MECHANISMS OF HIV-1 TRAFFICKING IN THE CNS
Release Date: January 18, 2000
RFA: MH-00-010
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke
Letter of Intent Receipt Date: April 24, 2000
Application Receipt Date: May 24, 2000
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA.
PURPOSE
HIV-1 infection of central nervous system (CNS) tissues results in neurological
and neuropsychiatric abnormalities in a significant number of patients. HIV-1
localization in CNS parenchyma and CSF has been well documented. Advances in
highly active anti-retroviral therapy (HAART) have resulted in significant
reductions in viral load in peripheral as well as CNS tissues in many patients.
However, the presence of the blood-brain barrier (BBB) precludes efficient drug
penetration into the CNS compartment and thus current therapies may not
eradicate latent viral reservoirs in the brain. Therefore, the CNS may serve as
an important viral reservoir for re-infection of peripheral tissues subsequent
to viral clearing in response to effective treatment. The BBB serves as a
critical gatekeeper for regulating HIV-1 transit into and out of the CNS. It is
therefore imperative to understand the mechanisms of viral passage through the
blood-brain barrier in order to develop strategies for blocking early infection
of this compartment as well as subsequent reinfection of peripheral tissues.
This RFA solicits applications that will examine potential pathways and
mechanisms for HIV-1 entry into and out of the CNS through the BBB. In vivo and
in vitro models may be proposed to study the involvement of leukocyte and
monocyte trafficking, proinflammatory cytokines, chemokines, chemokine
receptors, adhesion molecules, viral proteins (Tat, Vpr, Nef, gp120), adsorptive
endocytosis, transcytosis, changes in BBB permeability, excitotoxic damage to
endothelial cells, glial and endothelial apoptosis, and infection of endothelial
cells or glial cells in promoting HIV-1 entry into the brain. The study of
interactions of viral and host factors may lead to an improved understanding of
the mechanism of establishment of CNS viral reservoirs and approaches to prevent
passage of HIV-1 through the blood-brain barrier.
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 Request for Applications (RFA),
Mechanisms of HIV-1 Trafficking in the CNS, is related to the priority areas of
HIV-1 infection and Mental Health and Mental Disorders. Potential applicants
may obtain a copy of "Healthy People 2000" at
http://odphp.osophs.dhhs.gov/pubs/hp2000/
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government. Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
MECHANISM OF SUPPORT
This RFA will use the National Institutes of Health (NIH) 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 an application submitted in response to this RFA may not exceed 5
years. This RFA is a one-time solicitation. Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary peer review procedures.
The anticipated award date is September 29, 2000.
For all applications requesting up to $250,000 direct costs per year, specific
application instructions have been modified to reflect MODULAR GRANT and
JUST-IN-TIME streamlining efforts being undertaken at NIH. More detailed
information about modular grant applications, including a sample budget
narrative justification pages and a sample biographical sketch, is available via
the Internet at: http://grants.nih.gov/grants/funding/modular/modular.htm.
Applications that request more than $250,000 in any year must use the standard
PHS 398 (rev. 4/98) application instructions.
FUNDS AVAILABLE
The NIMH intends to commit approximately $1,000,000 in FY 2000 to fund 3-5 new
and/or competitive continuation grants in response to this RFA. The NINDS
intends to commit approximately $500,000 in FY 2000 to fund 2-3 new and/or
competitive continuation grants in response to this RFA. An applicant may
request a project period of up to 5 years. Because the nature and scope of the
research proposed may vary, it is anticipated that the size of each award will
also vary. It is expected that the direct costs will be awarded in modules of
$25,000, however program and grants management adjustments may be necessary
prior to this award. Although the financial plans of the Institute provide
support for this program, awards pursuant to this RFA are contingent upon the
availability of funds and the receipt of a sufficient number of applications of
outstanding scientific and technical merit. At this time, it is not known if
competing renewal applications will be accepted and/or if this RFA will be
reissued.
RESEARCH OBJECTIVES
Background
It is well established that HIV-1 can penetrate the central nervous system
(CNS), frequently very soon after infection. One of the consequences of HIV-1
infection is HIV-1-associated dementia (HAD) which occurs to varying degrees in
up to 20-30 percent of infected individuals. HAD consists of a spectrum of
progressive cognitive, motor, and behavioral impairments in the absence of HIV-
1-related opportunistic infection or malignancy. The neuropathogenesis of human
immunodeficiency virus (HIV-1)-associated dementia has remained elusive, despite
identification of HIV-1 as the causal agent. Although a number of contributing
factors have been identified, the series of events that culminate in motor and
cognitive impairments following HIV-1 infection of the CNS are still not known.
Only with better understanding of neuropathogenesis will the opportunity to
interrupt progression and to design better treatments for HAD be realized.
HIV-1 entry into the CNS is believed to occur primarily through trafficking of
HIV-1 infected monocyte/macrophages or T-cells through the blood-brain barrier.
