MULTICENTER AIDS COHORT STUDY PATHOGENESIS RESEARCH LABORATORIES

Release Date:  January 8, 1999

RFA:  AI-99-002

P.T.

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  May 3, 1999
Application Receipt Date:  July 13, 1999

PURPOSE

The Epidemiology Branch (EB) of the Division of AIDS (DAIDS), NIAID administers
a major, prospective study of HIV infection and disease.  The Multicenter AIDS
Cohort Study (MACS) is 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 purpose of this Request for Applications (RFA) is to fund separate
laboratories or consortia of laboratories to study the immunologic, virologic,
and other biologic determinants of disease progression; factors which mitigate
HIV-mediated immune system destruction; and factors which might protect
individuals from acquiring HIV infection among participants in the Multicenter
AIDS Cohort Study (MACS).  The work to be accomplished requires collaborative,
multidisciplinary expertise in HIV virology, immunology, and immunopathogenesis
which must be applied in a highly coordinated manner to adequately address the
issues of interest.  Therefore, proposed studies should utilize a
multidisciplinary approach in which the research plans are well integrated,
composed of two or more laboratories, at the same or different institutions
specializing in different scientific disciplines.

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, Multicenter AIDS Cohort Study
Pathogenesis Research Laboratories, is related to the priority areas of HIV
infection immunization and infectious diseases, and sexually transmitted
diseases.  Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private institutions, such as universities, colleges,
hospitals, laboratories, units of State and local governments; and eligible
agencies of the Federal government.  Foreign institutions are not eligible to
apply.  Racial/ethnic minority individuals, women, and persons with disabilities
are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this program
will be the Cooperative Agreement (U01), an "assistance" mechanism, rather than
an "acquisition" mechanism, in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during the performance
of the activity.  Under the cooperative agreement, the NIH purpose is to support
and/or stimulate the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to assume
direction, prime responsibility, or a dominant role in the activity.  Details of
the responsibilities, relationships, and governance of a study funded under
cooperative agreement(s) are discussed later in this document under the section
Terms and Conditions of Award.

The total project period for applications submitted in response to this RFA may
not exceed four years.  At present, the NIAID is administratively limiting the
duration of U01 cooperative agreements to four years; this administrative
limitation may change in the future.  At this time, the NIAID has not determined
whether and how this solicitation will be continued beyond the present RFA.

FUNDS AVAILABLE

Approximately $1,750,000 will be available for funding the total costs, both
direct and indirect, for the initial year of awards made pursuant to this RFA. 
NIAID anticipates making 3 awards (maximum $500,000 to $600,000 total costs each)
as a result of this RFA.  The issuance of the final awards will be dependent upon
receipt of applications of high scientific merit that cover the range of
scientific objectives and upon the availability of funds.

The usual PHS policies governing grants administration and management will apply. 
Although this program is provided for in the financial plans of the NIAID, awards
pursuant to this RFA are contingent upon the availability of funds for this
purpose and the receipt of a sufficient number of applications of high scientific
merit.  Funding beyond the first and subsequent years of the grant will be
contingent upon satisfactory progress during the preceding years and availability
of funds.

RESEARCH OBJECTIVES

Background

The MACS is supported by the EB, DAIDS, NIAID.  Studies of HIV-related malignancy
in the MACS are co-funded by the NCI.  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 less than 20% among HIV-infected men after ten years.  MACS study
sites 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 of MACS Data (CAMACS) is located at
Johns Hopkins University in Baltimore, MD.  In 1995, two MACS Pathogenesis
research laboratories were funded to investigate HIV pathogenesis using MACS
specimens and data.  These laboratories are located at Johns Hopkins University,
Baltimore, MD and the University of California at Los Angeles in Los Angeles, CA.

Because of the continuing unique scientific contributions of this large
prospective, multi-site cohort study, the NIAID, through a separate funding
mechanism, intends to renew support for the MACS to follow selected study
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 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 2005.

Since 1984, MACS investigations have covered a broad spectrum of research
relating to HIV infection and disease.  These studies have included:

1) Clinical effects of therapy, trends in survival, and trends in HIV-related
clinical events, including opportunistic infections and HIV-related malignancies;

2) Correlation of host immune responses to the development of HIV disease;

3) Use of plasma HIV-1 RNA (viral load) as a CD4+ T cell-independent predictor
of outcome following HIV-1 seroconversion;

4) Use of intrinsic viral factors, including HIV phenotype and sequence
variation, in determining disease outcome;

5) Identification of polymorphisms in chemokine receptors that correlate with
susceptibility to HIV infection and progression to AIDS;

6) Epidemiologic and laboratory correlates of HIV-related malignancy (funded
through an Interagency Agreement with the National Cancer Institute);

7) HIV-related neuropsychological outcomes and neuro-pathological events;

8) Trends in the patterns of health service utilization throughout the course of
HIV infection.

