Full Text AI-94-018

MECHANISMS OF AIDS PATHOGENESIS

NIH GUIDE, Volume 23, Number 17, May 6, 1994

RFA:  AI-94-018

P.T. 34

Keywords: 
  AIDS 
  Pathogenesis 
  0705048 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  September 16, 1994
Application Receipt Date:  November 16, 1994

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications from single institutions or consortia of
institutions for research project grants focusing on a hypothesis for
AIDS-related pathogenesis.  This Request for Applications (RFA)
specifically solicits applications for in vivo research of
AIDS-related pathogenesis utilizing state-of-the-art methods and
approaches.  In vivo research includes studies of human clinical or
epidemiologic cohorts, of animal models, or of appropriate specimens
from humans or animals. Research supported by this RFA is limited to
one or more of three scientific areas:  (1) non-human primate models
of HIV immunopathogenesis, (2) sexual/mucosal transmission of HIV or
SIV, and (3) host factors that modulate HIV or SIV infection or
disease.

Where scientifically justified, applicants are encouraged to include
both human and animal studies.  Although the research necessary to
test a proposed pathogenesis hypothesis may be possible within a
single laboratory, highly competitive applications may require
separate components at the same or different institutions
specializing in different scientific disciplines (e.g., molecular
biology, biochemistry, cellular biology, cellular immunology,
genetics and biophysics).

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,
Mechanisms of Aids Pathogenesis, 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 "Healthy
People 2000" (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and
non-profit, public and private organizations, such as universities,
colleges, hospitals,laboratories, units of State or local government,
and eligible agencies of the Federal government.  Successful
applications from foreign institutions are limited to three years of
support for direct costs; domestic applications may include
international components, but these components will receive no
support for indirect costs.  Applications from minority individuals
and women are encouraged.

MECHANISM OF SUPPORT

Awards made under this RFA will use the National Institutes of Health
(NIH) individual research project grant (R01) award mechanism.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total
project period for applications submitted by domestic institutions
may not exceed four years; the total project period for applications
submitted by foreign institutions may not exceed three years.

Applicants are strongly encouraged to coordinate, through the use of
consortium arrangements or subcontracts, integrated approaches with
individuals or institutions having relevant reagents and expertise in
their use, demonstrated ability in a particular area of relevant
research, or access to relevant animal or patient populations.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC Program Director or Principal Investigator should be included in
the application.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for
the first year of support for awards under this RFA will be $6
million.  Because the nature and scope of the research proposed in
response to this RFA may vary, it is anticipated that the size of the
awards will vary also.  The NIAID anticipates 8 to 16 awards under
this RFA.  It is the intent of the NIAID to fund applications in each
of the three scientific areas described in RESEARCH OBJECTIVES below.
The number of awards and the levels of support will depend upon the
receipt of a sufficient number of applications of high scientific
merit.  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. Continued funding beyond the
first and subsequent years of a grant will be contingent upon
satisfactory progress and availability of funds.

Applicants are encouraged to discuss budget requests with Division of
AIDS (DAIDS) program staff (listed under INQUIRIES) prior to
submission.  Requests for expensive equipment are not encouraged.
Investigators are encouraged to use animals efficiently and to
minimize expenses for animal purchase and/or support.  The purchase
of animals must be strongly justified.

This RFA is a one-time solicitation.  Future competing continuation
applications will compete with unsolicited investigator-initiated
applications and be reviewed by an appropriate Study Section
according to the customary NIH referral and peer review procedures.

RESEARCH OBJECTIVES

A.  Background

Non-Human Primate Models of HIV Immunopathogenesis

Non-human primate models of HIV disease are vital tools for
pathogenesis research.  Where no single animal model satisfies all
investigative requirements, comparison of data from multiple models
may contribute to the understanding of the pathogenic aspects of HIV
disease.  The simian immunodeficiency virus (SIV) and chimeric
SIV-HIV infections of macaques are well described.  Clues to HIV
pathogenesis also may be discovered from analyses of
lentivirus-infected non-human primates in which there is little or no
apparent disease, e.g., HIV-infected chimpanzees and African green
monkeys infected with African Green Monkey (AGM) lentiviruses.

