical centers every six
months, where they respond to a detailed health questionnaire,
receive a physical examination, and have blood specimens taken.
Blood specimens are processed and stored as frozen serum, plasma, and
cells in the NIAID HIV Vaccine Trials and Epidemiology Specimen
Repository. These stored specimens will be made available to the MACS
Pathogenesis Research Laboratory.  In addition, arrangements may be
made with the MACS sites via the NIAID Program Officer to
prospectively collect samples of blood and other body fluids and
tissues, such as semen and lymph nodes, for specific MACS
pathogenesis protocols, and to increase the frequency of follow-up
for a small number of participants where necessary.  Availability of
these additional specimens and ability to increase follow-up
frequency will be contingent on study feasibility, obtaining local
IRB approval and necessary informed consent, and the agreement of the
participants who comprise the MACS cohort.

Further information regarding the MACS research infrastructure,
cohort organization, sample sizes, MACS publications bibliography,
specific characteristics of MACS participants (e.g., men who are
rapid progressors, seroconverters, and slow progressors) and specific
features of the stored specimens (e.g., numbers, types, prior
experience with quality of stored cells) will be provided upon
contacting the MACS Program Officer listed under INQUIRIES.

Research Scope

Additional study of host immunologic, virologic, genetic, and other
determinants of HIV infection and disease progression is needed to
gain a better understanding of the pathogenesis of HIV/AIDS.  This
information is crucial for the development of effective therapies for
HIV/AIDS and design of vaccines against HIV infection.  Accordingly,
the NIAID is encouraging intensive broad-based laboratory studies
including state-of-the-art and innovative approaches to the study of
host and viral factors that contribute to the pathogenesis of HIV
infection and disease.

Applications are invited from investigators to conduct laboratory
investigations on the pathogenesis of HIV infection using clinical
specimens available from the MACS.  The proposed studies should
emphasize close integration of the immunologic, virologic, and other
biological investigations being planned.  Preference will be given
for studies of high scientific merit for which the cohort research
approach is essential, including effective utilization of the unique
MACS database and the MACS-derived specimens stored at the NIAID HIV
Vaccine Trials and Epidemiology Branch Specimen Repository.

Each application must address the first of the following two areas of
pathogenesis research.  Applicants have the option of addressing the
second area of pathogenesis research listed below:

1.  The identification and characterization of the host immunologic
factors and the virologic factors that correlate with the progression
and/or non-progression of HIV disease in individuals who maintain
high (e.g., above 500 CD4+ cells per microliter), stable CD4+ cell
counts despite long periods of HIV infection;

2.  The identification and characterization of the host immunologic
factors and the virologic factors that correlate with the progression
and/or non-progression of HIV disease in individuals whose CD4+ cell
counts decline to low levels (e.g., below 200 CD4+ cells per
microliter) but who remain clinically stable for prolonged periods.

Highly innovative and creative approaches to studying the general
areas covered in item (1) above (required) and item (2) above
(optional), as well as related issues concerning the study of HIV
pathogenesis in MACS participants, are encouraged.  Examples of
investigations sought through this RFA include, but are not limited
to, those listed below:

o  Studies of humoral antibody responses (e.g., binding,
neutralizing, enhancing, ADCC), cell-mediated responses (e.g.,
cytotoxic T cell activity), and nonspecific immune responses or
immunoregulatory events (e.g., lymphokine secretion, natural killer
cell activity, apoptosis) that may mediate or protect against immune
system destruction or other HIV-related pathology, including
characterization of the pattern of responses in the various stages of
HIV infection and identification of the specific epitopes of HIV
involved;

o  Studies of viral variables correlated with HIV pathogenesis (e.g.,
HIV phenotype, viral load, pattern of sequence variation during
infection);

o  Studies of host and viral factors that may explain long-term
clinical stability sometimes noted in subjects with low CD4+ cell
counts;

o  Studies of other host factors that enhance viral replication, HIV
pathogenesis, (e.g., studies of histopathology, immune dysregulation,
genetic susceptibility, etc.) during the course of HIV infection from
initial infection through development of disease.