MACS data have shown that the median time from infection with HIV to development
of AIDS is approximately 10 years, although this time period for individuals is
highly variable.  A small proportion of the cohort participants who seroconverted
in the study developed AIDS and died within two or three years of HIV infection,
while others have maintained stable, high CD4+ cell counts for more than six
years following HIV infection.  To date, plasma HIV RNA levels are the single
most important predictor of disease progression.  Additional studies of host
immunologic, virologic, genetic, and other determinants of HIV infection and
disease progression are needed however, to gain a better understanding of what
mediates the plasma HIV RNA levels and its contribution to 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.

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

1) A sixteen 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;

4) Extensive expertise in human genetics, particularly the effect of various
polymorphisms on susceptibility to infection and disease progression via a
special collaboration between the MACS and the Laboratory of Genomic Diversity
(LGD), NCI (Stephen O'Brien, Principal Investigator)

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 displayed no CD4+ cell loss despite at
least nine years of HIV infection, and without receipt of antiretroviral therapy,
although the CD4 counts of many of these men have demonstrated decline during
extensive follow-up.  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 at six month intervals,
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 AIDS Specimen Repository. 
These stored specimens will be made available to the MACS Pathogenesis Research
Laboratories.  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.  Availability of these additional specimens will be contingent on
study feasibility and obtaining local institutional review board approval and
necessary informed consent.

To design valid tests of hypotheses on the pathogenesis of HIV, it will be
crucial to select appropriate case and control groups.  The continually expanding
MACS database with its breadth of clinical, behavioral, and laboratory variables
will enable the selection of the relevant nested case and control groups for this
purpose.  MACS biostatisticians and epidemiologists who have developed the
comprehensive MACS database will be available to provide vital assistance in
specimen selection and design of these laboratory-based studies.  Moreover, the
ongoing clinical and epidemiologic investigations in the MACS will likely
generate new questions and opportunities for laboratory investigations of HIV
pathogenesis. However, for the purposes of your response to this RFA, please
submit completely designed study protocols.

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, slow progressors, exposed to HIV but uninfected), specific
features of the stored specimens (e.g., numbers, types, prior experience with
quality of stored cells), and specific aspects of the collaboration between MACS
and the LGD will be provided to all RFA requesters upon receipt of a letter of
intent.

Research Objectives and Scope

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 AIDS Specimen
Repository.  Examples of research areas that would be responsive to the RFA are
listed below.  Highly innovative and creative approaches concerning the study of
HIV pathogenesis in MACS participants, are encouraged.

o  Humoral antibody responses (e.g., binding, neutralizing, enhancing, ADCC),
cell-mediated responses (e.g., cytotoxic T cell activity, T helper responses),
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  Viral variables associated with HIV pathogenesis (e.g., HIV phenotype, viral
load, pattern of sequence variation during infection).

o  Viral variables associated with latent reservoirs (e.g.; tropism, chemokine
receptor usage, cytopathicity, resistance to antiretroviral agents).

o  Definition of the size, turnover rate, and immunologic and virologic
characteristics of latent cellular reservoirs for HIV-1, particularly viral
reservoirs that persist in patients on HAART and development of an experimental
system of identifying stimuli that could be used to mobilize latent reservoirs
for elimination.

o  Host and viral factors that may explain long-term clinical stability sometimes
noted in subjects with low CD4+ cell counts.

o  Immunologic and virologic factors associated with non-infection despite
continual high risk sexual behavior.  (Note: These experiments may be planned
utilizing the approximately 250 HIV-seronegative MACS participants with a history
of high risk sexual behavior and the 30 discordant couple pairs followed in the
MACS).

o  Other host factors that enhance viral replication, HIV pathogenesis, (e.g.,
studies of histopathology, immune dysregulation, 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 Laboratories will propose and conduct the relevant
studies in collaboration with the MACS research infrastructure.  As work
progresses, the Principal Investigators may seek input from the MACS 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 Investigators of the MACS Pathogenesis Research Laboratories will
be responsible for the scientific conduct of these collaborative studies.  The
Principal Investigators of the MACS clinical sites and CAMACS will be responsible
for the quality of the data and specimens obtained from cohort participants.  The
NIAID Program Officer will be responsible for facilitating collaborations between
the MACS Pathogenesis Research Laboratories, MACS clinical sites, CAMACS and will
have the final authority for release of the study specimens from the NIAID AIDS
Specimen Repository.  For more information, refer to "Terms and Conditions of
Awards."

