BIOLOGICAL FACTORS INFLUENCING SEXUAL TRANSMISSION OF HUMANIMMUNODEFICIENCY VIRUS



NIH GUIDE, Volume 22, Number 19, May 21, 1993



PA NUMBER:  PA-93-085



P.T. 34



Keywords:

  Sexually Transmitted Diseases 

  Biological Sciences 



National Institute of Allergy and Infectious Diseases

National Institute of Child Health and Human Development

National Institute of Diabetes and Digestive and Kidney Diseases



PURPOSE



Knowledge of the biological factors that influence the sexual

transmission of HIV is critical to prevention efforts, including

vaccine and topical virucide development.  Although some progress has

been made in identifying behavioral risk factors for sexual

transmission of human immunodeficiency virus (HIV), little is known

about the biologic determinants of infectivity and susceptibility.

The National Institute of Allergy and Infectious Diseases (NIAID),

the National Institute of Child Health and Human Development (NICHD),

and the National Institute of Diabetes and Digestive and Kidney

Diseases (NIDDK) invite investigator-initiated research applications

focused on the studies directed at elucidation of the biology of

sexual transmission of HIV.  Prior to preparing an application,

prospective applicants are strongly encouraged to consult with the

NIH staff.



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 Program

Announcement (PA), Biological Factors Influencing Sexual Transmission

of HIV, includes the priority areas of immunization and infectious

diseases, sexually transmitted diseases, and HIV infection.

Potential applicants may obtain a copy of a "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 organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State or local

governments, and eligible agencies of the Federal government.

Applications from minority individuals and women are encouraged.

Foreign institutions are not eligible for the First Independent

Research Support and Transition (FIRST) (R29) award.



MECHANISMS OF SUPPORT



Applications considered appropriate responses to this announcement

are the research project grant (R01) and the FIRST award (R29).

Although no funds are specifically set aside for funding grants

submitted in response to this program announcement, the NIAID, NICHD,

and NIDDK regard research in this area as a high priority, and of

great significance.



RESEARCH OBJECTIVE



Background



Currently, the Division of AIDS, NIAID, is supporting epidemiological

studies on sexual transmission, e.g., the Heterosexual AIDS

Transmission Study, Multicenter AIDS Cohort Study, and the San

Francisco Young Men's Health Study for understanding conditions or

behaviors that promote sexual transmission.  Studies on strategies

for eliciting protective regional mucosal immunity in the female or

male reproductive tracts, and in the rectum to block the transmission

of HIV will be supported by a recently issued RFA, Collaborative

Mucosal Immunology Groups for AIDS Vaccines (AI-93-008).  Because

there is very limited information on biological/cellular aspects that

affect sexual transmission, there is a need to stimulate research in

this area.



The objective of this program announcement is to stimulate research

on the biological factors influencing HIV sexual transmission.  It is

anticipated that the investigators may collaborate to test hypotheses

in animal models and to evaluate human studies including clinical

samples.  The NIH staff will assist investigators in identifying

potential collaborators and resources including cohorts for the

study.  Examples of research studies encouraged include, but are not

limited to, the following:



o  Biological mechanism of cell-free versus cell- associated viral

entry across the genital mucosal barrier, including such aspects as

virus variability, tropism, and stability.



o  Cell types and location of HIV infected cells in the reproductive

tract and in vaginal, seminal, and rectal fluids.



o  Cells initially infected by HIV during sexual transmission and how

the virus is disseminated into circulation.



o  Changes in HIV transmissibility that correlate with disease

progression by comparing HIV in vaginal, seminal, and rectal fluids

by comparison with HIV from blood/serum or lymphoid tissue, the

number of CD4 positive cells and/or other surrogate markers of HIV

progression.



o  Biological factors in vaginal and cervical mucosal tissues that

may affect host susceptibility to HIV; e.g., infection with other

pathogens, irritation or inflammation from any cause, and confection

with other sexually transmitted pathogens; menstrual cycle,

pregnancy, menopause, or hormones.



o  Biological factors that may affect the level and transmissibility

of cell-free HIV and/or cell-associated virus in vaginal, seminal and

rectal fluids i.e., infection with other pathogens including those

that are sexually transmitted, irritation and inflammation from any

cause; menstrual cycle, pregnancy, menopause, or hormones.



o  Effect of anti-retroviral or other therapeutic interventions on

the level and transmissibility of HIV in vaginal, seminal, and rectal

fluids or tissues.



o  Potential role of immunosuppressive/immunomodulating factors in

the reproductive tract, including studies of

neutralization/facilitation of HIV transmission by antibodies to HIV

in semen and vaginal secretions.



o  Role of antiviral defense mechanisms in HIV transmission, e.g.,

the effect of low pH, lysozyme, hydrogen peroxide, and lactoferrin in

vaginal fluids.



o  Sexual transmission of SIV/HIV in monkey animal models; e.g.,

determination of how virus gets through the reproductive tract into

the blood stream; to identify target cells infected in vaginal and

rectal mucosa; delineation of mechanisms of SIV/HIV spread from

mucosal to systemic lymphoid systems in the male and female

reproductive tracts; study of the effects of menstrual cycle

including menopause, pregnancy, oral or injectable steroid

contraceptives, and assessment of the role of irritation and

inflammation due to any cause including infection with other

pathogens in increasing susceptibility following SIV/HIV exposure.

The effect of anti-HIV/SIV antibody coated virus on transmission

would also be of interest.