Sexual/Mucosal Transmission

The overwhelmingly predominant mode of transmission of HIV is through
exposure of mucosal surfaces to infected sexual fluids (semen,
cervical/vaginal, rectal) and during birth.  However, epidemiological
data suggest that sexual transmission, in general, is relatively
inefficient, in that exposure does not always produce infection.
Some individuals who are exposed to HIV via mucosal surfaces over
prolonged periods remain seronegative.  The likelihood of
transmission is increased by factors that decrease the integrity of
the mucosal epithelium.  Epidemiologic studies have implicated
sexually transmitted diseases that produce genital ulcerations or
inflammation, use of intrauterine devices, and lack of male
circumcision as cofactors facilitating HIV transmission.

Studies in the SIV monkey model indicate that 100- to 1,000-fold more
infectious virus is required to produce infection following
application to intact genital mucosal surfaces than by intravenous
injection.  Studies of mucosal infection in the SIV model suggest
that mucosal dendritic cells may be the first cells infected.
Subsequently, infected dendritic cells may migrate to lymph nodes
where they infect other cells.

Host Resistance to Infection or Disease

Genes that confer host resistance to retroviral infection in animals
have been described and include both immune response genes and
non-immune response genes.  For example, the product of the Fv-1
allele prevents the development of leukemia in inbred mice infected
with specific MuLV strains.  Recent experimental evidence suggests
that host genes may also modulate infection or disease caused by
lentiviruses including HIV.  In vitro evidence for the relative
resistance of human T lymphocytes to HIV infection has been
described.  Resistance of PBMCs from individual monkeys to infection
by SIV has also been observed and has been reported to be predictive
of disease course.  Investigation of these and other resistance
mechanisms may reveal novel events in infection or replication of
lentiviruses and could lead to novel prevention or therapeutic
strategies.

The NIAID Multicenter AIDS Cohort Study (MACS) has shown that the
median time from infection with HIV to development of AIDS is
approximately 10 years, although this time period is highly variable
among different individuals.  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 ten or more years following
HIV infection.  To date, no independent epidemiologic factor or set
of host or viral factors has been identified that reliably predicts
disease progression or a state of relative "immunologic
non-progression" (as judged by CD4+ cell stability).  Studies of host
factors and other determinants of HIV infection and disease are
needed to gain a better understanding of the pathogenesis of HIV.

B.  Goals

The NIAID HIV/AIDS Research Agenda (October 1993) identified eight
critical areas of research in HIV pathogenesis:

o  molecular biology of viral and cellular processes;
o  cellular biology and immunology related to the course and dynamics
of HIV infection;
o  viral genetic and phenotypic correlation with disease;
o  host factors affecting infection and/or progression;
o  external factors affecting infection and/or progression;
o  mechanisms of HIV-related immunodeficiency;
o  animal models of HIV infection and/or pathogenesis; and
o  mechanisms of sexual transmission and mucosal immunity.

Reviews of the DAIDS pathogenesis programs by an ad hoc committee and
by the AIDS Research Advisory Committee (ARAC) concurred with these
eight critical areas of research and recommended that three receive
particular emphasis, specifically: non-human primate models of HIV
immunopathogenesis, sexual/mucosal transmission of HIV or SIV, and
host factors that modulate HIV or SIV infection or disease.  The
reviews strongly encouraged NIAID to promote studies of in vivo
pathogenesis in these areas utilizing state-of-the-art in vitro
approaches.

This RFA is intended to foster applications for integrated,
multi-disciplinary pathogenesis research linking in vitro studies to
in vivo disease and focusing specifically on these three scientific
areas. The most relevant studies are expected to examine molecular
and cellular biology, virology, and immunology within the context of
animal models and/or well-defined human cohorts or patient samples.

C.  Research Scope

Research grant applications responsive to this RFA should provide
innovative focused approaches to test a hypothesis of HIV
pathogenesis in non-human primate models, HIV or SIV sexual/mucosal
transmission, or host factors that modulate HIV or SIV infection or
disease.  The NIAID anticipates that investigators will propose
studies testing hypotheses using state-of-the-art methods on
specimens from human and/or animal models.  Although the research
necessary to test a proposed pathogenesis hypothesis may be possible
within a single laboratory,  highly competitive applications may
require separate components at the same or different institutions
specializing in different scientific disciplines (e.g., molecular
biology, biochemistry, cellular biology, cellular immunology,
genetics, and biophysics).  If applicable, applicants are encouraged
to select component leaders based on scientific excellence rather
than proximity.  If multiple components are proposed, the interactive
role of each component in investigating the hypothesis should be
described.