The Principal Investigators of the MACS Pathogenesis Research Laboratories will
serve as members of the Executive Advisory Committee (EAC) of the MACS.  This
participation will facilitate integration and coordination of the collaborative
pathogenesis research within the MACS.  The MACS EAC membership includes
Principal Investigators of the clinical sites and CAMACS, the NIAID Program
Officer, and the NCI Associate Program Officer.  The EAC has monthly conference
calls and meets approximately three times yearly, either in the Rockville, MD
area or in conjunction with national HIV/AIDS scientific meetings.

Senior investigators of the MACS Pathogenesis Research Laboratories are also
expected to participate as committee members of the MACS Laboratory Research
Working Group (LRWG).  This group, which includes the senior investigators in the
MACS clinical site laboratories, has regular conference calls and two annual
meetings per year that are usually held at one of the MACS clinical sites.  In
addition, each senior investigator of the MACS Pathogenesis Research Laboratories
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 EAC 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 AIDS Specimen Repository. 
Fresh blood and body fluid specimens, and biopsy and necropsy tissue specimens,
will be made available to the MACS Pathogenesis Research Laboratories according
to the needs of specific protocols.  In special cases when specimens are no
longer available from the NIAID AIDS Specimen Repository, (e.g., due to their
prior usage) replacement specimens may be obtained through the MACS Principal
Investigators with approval of the MACS Executive Advisory Committee.

Applicants to this RFA should be aware that the MACS Pathogenesis Research
Laboratories will not have sole access to MACS specimens in the NIAID AIDS
Specimen Repository.  MACS specimens also will be made available to independent
investigators upon review and approval of requests for specific research
purposes.  NIAID program staff will be responsible for ensuring that research
conducted with these specimens complements but does not duplicate research in
other NIAID sponsored laboratories.

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, plasma HIV RNA levels 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 proposal, in collaboration with the MACS clinical
sites, CAMACS, and NIAID staff, through the MACS Executive Advisory Committee as
detailed below.  A list of the specific assays and studies to be performed by the
MACS core laboratories is available from the Program Officer (address listed
under "INQUIRIES").

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

In addition to the reporting currently required of all awardees of traditional
NIH research project grants, the following apply:

1.  A summary of the progress of the research supported by this cooperative
agreement shall be sent annually to the NIAID Program Officer.

2.  Drafts of all manuscripts resulting from this cooperative agreement shall be
sent to the Program Officer at the time of their circulation to co-authors.  A
copy of all published articles also shall be sent to the NIAID Program office.

Program staff will have access to all study protocols and data generated under
this cooperative agreement.  Information obtained from the data may be used by
NIAID for the preparation of internal reports on MACS activities.  Awardees will
retain rights to the data (see below).

All MACS Pathogenesis Research Laboratory data that requires analysis with other
MACS data will be submitted to CAMACS.  These laboratory data will remain the
intellectual property of the awardee from which they originated, even following
submission to CAMACS, 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 CAMACS will be developed by CAMACS with the technical assistance of the
grantee.

Publication policies for data involving collaborative epidemiologic, clinical,
genetic or statistical work will be established with the EAC to ensure fair and
equitable participation of other MACS investigators in the research activities
and publication of results.  Applicants to this RFA should understand that the
MACS epidemiologic and clinical laboratory database is a support component shared
by all of the participating sites.  Therefore the use and publication of material
derived from the overall MACS database will be governed by policies established
by the EAC, within the guidelines outlined above.

When MACS Pathogenesis Research Laboratory data are derived from minimally
characterized specimens (e.g., date, patient age, general clinical status) it
will not be necessary to involve the EAC in the publication considerations.  In
any case, notification of the work in progress must be made to NIAID program
officials and to the EAC to ensure that inappropriate or unintentional
duplications of effort do not occur.  Publication or oral presentation of work
performed under this agreement must include appropriate acknowledgment of NIAID
support.

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 require consultation with, or assistance from the NIAID Program Officer.

1.  Awardee Rights and Responsibilities

The Principal Investigators of the MACS Pathogenesis Research Laboratories 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.

Applicant institutions are reminded that adequate protection for human subjects
in research is an essential requirement of the NIH.  The investigators in the
laboratories or laboratory consortia 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.

2.  NIAID Rights and Responsibilities

The NIAID Program Officer and NIAID staff 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 staff will assist the Principal Investigators of the MACS Pathogenesis
Research Laboratories selected under this RFA through a Program official who will
be designated by the DAIDS.  The NIAID Program Officer will have overall
responsibility to ensure the scientific and technical integrity of the project
on behalf of the Institute.  The role of NIAID will be to facilitate and not to
direct the activities of the laboratory investigators funded through this
cooperative agreement.