Multiple chemokines, proinflammatory cytokines and adhesion molecules
orchestrate trafficking of lymphocytes and monocytes. There is evidence that
viral proteins such as Tat modulates the expression of chemokines, chemokine
receptors as well as adhesion molecules (VCAM-1, ICAM-1, VLA-4, LFA-1) on
monocytes as well as cells lining the blood-brain barrier(endothelial cells and
astrocytes). Proinflammatory cytokines (TNF-alpha, IL-1) induced by virus
infection or viral proteins regulate adhesion and transendothelial migration of
inflammatory cells. HIV-1 viral proteins (Tat and Nef) demonstrate chemotactic
properties and promote leukocyte recruitment into the CNS. The mechanisms of
action of viral proteins through transcriptional regulation or modulation of
signalling pathways involved in controlling expression of adhesion molecules,
chemokines and cytokines are areas of potential interest. Studies on the role
of astrocytes are also highly relevant because they contribute to maintaining
the integrity of the blood-brain barrier as well as induction of various
molecules involved in leukocyte trafficking. Astrocyte-endothelial interactions
as well as astrocyte factors may be critically involved in transendothelial
migration of HIV-1 infected cells into and out of the CNS.
Another potential mechanism of HIV-1 passage is through infection of endothelial
cells lining the blood-brain barrier. The role of endothelial cell infection
and viral replication in this cell type as a mechanism for seeding the brain is
highly controversial. While some investigators have demonstrated infection of
brain-derived endothelial cells using human as well as SIV models others have
been unable to do so. If the endothelial cells can be infected, further studies
on the host and viral molecular determinants regulating this process are
warranted.
A third and less explored possibility is the role of adsorptive endocytosis and
transcytosis through the endothelial cells as an mechanism for HIV-1 entry into
the CNS. Studies with gp120 have suggested a role for adsorptive endocytosis in
viral trafficking. However a definite role for this mechanism in whole virus
entry has not been established.
Finally the integrity of the blood brain barrier may be compromised by various
factors associated with viral infection. These could include changes in
membrane permeability as a result of exposure to viral proteins (gp120, Vpr) or
induced matrix metalloproteinases, or excitotoxic damage to BBB by nitrates,
nitrites or glutamates. Apoptotic cell death induced by HIV-1 proteins (Tat,
Vpr) or other mediators may damage the endothelial cells, thus compromising the
integrity of the BBB and allowing the passage of HIV-1 into and out of the
brain.
As described above multiple factors are involved in regulating virus trafficking
between CNS and peripheral compartments. This RFA is intended to stimulate
additional research in defining mechanisms of HIV-1 passage through the BBB.
Examples of research include, but are not limited to the following:
o Defining novel endothelial and leukocyte adhesion pathways involved in HIV-1
infected leukocyte-transendothelial migration.
o Role and characterization of CNS derived (macrophage, microglial,
endothelial) chemokines and proinflammatory cytokines involved in regulating
trafficking of infected cells through BBB.
o Study of expression of chemokine receptors by CNS endothelial cells,
astrocyte, macrophages, microglial cells and their potential impact on virus
infection as well as response to chemokines.
o Role of viral proteins (Tat, Vpr, Nef, gp120) in stimulating adhesion
molecules, cytokines, chemokines and chemokine receptor expression by
endothelial cells and astrocytes.
o Regulation of leukocyte adhesion and transendothelial migration by viral
proteins.
o Chemotactic functions of HIV-1 viral proteins.
o Development of in vitro and in vivo BBB models to study leukocyte adhesion
and transendothelial migration.
o Role of astrocyte-endothelial interactions in regulation of HIV-1 infected
leukocyte trafficking.
o Impact of astrocyte derived factors (chemokines, cytokines) in regulating
HIV-1 infected leukocyte migration through BBB.
o Identification of factors that control permeability (matrix
metalloproteinases, Vpr) or damage (serum nitrates or nitrites, glutamates) the
BBB following HIV-1 infection.
o Role of viral proteins and induced factors in apoptosis of BBB derived cells.
o Mechanisms of HIV-1 induced apoptosis of cells lining the BBB (endothelial
cells and astrocytes).
o Identification of host and viral molecular determinants that influence
endothelial cell tropisms.
o Role of adsorptive endocytosis and transcytosis as a mechanism for HIV-1
passage through the BBB.
o Isolation and molecular characterization of viral isolates that infect CNS
endothelial cells and/or astrocytes.
o Identification of HIV-1 envelope sequences that regulate endothelial
tropisms.
o Identification of endothelial receptors involved in interaction with
endotheliotropic HIV-1 envelope sequences(if identified).
o Effects of drugs of abuse (Cocaine, Methamphetamines) in facilitating HIV-1
neuroinvasion through the BBB.
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
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).
All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the web at:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES. Program staff may also provide additional relevant information
concerning the policy.