The following are examples of major issues or gaps in knowledge in
the three RFA scientific areas that were identified in the NIAID
HIV/AIDS Research Agenda:

Pathogenesis In Humans And Non-Human Primates

o  Course of infection (infected cells, non-productively infected
cells, virus production, altered biology of infected and uninfected
cells) in different organ systems (blood, thymus, lymph nodes,
gastrointestinal tract, bone marrow, spleen, nervous system, etc.)
from early to systemic disease.

o  Clinical course and mechanisms of disease following infection with
viruses of differing tropisms (macrophage, T-cell, neurotropic),
high/low replication properties, or syncytium /non-syncytium inducing
abilities.

o  Role of accessory viral genes (vif, nef, vpu, vpr, etc.) in
infection, cellular tropism, and disease progression in vivo.

o  Steps in T-cell development and/or regulation that are affected by
lentivirus infection and the lentivirus genes or gene products that
are responsible.

o  Mechanisms of defects in T-cell signalling in uninfected and SIV
(SHIV or HIV) infected cells.

o  Differences in pathogenesis between control and treated infected
non-human primates in ongoing (already funded) therapeutic and
vaccine SIV or SHIV studies.

HIV or SIV Sexual/Mucosal Transmission

o  Mechanisms of mucosal transmission by free virus, cell-associated
virus, or both.

o  Genetic composition of HIV in the donor compared to HIV
phenotype/genotype that is sexually transmitted to the recipient.

o  Types of cells initially infected (i.e., lymphocytes, macrophages,
and dendritic cells).

o  Mechanisms, time course, and pathways of viral spread from site of
initial infection.

o  Differences, if any, in the mechanisms of establishment of HIV
infection by rectal, vaginal, oral, or other mucosal routes.

o  Host mechanisms operative at mucosal surfaces that protect exposed
individuals from HIV infection.

o  Role of co-factors other than STDs in facilitating or hindering
mucosal transmission in vivo.

Host Factors that Modulate HIV or SIV Infection or Disease

o  Mechanisms for differences in susceptibility of cells from
different hosts to HIV or SIV infection in vitro.

o  Identification of host genes (alleles) and/or factors that prevent
or enhance infection, resistance to infection, and/or disease
progression.  Investigations of variations in normal immune response
are not included under this topic.

o  Mechanisms by which host factors prevent or enhance infection,
provide resistance to infection, and/or disease progression in vitro
and in vivo.

o  Mechanisms by which primates are resistant to lentivirus disease;
i.e., chimpanzees infected with HIV and African Green monkeys
infected with AGM virus.

o  Mechanisms responsible for observed variations in susceptibility
to HIV or SIV infection and/or rates of progression in different
individuals.

o  Comparison of known mechanisms of resistance to retroviruses in
non-primates (mice, chickens, etc.) with observations in primates.

D.  Restrictions and Exclusions

Descriptive, non-hypothesis driven, research is not within the scope
of this RFA.  For example, natural history epidemiologic studies in
many DAIDS-supported cohorts are critically important for collecting
information on cause and course of disease.  The information provided
by such studies may provide a foundation for hypotheses that may be
tested in research supported by this RFA.  This RFA is intended to
support the next step in research, the testing of these hypotheses.

This initiative will not support drug or vaccine trials in animals or
humans.

Proposed studies should minimize expenses for animal support and
maximize the use of animals in ongoing non-human primate research.
For example, the applicant may be able to coordinate SIV pathogenesis
projects with DAIDS-supported vaccine or drug development studies in
macaques.  The applicant is responsible for establishing components
and/or collaborative arrangements.  A list of Principal Investigators
who have access to non-human primates in NIAID-sponsored research is
available from DAIDS program staff (see INQUIRIES) upon request, but
these investigators are under no obligation to collaborate with RFA
applicants.