Applications should each focus on a central theme.  Because issues of

molecular biology, immunology, virology, reproductive physiology and

pathology, sexually transmitted diseases, clinical care,

epidemiology, biostatistics and SIV/HIV animal models may need to be

addressed in a coordinated manner, collaboration among investigators

having expertise in these and other appropriate disciplines is

strongly encouraged.



Applicants are encouraged to coordinate, through the use of

consortium arrangements or subcontracts, integrated approaches with

investigators or institutions with demonstrated ability in a

particular area of research, or who have access to relevant, already

enrolled, patient populations or are conducting studies on animal

models in AIDS research.  Involvement of such institutions to obtain

specimens at little or no extra cost to the grant is encouraged.

Listings of institutions and PIs conducting such studies and/or

resources will be provided.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for clinical research grants and

cooperative agreements are required to include minorities and women

in study populations so that research findings can be of benefit to

all persons at risk of the disease, disorder or condition under

study; special emphasis must be placed on the need for inclusion of

minorities and women in studies of diseases, disorders and conditions

that disproportionately affect them.  This policy is intended to

apply to males and females of all ages.  If women or minorities are

excluded or inadequately represented in clinical research,

particularly in proposed population-based studies, a clear compelling

rationale must be provided.



The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study.  This information must be included in the form PHS 398

(rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in

Section 5, Human Subjects.  Applicants are urged to assess carefully

the feasibility of including the broadest possible representation of

minority groups.  However, NIH recognizes that it may not be feasible

or appropriate in all research projects to include representation of

the full array of United States racial/ethnic minority populations

(i.e., Native Americans (including American Indians or Alaskan

Natives), Asian/Pacific Islanders, Blacks, Hispanics).  The rationale

for studies on single minority population groups must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.



The NIH policies concerning research on human subjects also apply.

Basic research or clinical studies in which human tissues cannot be

identified or linked to individuals are excluded.  However, every

effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.  For

foreign awards, the policy on inclusion of women applies fully; since

the definition of minority differs in other countries, the applicant

must discuss the relevance of research involving foreign population

groups to the United States' populations, including minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.



Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.



If the representation of women or minorities in a study design is

inadequate to answer the scientific question(s) addressed AND the

justification for the selected study population is inadequate, it

will be considered a scientific weakness or deficiency in the study

design and will be reflected in assigning the priority score to the

application.



All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these

policies.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) and will be accepted at the receipt dates for

applications for AIDS-related research:  January 2, May 1, and

September 1.  Application kits are available at most institutional

offices for sponsored research and may be obtained from the Office of

Grants Inquiries, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

(301) 710-0267.  The title and number of the announcement must be

typed in Section 2a on the face page of the application and the "YES"

box marked.



The completed original and five legible copies must be sent or

delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



FIRST (R29) applications must include at least three sealed letters

of reference attached to the face page of the original application.

FIRST applications submitted without the required number of reference

letters will be considered incomplete and will be returned without

review.



Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center of Research Resources

may wish to identify the Center as a resource for conducting the

proposed research.  If so, a letter of agreement from the GCRC

Program Director must be included in the application material.



REVIEW CONSIDERATIONS



Applications in response to this announcement will be assigned on the

basis of established Public Health Service Referral Guidelines.  Each

application must be complete in itself and must be able to stand on

its own merit.  Applications will be reviewed independently for

scientific and technical merit by study sections of the Division of

Research Grants, NIH, and in accordance with the standard NIH peer

review criteria for traditional research grant applications.  A

second-level of review will be provided by the appropriate national

advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other

applications of significant and substantial merit assigned to that

institute.  The following will be considered when making funding

decisions:  quality of the proposed project as determined by peer

review, program balance among research areas of the announcement, and

availability of funds.



INQUIRIES



Written and telephone inquiries concerning the objectives and scope

of this PA and inquiries about whether or not specific proposed

research would be appropriate for this mechanism are encouraged.

Direct inquiries regarding programmatic issues to:



Dr. Opendra K. Sharma, or Dr. Gregory Milman

Division of AIDS

National Institute of Allergy and Infectious Diseases

6003 Executive Boulevard, Room 2B-35

Bethesda, MD  20892

Telephone:  (301) 496-8378

FAX:  (301) 480-5703



Dr. Nancy J. Alexander

Center for Population Research

National Institute of Child Health and Human Development

6100 Executive Boulevard, Room 8B-13

Bethesda, MD  20892

Telephone:  (301) 496-1661

FAX:  (301) 496-0962



Dr. Leroy M. Nyberg

Division of Kidney, Urologic, and Hematologic Disorders

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 3A-05A

Bethesda, MD  20892

Telephone:  (301) 594-7522

FAX:  (301) 594-7501



Direct inquiries regarding fiscal matters may be directed to:



Ms. Jane Unsworth

AIDS Grants Management Section

National Institute of Allergy and Infectious Diseases

6003 Executive Boulevard, Room 4B-25

Bethesda, MD  20892

Telephone:  (301) 496-6177

FAX:  (301) 402-1506



AUTHORITY AND REGULATIONS



This program is described in Catalogue of Federal Domestic

Assistance, Nos. 93.855, Immunology, Allergy and Immunology Diseases

Research; 93.856, Microbiology and Infectious Diseases Research.

Awards are made under authorization of the Public Health Service Act,

Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158,

42 USC 241 and 285) and administered under PHS grants policies and

Federal Regulations at 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 review.



.

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