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel and
participating institutions, and the number and title of the RFA in response to
which the application may be submitted. Although a letter of intent is not
required, is not binding, and does not enter into the review of a subsequent
application, the information that it contains allows Institute staff to estimate
the potential review workload and avoid conflict of interest in the review.
The letter of intent is to be sent to the program staff listed under INQUIRIES
by April 24, 2000.
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants. These forms are available at most institutional
offices of sponsored research and from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, Email:
GrantsInfo@nih.gov. The application is also available at
http://grants.nih.gov/grants/funding/phs398/phs398.html
SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS
The modular grant concept establishes specific modules in which direct costs may
be requested as well as a maximum level for requested budgets. Only limited
budgetary information is required under this approach. The just-in-time concept
allows applicants to submit certain information only when there is a possibility
for an award. It is anticipated that these changes will reduce the
administrative burden for the applicants, reviewers and Institute staff. The
research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants, with the modifications noted below.
BUDGET INSTRUCTIONS
Modular Grant applications will request direct costs in $25,000 modules, up to a
total direct cost request of $250,000 per year. (Applications that request more
than $250,000 direct costs in any year must follow the traditional PHS 398
application instructions.) The total direct costs must be requested in
accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:
PHS 398
FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments) and Total Costs [Modular Total Direct plus Facilities and
Administrative (F&A) costs] for the initial budget period. Items 8a and 8b
should be completed indicating the Direct and Total Costs for the entire
proposed period of support.
DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of
the PHS 398 (rev 4/98). It is not required nor will it be accepted at the time
of application.
BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.
o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages.) At the top of the page, enter the total direct costs requested for each
year. This is not a Form page.
o Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should be
provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.
For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000. List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project. Indicate whether the collaborating institution is foreign or
domestic. The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount. Include the Letter of
Intent to establish a consortium.
Provide an additional narrative budget justification for any variation in the
number of modules requested.
o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual"s qualifications for a specific
role in the proposed project, as well as to evaluate the overall qualifications
of the research team. A biographical sketch is required for all key personnel,
following the instructions below. No more than three pages may be used for each
person. A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm
- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on research
projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations,
o CHECKLIST - This page should be completed and submitted with the application.
If the F&A rate agreement has been established, indicate the type of agreement
and the date. All appropriate exclusions must be applied in the calculation of
the F&A costs for the initial budget period and all future budget years.
o The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information is
necessary following the initial review.
The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application and must display the
RFA number MH-00-010. A sample modified mailing label is available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is
in pdf format. 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, Mechanisms of HIV-1 Trafficking
in the CNS, RFA MH-00-010, must be typed on line 2 of the face page of the
application form and the YES box must be marked.
Submit a signed, typewritten original of the application, including the
Checklist, and three signed 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 copies of the application must be sent
to:
Jeymohan Joseph, Ph.D
Center for Mental Health Research on AIDS
National Institute of Mental Health
6001 Executive Boulevard, Room 6202, MSC 9619
Bethesda, MD 20892-9605
Applications must be received by May 24, 2000. If an application is received
after that date, it will be returned to the applicant without review.
The Center for Scientific Review (CSR) 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 CSR
will not accept any application that is essentially the same as one already
reviewed. This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIMH staff. Incomplete and/or non-responsive applications
will be returned to the applicant without further consideration.
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
NIMH 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
Council or Board.
Review Criteria
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In the
written comments reviewers will be asked to discuss the following aspects of the
application 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 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 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, 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 methods?
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 work proposed 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?
The initial review group will also examine: the appropriateness of proposed
project budget and duration, the adequacy of plans to include both genders,
minorities and their subgroups, and children as appropriate for the scientific
goals of the research and plans for the recruitment and retention of subjects,
the provisions for the protection of human and animal subjects, and the safety
of the research environment.
Schedule
Letter of Intent Receipt Date: April 24, 2000
Application Receipt Date: May 24, 2000
Peer Review Date: August 2000
Council Review: September 2000
Earliest Anticipated Start Date: September 29, 2000
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o scientific merit (as determined by peer review)
o availability of funds
o programmatic priorities.
INQUIRIES
Inquiries concerning this RFA are encouraged. The opportunity to clarify any
issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Jeymohan Joseph, Ph.D
Center for Mental Health Research on AIDS
National Institute of Mental Health
6001 Executive Boulevard, Room 6202, MSC 9619
Bethesda, MD 20892-9605
Telephone: (301) 443-6100
FAX: (301) 443-9719
Email: jjeymoha@mail.nih.gov
F.J. Brinley, Jr., M.D., Ph.D
Associate Director for Infection and Immunity
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2114
Bethesda, MD 20892-9521
Telephone: (301) 496-6541
Fax: (301) 402-0302
Email: fbl8u@nih.gov
Direct inquiries regarding fiscal matters to:
Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2805
FAX: (301) 443-6885
Email: Diana_Trunnell@nih.gov
Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3621
Bethesda, MD 20892-9619
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: dj35j@nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.242 (NIMH) and 93.853 (NINDS). 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 NIH 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 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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