Release Date:  July 25, 2000

PA NUMBER:  PAS-00-123

National Institute of Neurological Disorders and Stroke
National Institute on Deafness and Other Communication Disorders
National Institute of Mental Health



The National Institute of Neurological Disorders and Stroke (NINDS) ,the 
National Institute of Deafness and Other Communication Disorders (NIDCD),  
and the National Institute of Mental Health (NIMH) invite investigator-
initiated research grant proposals to study the effect of HIV-1 infection on 
the peripheral nervous system and sensory organs.  Although abnormalities of 
the peripheral nervous system associated with HIV-1 infection are not 
generally life threatening, they tend to occur relatively early in the course 
of the disease and contribute significant morbidity.  Prompt recognition and 
effective treatment of these disorders could dramatically improve the quality 
of life of the patient.



Symptomatic abnormalities of peripheral nerve function are among the most 
common complications of HIV-1 infection.  About one-third of HIV-1 positive 
individuals develop some form of peripheral neuropathy, frequently relatively 
early in the course of their disease.  Although the use of highly active 
anti-retroviral therapy (HAART) has been successful in ameliorating the 
constitutional manifestations of AIDS, there has been no significant impact 
on the incidence of peripheral neuropathy.  In fact, given the increased 
longevity of patients treated with HAART, one might anticipate that 
peripheral neuropathy will become more of a clinical problem in the future.

The neuropathic syndromes associated with HIV-1 infection are diverse and 
include both the somatic and autonomic nervous systems.  The primary 
pathological abnormality may be demyelination, both acute and chronic, or 
axonal degeneration.  Either single or multiple nerves may be involved 
leading to mono-or polyneuropathy.  Polyradiculopathy and rare cases of 
primary ganglioneuronitis have been described.

There are multiple etiologies for HIV-1 associated neuropathies.  
Inflammatory demyelinating polyneuropathy of the Guillain-Barre type, 
mononeuropathy multiplex, and progressive polyradiculopathy are clearly 
associated with concomitant infection with cytomegalovirus (CMV).  Various 
nutritional deficiencies, specifically vitamin B12 deficiency, have also been 
implicated but the evidence is rather weak.  Some anti-retroviral agents used 
in the treatment of HIV infection are known neurotoxins and can produce 
neuropathies, particularly distal symmetrical polyneuropathy (DSP).  However 
most cases of DSP, which is by far the most common of the HIV-1 associated 
neuropathies are of unknown etiology.

Additional research is required to clarify the diverse etiologies of the 
peripheral neuropathies associated with HIV-1 infection.  Even for those 
neuropathies in which CMV infection has been definitely implicated, it is not 
clear if the pathological findings reflect primarily CMV infection per se, 
invasive HIV-1 infection facilitated by CMV attack upon the immune system, a 
synergistic interaction of CMV and HIV-1, or a combination of factors.  Even 
a single clinical entity may have more than one etiology.  For example, the 
HIV associated demyelinating neuropathies are associated with CMV infection, 
but demyelination also occurs occasionally in distal symmetrical neuropathy 
suggesting that CMV may play a role in at least some cases of DSP.

Although the most obvious histological changes in HIV-1 associated 
neuropathies involve the peripheral nerves, inflammatory infiltrates and 
neuronal loss have been observed in dorsal root ganglia, as well as 
degeneration of the gracile tracts in the spinal cord suggesting that a 
component of the neuropathy may involve the dorsal root ganglionic neurons.

The critical importance of the blood brain barrier in controlling the entry 
of HIV-1, macrophages and/or macrophages into the brain is well-recognized, 
as well as its role as a barrier to the entry of drugs used in HAART therapy.  
The blood-spinal cord barrier and the blood-nerve barrier (BNB) may have a 
similar importance in the development and/or treatment of HIV associated 
peripheral neuropathies but have been much less well studied.  What 
information is available suggest that the permeability properties of the BNB 
are quite different from the BBB.  For example, large molecules such as 
horseradish peroxidase can freely cross the blood nerve barrier but not the 
blood brain barrier.  Differences in both normal and abnormal permeability of 
the BBB and BNB occasioned by HIV-1 infection may explain the large numbers 
of circulating activated macrophages found in the endoneurium of peripheral 
nerves, in HIV-1 associative neuropathies, and possibly the neurotoxic 
effects of antiretroviral agents on the peripheral but not the central 
nervous systems.  Research on these barriers would not only be of basic 
science interest in defining the normal properties of these barriers, but 
also could have direct relevance to understanding the pathogenesis of and 
developing treatments for HIV associated neuropathy.

Although HAART therapy has produced dramatic reductions in the systemic viral 
load and a marked reduction in the incidence of opportunistic infections, and 
an increase in well-being in the AIDS patients and has become the standard of 
care for HIV-1 infection in United States, some of the most effective drugs 
are associated with toxic neuropathies, which in some cases are sufficiently 
serious so as to require discontinuation or suboptimal modification of HAART 
therapy.  The development of effective drugs without neurotoxic effects, 
resulting from research on the mechanisms of the HAART-induced neuropathies, 
would be a major advance in the treatment of HIV-1 infection.