SPECIAL REQUIREMENTS

A.  Cooperation, Collaboration and Meetings

The MACS Pathogenesis Research Laboratory(s) will propose and conduct
the relevant pathogenesis studies in the areas of research listed
above.  As work progresses, the Principal Investigator(s) may seek
input from the MACS clinical and data centers and the NIAID Program
Officer regarding design and implementation of studies.  Therefore,
to be considered responsive to this RFA, an applicant must include a
statement of willingness to work in close cooperation and
collaboration with the MACS research infrastructure, whenever this is
indicated.

The Principal Investigator(s) of the MACS Pathogenesis Research
Laboratory(s) will be members of the MACS Pathogenesis Steering
Committee established under this RFA.  The MACS Pathogenesis Steering
Committee will be composed of the Principal Investigator(s) from the
MACS Pathogenesis Research Laboratory(s), the Principal Investigators
of the MACS clinical sites, the Principal Investigator from the MACS
data center, and the NIAID Program Officer.  Each member of the
Steering Committee will have one vote.  The chairperson, who will be
someone other than the NIAID Program Officer, will be selected by the
Steering Committee.  Subcommittees will be established by the
Steering Committee as it deems appropriate; the Program Officer will
serve on subcommittees as he/she deems appropriate.  Awardees will be
required to accept and implement the protocols and procedures
approved by the Steering Committee.

The MACS Pathogenesis Steering Committee will be the primary
organization responsible for the coordination of the activities of
the MACS Pathogenesis Research Laboratory(s) with the MACS clinical
centers and the MACS data center.  The NIAID Program Officer will
help facilitate coordination of pathogenesis research activities
between the MACS Pathogenesis Research Laboratory(s), the MACS
clinical centers, and the MACS data center.  The MACS Pathogenesis
Steering Committee will have monthly conference calls and will meet
approximately three times yearly, either in the Washington, DC
metropolitan area or in conjunction with national HIV/AIDS scientific
meetings.

Senior investigators of the MACS Pathogenesis Research Laboratory(s)
are also expected to participate as members of the MACS Laboratory
Research Working Group, created under this RFA.  This group will
include senior investigators in the MACS "core" laboratories
performing routine laboratory and virology assays at the MACS
clinical sites (described in greater detail under "Specimens",
below), as well as a representative from the MACS data center.  The
LRWG will have regular conference calls and two annual meetings per
year that usually will be held at one of the MACS clinical sites, or
at the site(s) of the MACS Pathogenesis Research Laboratory(s).  In
addition, senior investigators from the MACS Pathogenesis Research
Laboratory(s) will be expected to attend and present data at the
Annual Research Meeting of the MACS, which is held in the Rockville,
MD area.

Applicants should include in their application a statement of their
willingness to participate in the required meetings described above
and should include funds for these meetings in their budget requests.
Note that one of the Pathogenesis Steering Committee meetings and one
of the LRWG meetings will be held in conjunction with the annual
research meeting of the MACS.

B.  Specimens

MACS specimens for the conduct of studies undertaken by the MACS
Pathogenesis Research Laboratory(s) will be provided from the NIAID
HIV Vaccine Trials and Epidemiology Specimen Repository.  Fresh blood
and body fluid specimens, and biopsy and necropsy tissue specimens,
will be made available to the MACS Pathogenesis Research
Laboratory(s) according to the needs of specific protocols.  In
special cases when specimens are no longer available from the NIAID
HIV Vaccine Trials and Epidemiology Specimen Repository, (e.g., due
to their prior usage), the NIAID Program Officer will facilitate the
efforts of the MACS Pathogenesis Research Laboratory(s) in obtaining
appropriate specimens from the MACS clinical centers.

Applicants to this RFA should be aware that the MACS Pathogenesis
Research Laboratory(s) will not have sole access to MACS specimens in
the NIAID HIV Vaccine Trials and Epidemiology Specimen Repository.
MACS specimens also will be made available by the NIAID to
independent investigators upon review and approval of requests for
specific research purposes.  However, the release of MACS specimens
for studies to be undertaken by the MACS Pathogenesis Research
Laboratories will be based upon an expedited approval process,
requiring NIAID Program Officer approval of specimen utilization.
Use of MACS samples from the NIAID VTEB Repository will require
review and approval by the DAIDS repository review process.  The
NIAID Program Officer will be responsible for ensuring that the
efforts of the MACS Pathogenesis Research Laboratory(s) are
compatible with those sponsored by other NIAID groups, particularly
the contract anticipated to be awarded in 1994 for "Correlates of
Immune Protection in AIDS."