Clinical trials involving the recruitment or retention of cohorts
will not be supported under this RFA.  However, costs for patient
visits, sample storage, and handling specific to the applicant's
proposed research are appropriate.  Analyses of samples acquired from
epidemiologic or clinical trials are also appropriate.  Proposed
studies should maximize the use of epidemiologic or clinical cohorts
in ongoing research to minimize expenses.  A list of Principal
Investigators who have access to epidemiologic or clinical cohorts in
NIAID-sponsored research will be available from DAIDS program staff
(see INQUIRIES) upon request, but these investigators are under no
obligation to collaborate with RFA applicants.

Special Requirements

A.  Travel -- NIAID AIDS Pathogenesis Meeting

Principal Investigators and other key members of the projects will be
requested to attend an annual NIAID AIDS Pathogenesis Meeting, a
grantees of the Mechanisms of AIDS Pathogenesis RFA, to be held each
year at a site designated by NIAID (Bethesda, Maryland is
anticipated).  Principal Investigators and component leaders will be
requested to present significant findings in symposium format.  Data
are to be selected by the individual presenters in consultation with
their Principal Investigator thus affording appropriate protection of
proprietary or commercially sensitive information.  At the discretion
of the DAIDS program staff, other investigators may also be invited
to attend.  Funds for the Principal Investigator and key scientific
personnel to travel to these meetings should be included in the
application budget.  For budgetary purposes, applicants should
anticipate lodging for three nights in the Bethesda, Maryland area
(estimated food and lodging costs for 1994 = $158/night) and travel
at economy airfares.

B.  No Initial Review Site Visit

One important factor that should influence the care and detail with
which applications in response to this RFA are prepared is a
long-standing NIAID policy that there will be no site visits in the
initial review of applications.  Peer reviewers will base their
comments and recommendations solely on the written application, which
must be complete and prepared according to the RFA guidelines.
Applicants are strongly encouraged to discuss research plans and
organizational structure with DAIDS program staff in the early stages
of preparation of the application.  (See program contact list in
INQUIRIES.)

STUDY POPULATIONS

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This 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 new
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 9, 1994 (FR 59 11146-11151), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.]

Investigators may obtain copies of the policy from program staff
listed in INQUIRIES, who may also provide additional information
concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by September 16, 1994, a
letter of intent that includes a descriptive title of the project;
the names, addresses, telephone numbers, and EMAIL addresses (if
available) of the Principal Investigator, component leaders, and
other key personnel; the names of the primary institution and
component institutions (if different); and the number and title of
this RFA.

Although a letter of intent is not required, is not binding, and does
not enter into the review of the application, the information that it
contains is helpful in planning for the review of expected
applications.  It allows NIAID to estimate the potential workload for
reviewers and to avoid possible conflict of interest in the review
process.

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

APPLICATION PROCEDURES

Applications are to be submitted on form PHS 398 (rev. 9/91), the
standard application form for research grants.  Application kits are
available at most institutional offices of sponsored research and may
also be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 449, Bethesda, MD 20892, telephone 301/435-0714.  Applicants
must adhere to the format and requirements specified in the PHS 398
application kit.

For purposes of identification and processing, mark "YES" in item 2a
on the face page of the application and type in the RFA number
AI-94-018 and the title "MECHANISMS OF AIDS PATHOGENESIS."

The RFA label available in the form PHS 398 must be affixed to the
bottom of the face page of the original application.  Failure to use
this label could delay the processing of the application such that it
may not reach the review committee in time for review.

Questions regarding the format for submission of an R01 package may
be directed to the staff person listed under INQUIRIES.

Submit a signed, typewritten original of the application, including
the Checklist, and three exact, signed, single-sided 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 copies of the application
and five sets of appendices and reprints must also be sent to Dr.
Dianne Tingley at address listed under INQUIRIES.

To ensure their review, applications must be received by both the
Division of Research Grants (DRG) and Division of Extramural
Activities by November 16, 1994.  Applications not received by the
receipt date will be considered non-responsive and will be returned
to the applicant without review.  If the application submitted in
response to this RFA is substantially similar to an application  that
has already been submitted to the NIH but has not yet been reviewed,
the applicant will be asked to withdraw either the pending
application or the new one.  Simultaneous submission of essentially
identical applications is not allowed nor will essentially identical
applications be reviewed by different review committees.  Therefore,
an application cannot be submitted in response to this RFA that is
essentially identical to one that has already been 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.