Sensory impairments are frequent complaints associated with HIV infection.  
Complaints include sensorineural hearing loss, smell and taste distortions, 
and other problems.  For example, ear disease affects up to one-third of HIV-
infected patients and otitis media is a frequent finding.  Research is needed 
to assess whether sensory effects are the result of direct HIV infection, 
secondary opportunistic infections, or possibly neurotoxic effects of HIV 
drug treatment on the sensory organs.

A serious outcome of HIV induced neuropathy is chronic pain.  The impact of 
chronic pain on mental health outcomes is an area of significant interest to 
NIMH.  Chronic pain may result in depression, anxiety, and substance abuse.  
In addition, studies of the approaches used for coping with HIV induced 
neuropathic pain is also encouraged. 

Examples of relevant research include, but are not limited to, the following:

1.  Studies of the blood-nerve barrier (BNB) under normal and pathological 
conditions associated with HIV-1 infection including permeability of the 
barrier to HIV-1 virus, circulating macrophages, or neurotoxic agents 
produced systemically by activated macrophages.  Such studies might include 
investigation of the role of the vasculitis produced by inflammation and/or 
HIV-1 infection of the endothelial cells of the endoneurial blood capillaries 
in compromising the integrity of the BNB or the blood supply to nerve fibers.

2.  Study of the properties of the blood-spinal cord barrier under normal and 
pathological conditions associated with HIV-1 infection (as opposed to the 
blood-brain barrier) including the ability of the barrier to pass virus, 
macrophages, or cytotoxic materials.

3.  Studies of the etiology of distal symmetrical polyneuropathy (DSP) 
including the relative importance of direct HIV-1 infection of peripheral 
axons and neurotoxic effects of substances such as cytokines produced by 
activated macrophages.

4.  Studies of the pathogenesis of the demyelinating HIV-1 associated 
neuropathies including the role of activated resident and circulating 
macrophages in producing demyelination either by directly attacking myelin or 
by elaborating cytotoxic or demyelinating substances.

5.  Study of the role, in producing demyelination, of molecular mimicry 
resulting from homology of segments of HIV-1 genes and protein products with 
sequences in the myelin protein.

6.  Study of the relative roles of HIV-1 and macrophages in producing dorsal 
root ganglion cell damage and/or damage to the long sensory tracts in the 
spinal cord.

7.  Study of the differential effect which HIV-1 infection and/or therapeutic 
agents might have on small and large fiber function in peripheral sensory 

8.  Study of morphological changes, associated with HIV-1 infection, which 
occur in the distal terminals of nociceptive fibers and in the peripheral 
sensory organs.

9.  Study of the ability of drugs used in HAART therapy to pass the blood-
nerve barrier (BNB) in sufficient concentrations to be effective.

10.  Study of the mechanisms of the neurotoxic effects produced by drugs 
commonly used in HAART therapy and the development of less toxic agents.

11.  Studies of the relative importance of direct CMV infection of the 
peripheral nervous system as opposed to synergistic interaction of CMV with 
HIV-1 to produce elaboration of neurotoxic materials. 

12.  Studies of the ability of agents such as gancyclovir, acyclovir, or 
foscarnet, used to treat CMV infection to pass the blood-nerve barrier in 
sufficient concentration to be effective in the treatment of those peripheral 
neuropathies associated with CMV infection.

13.  Development of animal model of HIV associated peripheral neuropathy.

14.  Studies of maladaptive responses to HIV associated neuropathic pain.  
Maladaptive responses may lead to comorbid conditions such as depression, 
anxiety, and substance abuse.

15.  Study of adaptive responses, such as unique coping strategies for 
dealing with HIV induced neuropathic pain. 

16.  Studies of the effects of nucleoside analogs and protease inhibitors 
used as essential components of medications to treat HIV infection on taste 
quality perception that significantly impact on patient compliance, diet and 
nutrition.  Possible peripheral causes of altered taste quality perception 
are changes in the sensitivity of select populations of taste receptors and 
concomitant changes in the response profiles of gustatory afferent fibers, 
HIV-mediated changes in the peripheral trigeminal system, and changes in the 
oral environment as a consequence of compromised autonomic nervous system 

17.  Studies on the neurotoxic effects of HIV medications on the peripheral 
sensory organs.

Investigators also may obtain copies of these from the program staff listed 
under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


The mechanism of support will be the individual research project (R01).  
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total requested project 
period for an application submitted in response to this announcement may not 
exceed five years.  Because the nature and scope of the research proposed in 
response to this PA may vary, it is anticipated that the size of an award 
will vary also.  Collaborative efforts between research sites are acceptable.  
The NIDCD, NINDS, and NIMH may administratively limit the duration and the 
budget level of an award.  Standard receipt dates for AIDS applications will 
be used.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME” streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at  


The estimated total funds (direct and F&A costs) available for the support 
for all awards made under this PA will be $4.0 Million in FY 2001 or over 
multiple years.  Although this program is provided for in the financial plans 
of the NIDCD, NIMH and the NINDS, awards pursuant to this PA 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.


Applications may be submitted by domestic and foreign 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.  Racial/ethnic minority 
individuals, women, and persons with disabilities are encouraged to apply as 
Principal Investigators.


