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HIV/AIDS Research at NIH

Natural History, Epidemiolgy & Prevention

Research progress in this area includes:

• Developing a highly sensitive HIV diagnostic test
• Identifying and following cohorts of long-term nonprogressors
• Identifying HIV-1 RNA plasma levels as predictors of the rate of disease progression
• Developing new and evaluating existing spermicides/microbicides as well as other barriers to HIV transmission
• Identifying transmission factors and risks in injection drug use
• Identifying trends in subpopulations of the AIDS epidemic
• Identifying prolonged membrane rupture as a risk factor in HIV transmission from mother to infant
• Discovering a gamma-herpesvirus linked to Kaposi's sarcoma
• Identifying an anti-HIV protein in human saliva

Status

Epidemiologic research has shown the demographics of HIV infection and AIDS in the United States changing from an illness primarily affecting homosexual and bisexual men to the current epidemic, with increasing rates of infection in heterosexual men and women, adolescents, minorities, and drug users. The NIH conducts studies to examine the transmission of HIV and the progression of HIV-related disease, including opportunistic infections (OIs); malignancies; neurological, neurobehavioral, and oral manifestations; and other sequelae. Such studies examine the effects of viral factors, host factors, and other factors on the risk of infection and disease progression. Cohorts of HIV-infected individuals and HIV-uninfected individuals at risk of infection are followed in clinical epidemiology studies at domestic and international sites. Major ongoing studies include:

• the Multicenter AIDS Cohort Study (MACS), a longitudinal study of HIV infection in homosexual and bisexual men;
• the Women's Interagency HIV Study (WIHS), examining HIV infection and disease course in HIV-infected and high-risk HIV-uninfected women;
• the Vaccine Preparedness Study (VPS), a prospective, multicenter epidemiologic study of approximately 5,000 men and women at high risk of HIV infection through homosexual/heterosexual intercourse and injection drug use (IDU) that is designed to establish the feasibility of conducting future efficacy trials of HIV vaccines and other HIV preventive interventions;
• the Multicenter Hemophilia Cohort Study (MHCS), a 16-center study of HIV disease progression and heterosexual transmission begun in 1982;
• the Hemophilia Growth and Development Study, a 14-center study of HIV disease progression in hemophiliac children;
• the Adolescent Medicine HIV/AIDS Research Network (AMHARN) study on HIV infection among adolescents infected via IDU or sexual routes;
• the Women and Infants Transmission Study (WITS), a multicenter study begun in 1988, examining perinatal transmission and the course of infection in HIV-infected pregnant women and their infants;
• the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study;
• the Heterosexual Transmission (HEX) Study in Trinidad, particularly the characterization of events during primary HIV infection;
• the Prospective Study of Pulmonary Complications of HIV Infection;
• the multicenter Retrovirus Epidemiology Donor Study (REDS), an epidemiologic study of retroviruses in volunteer blood donors;
• an AIDS Research Center study in a serological cohort evaluating the neurologic and neuropsychologic manifestations of HIV infection;
• prospective studies investigating biologic and behavioral factors related to HIV infection and disease progression among cohorts of drug users in urban minority populations;
• a study of the effects of maternal drug use on HIV disease progression in women and their infants;
• a number of projects to evaluate the efficacy of ongoing needle and syringe exchange programs in reducing HIV transmission among drug users.

NIAID supports the National AIDS Specimen Repository. The repository contains over one million biological specimens linked to a huge data base from fully characterized and longitudinally followed cohorts. These biomedical samples are available to the scientific community, in collaboration with study investigators. Similarly, the NCI supports a repository of specimens from subjects enrolled in cross-sectional and prospective studies, and the NHLBI supports a serum and cell repository of more than one million specimens from volunteer blood donors and recipients of blood components or plasma derivatives. The NIMH supports the National Neurological Research Specimen Bank, which collects and distributes central nervous system (CNS) specimens from HIV-infected donors and represents a valuable resource for basic science investigations.