REVIEW CONSIDERATIONS

A.  Review Procedures

Applications will be reviewed by DRG staff for completeness and by
NIAID staff for administrative and programmatic responsiveness to
this RFA.  To be considered responsive, the application must be
directed towards the attainment of the stated programmatic goals (see
RESEARCH OBJECTIVES).  Therefore, applicants are encouraged to
discuss their research plans with program staff before completing
their applications.

Those applications judged to be incomplete or nonresponsive will be
returned to the applicant without review.  Those applications that
are complete and responsive may be subjected to a triage to determine
their scientific competitiveness relative to the other applications
received in response to this RFA, based on the review initial
described below.  The NIAID will remove from further competition
those applications judged to be noncompetitive for award and will
notify the applicant and institutional business official.

Those applications judged to be competitive for award will be further
reviewed for scientific and technical merit by a review committee
convened by the Scientific Review Branch, Division of Extramural
Activities, NIAID.  A second level of review will be provided by the
National Advisory Allergy and Infectious Diseases Council.  In the
event of multiple highly qualified applications, final funding
recommendations will be based on program priorities.

B.  Review Criteria

The factors, to be considered in evaluating the scientific merit of
each application are:

1.  Adequacy of preliminary data leading to the hypothesis of the
proposed research including the adequacy of data for component
studies.

2.  Clarity and significance of the hypothesis to be tested.

3.  Relationship of the Specific Aims to the hypothesis, e.g.,

o  Will accomplishment of the Specific Aims provide significant proof
or refutation of the hypothesis?

o  Does the application justify additional components to fulfill the
Specific Aims?

o  Are necessary components included in the application?

4.  Integration of in vitro and in vivo approaches and of components.

5.  Innovativeness and technical merit of the experimental approach.

6.  Availability and acquisition of clinical specimens
(tissues/biological fluids), and cost savings achieved by utilization
of resources not funded through this application.  Documentation of
the availability of the specimens.

7.  Efficient use of animals, and utilization of animal resources not
funded through this R01 application.  Documentation of the
availability of animals or animal specimens.

8.  Adequacy of resources and environment including of biohazard
containment facilities if relevant.

9.  Documented research experience, accomplishments, and other
qualifications of the principal Investigator, key personnel, and
technical personnel in the proposed research areas.

10.  Time commitment of the Principal Investigators (and Component
Investigators) to conduct the proposed research;

AWARD CRITERIA

The number and specific amounts of awards to be made will depend upon
the following:

o  Results of the initial scientific and technical merit review;

o  Potential contribution of the proposed research to the goals and
objectives of the RFA;

o  Program balance within the three areas of research; and

o  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 written, telephone, or electronic mail (EMAIL) inquiries
regarding scientific and responsiveness issues to:

Dr. Gregory Milman
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2B35
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8378
EMAIL:  MAPS@EXEC.NIAID.PC.NIAID.NIH.GOV

Direct letters of intent, inquiries regarding the scientific review
process and format of applications, and two copies of the application
including five sets of appendices and reprints, to:

Dr. Dianne Tingley
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard
Solar Building, Room 4C16
Bethesda, MD  20892
Telephone:  (301) 496-0818
EMAIL:  MAPS@EXEC.NIAID.PC.NIAID.NIH.GOV

Direct inquiries regarding fiscal matters and budget format to:

Ms. Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard
Solar Building, Room 4B22
Bethesda, MD  20892
Telephone:  (301) 496-7075
EMAIL: MAPS@EXEC.NIAID.PC.NIAID.NIH.GOV

Schedule

Letter of Intent Receipt Date:  September 16, 1994
Application Receipt Date:       November 16, 1994
Scientific Review Date:         March 1995
Advisory Council Date:          June 1995
Earliest Award Date:            Sep 1995 and/or Nov - Dec 1995

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases Research
and 93.855 - Immunology, Allergy and Transplantation 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 Part 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 Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.

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