Written and telephone inquiries concerning this PA are encouraged.  The 
opportunity to clarify any issues or questions from potential applicants is 

Direct inquiries regarding programmatic issues to:

A.P. Kerza-Kwiatecki, Ph.D.
Program Director
Neural Environment Team
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2115
Bethesda, MD  20892-9521
Telephone: (301) 496-1431
FAX: (301) 402-2060

Julianna Gulya, MD
Director, Clinical Trials Program
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, 400D-7, MSC 7180
6120 Executive Blvd
Bethesda, Maryland 20892-7180
Telephone:  301-435-4085
Fax: 301-402-6251
E-mail: julie

Dianne Rausch, Ph.D
Center for Mental Health Research on AIDS
National Institute of Mental Health
6001 Executive Blvd, Room 6209, MSC 9619
Bethesda, MD 20892-9619
Telephone: (301)-443-7281
Fax: (301) 443-9719

Ms. Sharon Hunt
Chief, Grants Management Branch
National Institutes on Deafness and Other Communication Disorders
EPS, 400-B, MSC 7180
Bethesda, Maryland 20892-7180
Telephone: 301-402-0909
FAX: 301-402-1758

Direct inquiries regarding fiscal matters to:

Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3290
Bethesda, MD  20892-9537
Telephone: (301) 496-9231
FAX: (301) 402-0219

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Blvd, Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2805
Fax: (301) 443-6885
Email:  Diana


Applications are to be submitted on the grant application form PHS 398 (rev. 
4/98) and will be accepted at the standard application deadlines as indicated 
in the application kit.  Application kits are available at most institutional 
offices of sponsored research and may be obtained from the Grants Information 
Office, Office of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-
7910, telephone (301) 710-0267, email:

For purposes of identification and processing, item 2a on the face page of 
the application must be marked "YES" and the PA number (PAS-00-123) and the 

If the application submitted in response to this PA 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 PA.  This does not preclude the submission of 
substantial revisions of applications already reviewed, but such applications 
must include an introduction addressing the previous critique.

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that he or she must contact the 
Institute or Center (IC) program staff before submitting the application, 
i.e., as plans for the study are being developed. Furthermore, the 
application must obtain agreement from the IC staff that the IC will accept 
the application for consideration for award. Finally, the applicant must 
identify, in a cover letter sent with the application, the staff member and 
Institute or Center who agreed to accept assignment of the application. 

This policy requires an applicant to obtain agreement for acceptance of both 
any such application and any such subsequent amendment. Refer to the NIH 
Guide for Grants and Contracts, March 20, 1998 at

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.



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

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) 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.

of the PHS 398.  It is not required and will not be accepted with 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 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:
- 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 telephone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review. 

Submit a signed, typewritten original of the application, including the 
checklist, and five signed, exact, single-sided photocopies, and five sets of 
appendix material 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 mail or courier service)

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 with the application.


Upon receipt, applications will be reviewed for completeness by the NIH 
Center for Scientific Review (CSR) and will be assigned on the basis of 
established referral guidelines.  Applications that are complete will be 
evaluated for scientific and technical merit by an appropriate peer review 
group convened in accordance with NIH peer review procedures.  As part of the 
initial merit review, all applications will receive a written critique, and 
may undergo a process in which only those applications deemed to have the 
highest scientific merit will be discussed, assigned a priority score, and 
receive a second level review by a national advisory council or board.

Review Criteria

The five criteria to be used in the evaluation of grant applications are 
listed below.  To put those criteria in context, the following information is 
contained in instructions to the peer reviewers.

The goals of NIH-supported research are to advance our 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 

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?

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? 

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? 

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)?

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 
and minorities and their subgroups as appropriate for the scientific goals of 
the research and plans for the recruitment and retention of subjects; 
adequacy of plans for including children as appropriate for the scientific 
goals of the research; the reasonableness of the proposed budget and duration 
in relations to the proposed research; the provisions for the protection of 
human and animal subjects; and the safety of the research environment.


Funding decisions will be made on the basis of scientific and technical merit 
as determined by peer review, program balance, and the availability of funds.  


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 are provided that inclusion is 
inappropriate with respect to the health of the subjects of 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 have been published in the Federal Register of March 28, 
1994 (FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, 
No. 11, March 18, 1994.

Investigators may obtain copies from these sources or from program staff 
listed in INQUIRIES below who may also provide additional relevant 
information concerning the policy.


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 ethnical 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 


All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in a NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas.  This PA, “HIV-1 INFECTION 
AND THE PERIPHERAL NERVOUS SYSTEM”, is related to the priority area of 
hypothesis-driven studies of nervous system disease.  Potential applicants 
may obtain a copy of "Healthy People 2010" at


This program is described in the Catalog of Federal Domestic Assistance No. 
93.173 for NIDCD , No. 93.853 for NINDS, and 93.242 for NIMH. Awards are made 
under authorization of sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) and administered under NIH grants policies 
and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This program 
is not subject to the intergovernmental review requirements of Executive 
Order 12372 or Health Systems Agency review.

The Public Health Service 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 for 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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