Applicants for this RFA also should note that core laboratory studies
are conducted by the MACS clinical site laboratories, including
quantitation of CD4+ and CD8+ T cell subsets on all MACS participants
and HIV serology on all seronegative MACS participants.  These data
are included in the general MACS epidemiologic and clinical
laboratory database and are available for research sponsored under
this RFA, through collaboration with the MACS clinical sites and data
center as facilitated by the NIAID Program Officer.  A list of the
specific assays and studies to be performed by the MACS core
laboratories is available from the Program Officer listed under
INQUIRIES.

C.  Reporting, Access to Data, and Publication of Research Findings

The reporting requirements currently required of all awardees of
traditional NIH research project grants will apply to the
recipient(s) of this RFA.

Program staff will have access to all study protocols and data
generated under this cooperative agreement.  Awardee(s) will retain
rights to the data (see below).

All data from the MACS Pathogenesis Research Laboratory(s) that
require analysis with other MACS data will be submitted to the MACS
data center as facilitated by the NIAID Program Officer.  These
laboratory data will remain the intellectual property of the awardee
from which they originated, even following submission to the MACS
data center and will not be used without the permission of the
Principal Investigator of the specific MACS Pathogenesis Research
Laboratory which generated these data.  Data forms and software for
transferring laboratory data to the MACS data center will be
developed by the data center with the technical assistance of the
grantee.

Publications of results from MACS Pathogenesis Research Laboratory
investigations must make appropriate acknowledgement of contributions
made by MACS clinical and data centers.

D.  Terms and Conditions of Award

Consistent with the concept of a cooperative agreement, the dominant
role and prime responsibility for the activity resides with the
awardee(s) for the project as a whole, although specific tasks and
activities in carrying out the studies will be shared among the
awardee(s) and the NIAID Program Officer.

1.  Awardee Rights and Responsibilities

The Principal Investigator(s) of the MACS Pathogenesis Research
Laboratory(s) under this RFA will be responsible for the overall
conduct of the studies performed at the Principal Investigator's
institution or at the subcontracting laboratories within a proposed
consortium.  This responsibility includes the production of high
quality data and the analysis and publication of the research
results.

2.  NIAID Rights and Responsibilities

The NIAID will have substantial scientific-programmatic involvement
during conduct of this activity, through technical assistance,
advice, and coordination above and beyond normal program stewardship
for grants, as described below:

The NIAID will assist the Principal Investigator(s) of the MACS
Pathogenesis Research Laboratory(s) selected under this RFA through a
Program Officer who will be designated by the Chief, VTEB, CRP,
DAIDS.  The role of NIAID Program Officer will be to facilitate and
not to direct the activities of the laboratory investigators funded
through this cooperative agreement.

The NIAID Program Officer will support and facilitate the performance
of research efforts of the laboratory or laboratories selected under
this RFA in the following ways:

a.  by providing ongoing assistance and coordination in overall
research planning, data gathering methodologies, analysis, and
reporting;

b.  by providing the assistance of the MACS data center to support
the awardee or awardees in areas including statistical and data
collection, analysis, and publication;

c.  by ensuring that coordination of communication and facilitation
of information exchange occurs between the laboratory or laboratories
selected under this RFA and the MACS clinical sites, the MACS "core"
laboratories, the MACS clinical centers, and the MACS data center;

d.  by releasing relevant MACS specimens from the NIAID HIV Vaccine
Trials and Epidemiology Specimen Repository.

3.  Collaborative Responsibilities

The Principal Investigator(s) of the MACS Pathogenesis Research
Laboratory(s) will be responsible for the scientific conduct of these
studies.  The NIAID Program Officer will be responsible for
facilitating these collaborations.

