The National Institute of Allergy and Infectious Diseases (NIAID) has awarded five-year grants to continue the work of the Multicenter AIDS Cohort Study (MACS), the largest continually followed group of HIV-infected or at-risk individuals in the world. Approximately $6 million in first-year funding will be distributed among MACS research centers at The Johns Hopkins University; the University of Pittsburgh; Northwestern University; and the University of California at Los Angeles.
"We're delighted to continue supporting the MACS," says Anthony S. Fauci, M.D., director of NIAID. "This study has been instrumental in advancing our understanding of the pathogenesis and natural history of HIV disease, and thus has important implications for therapy."
The MACS has enrolled more than 5,600 individuals since 1984. Currently, there are 1,775 active enrollees, of which about 38 percent are HIV-positive. A total of 1,237 MACS volunteers have died of AIDS.
MACS data have contributed to nearly 700 publications in medical and scientific journals. The study's collection of clinical specimens spans most of the history of the HIV epidemic, from uninfected individuals of the early 1980s to long-term nonprogressors - people who remain healthy 10 years or more after becoming infected with HIV - today. Its size and longevity have uniquely positioned the MACS to answer questions that other studies could not easily approach.
"In its 15 years, the MACS has amassed a wealth of clinical information and biological specimens," says Jack Killen, M.D., director of the Division of AIDS at NIAID. "Together with the huge databases to which they are linked, these specimens provide the general scientific community with an invaluable research resource for multidisciplinary investigation." The availability of MACS specimens has led to research collaborations with more than 100 investigators outside the MACS.
The idea for the MACS evolved in the early 1980s, before anyone knew what caused AIDS, which, at that time, primarily affected homosexual men. With the hope of discovering the disease's cause, NIAID launched a multicenter effort to enroll volunteers at risk for developing AIDS. When the discovery of HIV and its subsequent link to AIDS occurred shortly thereafter, the focus of the study shifted toward investigating how the disease progresses and how to prevent it. The MACS originally was composed of clinical research centers at the institutions mentioned above and at the University of California at Berkeley. The Berkeley center left the MACS in 1988 to pursue an independent NIAID-funded investigation, the San Francisco Men's Health Study.
MACS volunteers are evaluated every six months. Volunteer visits include an interviewer-administered questionnaire, a physical examination, and the collection of blood samples for analysis of the immune system and to monitor volunteers' HIV status.
"It's really comforting to have been a part of this research from the beginning," says Louis Hughes, Jr., a Baltimore resident who enrolled in the MACS at the Johns Hopkins University site in 1984. "It's been a bittersweet struggle, but to see the progress from knowing so little about HIV/AIDS to where we are today when people with HIV are living longer, better lives is very exciting." Mr. Hughes, who is HIV-negative, notes that he has lost many friends to AIDS. "But I know that other friends of mine are benefiting from this research," he adds.
The MACS has played a crucial role in HIV/AIDS research over the past 15 years. One of the first major MACS breakthroughs came in 1988, when John P. Phair, M.D., and colleagues at Northwestern University reported that HIV-infected individuals' risk of contracting Pneumocystis carinii pneumonia (PCP) dramatically increased once their CD4+ T-cell levels dropped below 200 cells per cubic millimeter (mm3) of blood. This discovery provided a rational basis for initiating treatment to prevent PCP once T-cell levels dropped below that threshold.
In early 1990, the MACS underwent a fundamental change in focus. "Until that time, the MACS had largely focused on questions of clinical outcome," explains Carl Dieffenbach, Ph.D., associate director of the Basic Science Program in NIAID's Division of AIDS. "We started asking, 'What features of the interaction between HIV and the person it infects might explain variations in disease progression?'" To address this question, the MACS brought together teams of virologists, immunologists and epidemiologists.
"We knew we had to conduct these studies under the same roof with the same patients at the same time," says Dr. Dieffenbach. "The MACS really took the lead in organizing combined studies that united these various scientific disciplines within a study group."
Another groundbreaking discovery came in 1996, when John W. Mellors, M.D., and other MACS researchers from the University of Pittsburgh reported that viral load was the single most important indicator of HIV disease progression. Previously, physicians had used CD4+ T-cell counts as the primary determinant in treatment decisions.
More recently, MACS data have expanded knowledge of how differences in the genes that encode HIV co-receptors - the molecular handles on immune system cells to which the virus attaches itself - make individuals resistant to HIV infection or affect HIV disease progression. Analyses of cohort data have also contributed vital information to understanding AIDS-associated opportunistic infections, cancers and neurological disorders. Ongoing MACS research is examining the emergence of drug resistance to highly active antiretroviral therapy (HAART), as well as the metabolic side effects HAART produces in some individuals.
"In the coming years, we are confident that MACS will keep providing critical information as we pursue the best ways to treat, manage or prevent HIV infection," says Dr. Fauci. "There is no other study of its kind in the world, and it is important that we continue to support this vital multicenter effort."
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services. Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.