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

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

b) by providing the assistance of the MACS data center (CAMACS) to support the
grantee or grantees in areas including statistical and data collection, analysis,
and publication;

c) by ensuring that coordination of communication and facilitation of information
exchange occur between the laboratory or laboratories selected under this RFA and
the MACS clinical sites, the MACS EAC,  CAMACS and the LGD;

d) by releasing relevant MACS specimens from the NIAID AIDS Specimen Repository.

3.  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 Executive Advisory 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.

INCLUSION OF WOMEN, MINORITIES, AND CHILDREN IN CLINICAL RESEARCH STUDY
POPULATIONS

Ordinarily, for projects involving clinical research, NIH requires applicants to
give special attention to the inclusion of women, minorities and children 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 and children 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 which 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 the date listed under "SCHEDULE"
below, a short 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 the RFA in response to which the
application may be sent.  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 to help avoid conflict of interest
in the review process.

The letter of intent is to be sent to Dr. Dianne Tingley at the address listed
under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98).  Application 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.  Application kits are also available at:
http://grants.nih.gov/grants/forms.htm

The RFA label available in the application form PHS 398 must be affixed to the
bottom of the face page.  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 must be received by July 13, 1999.  Applications that are not
received as a single package on the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 4/98) Application Kit (as modified in,
and superseded by, the special instructions below, for the purposes of this RFA),
will be judged non-responsive and will be returned to the applicant.

If the application submitted in response to this RFA is substantially similar to
a grant application already submitted to the NIH for review, but that has not yet
been reviewed, the applicant will be asked to withdraw either the pending
application or the new one.  Simultaneous submission of identical applications
will not be allowed, nor will essentially identical applications be reviewed by
different review committees.  Therefore, an application that is essentially
identical to one that has already been reviewed cannot be submitted in response
to this RFA.  This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an introduction
addressing the previous critique.

It is highly recommended that the appropriate NIAID program contact be consulted
before submitting the letter of intent and during the early stages of preparation
of the application.  (See program contacts under INQUIRIES).

SPECIAL APPLICATION INSTRUCTIONS.  Because of the anticipated complexity of
applications, the page limit for the Research Plan (sections a-d) is increased
to 30 pages.

Submit a signed, typewritten original of the application, and three 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)

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

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review and for responsiveness by NIAID staff.  Incomplete and/or non-
responsive applications will be returned to the applicant without review. 
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 NIAID in accordance with the review criteria stated below.  As part of the
initial merit review, a process will be used by the initial review group in which
applications receive a written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally the top half
of the applications under review, will be discussed, assigned a priority score,
and receive a second level review by the National Advisory Allergy and Infectious
Diseases Council.

Review Criteria

The goals of NIH-supported research are to advance the 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, collaborative arrangements, design,
methods, and analyses adequately developed, well-integrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential problem areas
and consider alternative tactics?

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

4.  Investigator.  Is the investigator appropriately trained and well suited to
carry out this work?  Is the proposed work 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?

6.  Evidence of adequate quality assurance of laboratory assays.  The proposal
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 proposal 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 AIDS
Specimen Repository will provide blinded specimens on instruction by NIAID staff.

7.  Previous research productivity.  Does the applicant have experience in
design, evaluation and interpretation of data derived from cohort specimens? 
Have previous publications from the applicant critically impacted knowledge of
HIV pathogenesis and development of treatment strategies?

8.  Willingness to collaborate with MACS epidemiologic, clinical, and
biostatistical investigators through the MACS EAC and LRWG.

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include minorities and
their subgroups as appropriate for the scientific goals of the research and plans
for the recruitment and retention of subjects; the provisions for the protection
of human and animal subjects; and the safety of the research environment.

AWARD CRITERIA

It is anticipated that up to three MACS Pathogenesis Research Laboratories will
be selected under a cooperative agreement through this RFA.  Although not a
requirement for selection, it is anticipated that awardees 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
welcome.

Direct inquiries regarding programmatic (research scope and eligibility) issues
to:

Dr. Patricia D'Souza
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2C05
Bethesda, MD  20892
Telephone:  (301) 496-8379
FAX:  (301) 402-3211
Email:  PD6N@ NIH.GOV

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
6003 Executive Boulevard, Room 4C01
Bethesda, MD  20892
Telephone:  (301) 496-2250
FAX:  (301) 402-2638
Email:  dt15g@nih.gov

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

Ms. Ann Devine
Grants Management Branch
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B22
Bethesda, MD  20892
Telephone:  (301) 496-5601
FAX:  (301) 480-3780
Email:  ad22x@nih.gov

For express/courier services applicants should use:  Rockville, MD 20852

Schedule

Letter of Intent Receipt Date:  May 1, 1999
Application Receipt Date:       July 13, 1999
Anticipated Award Date:         March 1, 2000

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
Nos. 13.85 and 13.855.  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.

The PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.


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