The Principal Investigator(s) of the MACS Pathogenesis Research
Laboratory(s) will be members of the MACS Pathogenesis Steering
Committee established under this RFA.  The MACS Pathogenesis Steering
Committee will be composed of the Principal Investigator(s) from the
MACS Pathogenesis Research Laboratory(s), the Principal Investigators
from the MACS clinical sites, the Principal Investigator from the
MACS data center, and the NIAID Program Officer.  Awardees will be
required to accept and implement the protocols and procedures
approved by the Steering Committee.

Senior investigators of the MACS Pathogenesis Research Laboratory(s)
are also expected to participate as members of the MACS Laboratory
Research Working Group, created under this RFA.  This group will
include senior investigators in the MACS "core" laboratories
performing routine laboratory and virology assays at the MACS
clinical sites, as well as a representative from the MACS data
center.

4.  Arbitration

Any disagreement that may arise on scientific/programmatic matters
within the scope of the award, between award recipients and NIAID,
may be brought to arbitration.  An arbitration panel will be composed
of three members -- one selected by the MACS Pathogenesis Steering
Committee (or by the individual awardee in the event of an individual
disagreement), a second member selected by the NIAID, and a third
member selected by the two prior selected members.  This special
arbitration procedure in no way affects the awardee's right to appeal
an adverse action that is otherwise appealable in accordance with PHS
regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR
Part 16.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

Ordinarily, for projects involving clinical research, NIH requires
applicants to give special attention to the inclusion of women and
minorities in study populations.  However, the MACS is a study of
homosexual and bisexual men, including men of minority racial and
ethnic background. Hence, a specific justification for the absence of
women in this study need not be provided.

Seven hundred and fifty men of minority background were enrolled in
the MACS from 1984-1985.  An additional 432 minority men were
enrolled in the MACS from 1987-1991 in a targeted effort to enroll
men from minority backgrounds in the study.  Five hundred and seventy
one men of minority background continue to be followed in the MACS;
299 of these men are HIV-seropositive.  Applicants are encouraged to
include proposals for research projects that best utilize the
relatively limited specimens available from minority MACS
participants.

Biohazard and Biosafety Procedures

Applicants should ensure and document that adequate procedures are in
place for avoidance of biohazards and enhancing of biosafety.  The
following reference is available from the Occupational Safety and
Health Branch, NIH Division of Safety, telephone 301-496-2960:

Richmond JY, McKinney RW, eds. Biosafety in Microbiological and
Biomedical Laboratories, 1993.  Washington, DC: US Department of
Health and Human Services, Public Health Service. HHS Publication no.
(CDC) 93-8395.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 1, 1994, 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 (if applicable), and the number and title of this RFA.
The letter of intent does not commit the sender to submit an
application, is not a requirement for submission of an application,
and will not enter into the review of subsequent applications.  The
information contained in the letter will be used to allow NIAID staff
to estimate the number and scope of applications to be reviewed, and
help avoid conflict of interest in the review process.

Letters of intent are to be sent to Dr. Dianne Tingley at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these cooperative agreements.  These forms are
available at most institutional offices of sponsored research; the
Office of Grants Information, Division of Research Grants, National
Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD
20892, telephone 301/594- 7250; and from the NIH Program
Administrator listed under INQUIRIES.

The RFA label available in the PHS 398 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 2a of the face page of the application form and the YES box must
be marked.

Because of the inherent complexity of the research to be performed,
applicants will be permitted to utilize up to 35 pages when
submitting their research plans in sections 1-4 of the Research Plan
in form PHS 398.

Applicant institutions are reminded that adequate protection for
human subjects in research is an essential requirement of the NIH.
The investigators in the laboratory(s) or laboratory consortium(ia)
supported under this grant will be utilizing specimens obtained from
human subjects in an NIAID-sponsored clinical study, making this
concern applicable to the primary grant recipient as well as the
subcontractees.  As a condition of award, not as a condition of
application, applicants are required to demonstrate approval of the
research plan by an Institutional Review Board (IRB) or an equivalent
oversight body.  Applicants will be notified if additional
information is required on this matter.