International epidemiology studies conducted or supported by the NIH contribute significantly to the understanding of HIV transmission, progression of HIV-related disease, risk factors associated with HIV infection and AIDS, and biomedical preventive intervention strategies. NIAID has established the HIV Efficacy Trials Network (HIVNET) in preparation for vaccine and other prevention trials of biomedical interventions. These trials have already begun to evaluate mass STD treatment, microbicides, and perinatal interventions with antiretrovirals and immunotherapy, as well as behavioral approaches linked to biomedical interventions. The NIH-sponsored international collaborative epidemiology research activities such as the NIAID HIVNET and numerous studies supported by the NCI, NIDR, and FIC training programs, foster the development of research skills and infrastructure in countries where HIV infection and AIDS are epidemic, in order to facilitate biomedical and behavioral intervention trials as well as future international HIV vaccine efficacy trials.

Other studies are beginning to generate data on the transmissibility of non-B HIV clades and the reduction of HIV transmission through prevention and treatment of coexisting sexually transmitted infections as a means of primary HIV prevention. Another area of primary prevention research is focusing on reduction of perinatal transmission in the United States and worldwide, with particular emphasis on methods appropriate to the developing world.

The NIH investment in establishing and maintaining these domestic and international epidemiologic cohorts provides opportunities for epidemiologic and basic researchers to study unique populations, cooperatively pursue fundamental research on critical aspects of HIV transmission and disease, and understand in a population-based context the meaning of phenomena described by intensive lab-based studies. Population-based cohorts of high-risk HIV-uninfected persons remain critical to the elucidation of the natural history of primary HIV infection. Natural history and epidemiology research requires that special efforts be made to link the overall NIH research strategy with all facets of the international health research community through the OAR and FIC.

HIV Infection in Women

While many of the clinical manifestations of HIV infection in women are identical to those that occur in men, women also experience some that are unique and more prevalent than in men, such as vaginal and esophageal candidiasis, and chronic herpes simplex infections. The Women's Interagency HIV Study (WIHS), a major study conducted in collaboration with other PHS agencies, is identifying the nature and rate of HIV disease progression in women, characterizing clinical manifestations of HIV important to women, assessing the effects of therapeutic regimens, and identifying sociocultural and health care access factors that affect disease outcomes in women. An important concern is the impact of HIV on cervical cancer. Case reports suggest that HIV-associated cases progress more rapidly and are refractory to therapy. The NCI Surveillance, Epidemiology, and End Result (SEER) program has established a Special Surveillance Study to define more closely the incidence and spectrum of the histopathology of cervical cancer in HIV-infected women. The Multistate AIDS Cancer Match Registry is a project aimed at enhancing knowledge about HIV-associated cancer. Coinfection with human papillomavirus (HPV) is common in HIV-infected women. HPV and HIV have been shown to act synergistically to increase expression of individual viral genes. The enhanced expression of viral proteins results in increased viral replication, abrogates host tumor suppressor functions, and further exacerbates cellular immunodeficiency.

Disease Progression

Subsets of NIAID cohorts, both adult and pediatric, are being characterized in terms of the virologic and immunologic parameters of rapid and slow progression. New data have shown that the amount of HIV circulating in the bloodstream is predictive of the rapidity of disease progression. In particular, the NIAID is investigating individuals who (1) do not become infected despite repeated exposure to HIV; (2) appear to show clearing of the virus after initial documented infection; (3) manifest infection without immunologic progression (long-term nonprogressors); and (4) maintain stable clinical state even with prolonged immunosuppression (long-term survivors). Special focus is being placed on host genetics and possible states of "resistance" to HIV infection and on characteristics of the viral strain. Information from these cohorts will be crucial in designing and evaluating new therapeutic approaches and vaccines. New reverse transcriptase polymerase chain reaction (PCR) technology has made quantification of HIV in plasma or serum highly reproducible, sensitive, and predictive of AIDS. This technology likely will facilitate the elucidation of the in vivo natural history of HIV infection and also sexual and mother-to-child transmission, particularly if the technology can be adapted to the analysis of genital and other body fluids.