Submit a signed, typewritten original of the application, and three
signed, exact, single-space photocopies, in one package, to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional exact copies of the grant
application and all five sets of appendix material must also be sent
to Dr. Dianne Tingley at the address listed under INQUIRIES.

Applications must be received by June 15, 1994.  An application not
received by this date 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 also will not accept any application that is
essentially the same as one already reviewed.  This does not preclude
the submission of a substantial revision of an application already
reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

A.  Review Method

Upon receipt, applications will be reviewed by the DRG for
completeness and by NIAID staff for responsiveness to the RFA.
Incomplete or non-responsive applications will be returned to the
applicant without further consideration.  To be considered responsive
to this RFA, applications must address research goal (1) set forth
under the section "Research Scope"; researchers have the option of
responding to research goal (2).  A decision not to respond to
research goal (2) will not reflect negatively on any application
received.

Those applications judged to be complete and responsive will be
evaluated in accordance with the criteria stated below for
scientific/technical merit by an appropriate peer review group
convened by the NIAID.  This initial review may include a triage; the
NIAID will withdraw from further consideration applications judged to
be noncompetitive and will notify the Principal Investigator and the
official signing for the applicant's organization.  Those
applications judged to be competitive will be evaluated further for
scientific and technical merit by the usual peer review procedures.
Each application will receive a priority score based upon review
criteria listed below.  The second level of review will be provided
by the NIAID Council in February 1995.

B.  Review Criteria

Factors to be considered in the evaluation of each application will
be similar to those used in review of traditional research grant
applications.  Major factors to be considered in the evaluation of
applications will include:

1.  Scientific merit of the proposed projects, including innovation
and originality of hypotheses, feasibility of the scientific
approach, and development plans, status, and validity of the
laboratory methods to be applied; adequacy of the experimental design
and relevance to understanding HIV pathogenesis via effective
utilization of the unique resources offered by the MACS.

2.  Competence of the investigators to accomplish the proposed
research goals, including their prior experience in collaborative
research efforts and the time they will devote to this initiative.

3.  Adequacy of facilities for the performance of the proposed
research.

4.  Evidence of integration and coordination among the laboratory
disciplines within a given laboratory or consortium.

5.  Experience of the sponsoring organization or institution in
comparable laboratory research efforts.

6.  Evidence of adequate quality assurance of laboratory assays.  The
presentation should include discussions of sensitivity, specificity,
and reproducibility of proposed assays, or how these will be studied
if the proposed assays are in the early developmental phases.  The
presentation should also describe appropriate positive and negative
controls to be used in each assay.  External performance evaluation
procedures that will be done on panels of well characterized
specimens should be described.  To ensure objectivity in laboratory
assays, the NIAID HIV Vaccine Trials and Epidemiology Specimen
Repository will provide blinded specimens on instruction by NIAID
staff.

7.  Appropriateness of the plan to collaborate with MACS
epidemiologic, clinical, and biostatistical investigators through the
MACS Pathogenesis Steering Committee and the MACS Laboratory Research
Working Group.

8.  Appropriateness of the budget for the proposed research studies.

AWARD CRITERIA

It is anticipated that one or two MACS Pathogenesis Research
Laboratories will be selected under a cooperative agreement through
this RFA.  While not a requirement for selection, it is anticipated
that applicants will develop a consortium with other laboratories to
complement the research activities intended under this RFA.  The
number of awards and the specific amount to be awarded will depend on
the merit and scope of the applications received and on the
availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcomed.  Direct inquiries regarding programmatic or
scientific issues to:

Lewis K. Schrager, M.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2B-10
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-6177

Direct inquiries regarding review issues, address the letter of
intent to, and mail two copies of the application and five sets of
appendices to:

Dr. Dianne Tingley
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C01
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818

Questions regarding administrative policy and fiscal matters may be
addressed to:

Ms. Ann Devine
Grants Management Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B22
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075

Schedule

Letter of Intent Receipt Date:  April 1, 1994
Application Receipt Date:       June 15, 1994
Anticipated Award Date:         April 1, 1995

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.85 "Microbiology and Infectious Disease Research"
and No. 93.855 "Immunology," "Allergic and Immunologic Diseases
Research."  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 PHS
grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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