A team of scientists supported by the National Institutes of Health (NIH) has found multiple genes or gene combinations that appear to influence how long a person with HIV infection remains disease-free. A report describing the study appears in the April issue of Nature Medicine.
Although the median time from HIV infection to development of AIDS in adults is 10 years, individuals of similar age have highly variable rates of disease progression, a phenomenon that has remained unexplained," says lead author Richard A. Kaslow, M.D., formerly of the National Institute of Allergy and Infectious Diseases (NIAID) and now with the University of Alabama at Birmingham. "This new information could help guide investigators in exploring mechanisms that promote or retard deterioration of the immune system and in evaluating certain therapeutic approaches." However, Dr. Kaslow stresses that the genetic profile his team studied is not a sufficiently accurate predictor for use in making individual patient decisions.
The genes encode human leukocyte antigen (HLA), molecules that help regulate the immune response to HIV-1. "The findings from this study provide further support that the immune response to HIV is an important factor in determining the rate of HIV-mediated disease progression," commented Anthony S. Fauci, M.D., NIAID director.
In the study, the differential effects of these genes on disease prognosis became apparent within three to four years after seroconversion to HIV-1. The people identified by this profile to be at highest and lowest risk showed about a seven-year difference in median time to AIDS.
The scientists identified the genes by analyzing HLA markers in blood samples from 139 white homosexual and bisexual men enrolled in the Multicenter AIDS Cohort Study (MACS), a long-term study funded by NIAID. All the men in this subgroup of the MACS population had become infected with HIV since 1984-1985 when the study began. At the time of analysis, almost half (71) had developed AIDS while the remainder (68) had not developed AIDS for six years or more.
The HLA risk profile determined in the MACS volunteers was then verified in a second group of 102 homosexual and bisexual men -- all of whom are white -- enrolled since 1982 in another longitudinal study, the District of Columbia Gay (DCG) cohort, conducted by the Viral Epidemiology Branch of the National Cancer Institute (NCI). In this group, all of whom had relatively closely timed seroconversions to HIV-1, 66 had AIDS and 36 did not.
The analysis focused on products of the major histocompatibility complex (MHC), a cluster of genes that includes the HLA region. The MHC is important for immune recognition and for immune responsiveness to foreign antigens such as might derive from HIV-1. HLA (or MHC) class I markers, found on the surfaces of all nucleated cells and blood platelets, determine the immunologic acceptability of transplanted tissue. HLA (or MHC) class II markers, expressed on B cells, macrophages and other immune system cells, are required to initiate an immune response to foreign antigens such as HIV-1. Pieces of these foreign antigens are transported across the cell's interior by products of TAP genes (also in the MHC). The scientists examined all three classes of genes in the study.
The findings of numerous previous studies of HLA and HIV-1 disease progression have been inconsistent, Dr. Kaslow and his colleagues write, in part because of differences in the ethnicity of subjects, research designs and laboratory techniques. In addition, previous studies usually ignored the complex interrelationships between HLA gene products and between HLA genes that sit so close together on the chromosome that they are often co-inherited. The report's authors write, "The MHC seems to govern the rate of progression of HIV-1 infection through multiple interacting genes -- few of which show convincing individual relationships but which cumulatively have a substantial impact."
Each of the 20 single markers or marker combinations that showed a significant relationship to an AIDS-free interval was assigned a number representing its contribution to slow (+1) or rapid (-1) progression, respectively. Seven markers or marker combinations fell in the first category and 13 in the second.
Theoretically, each man could carry up to six contributory markers (two HLA-A's, two HLA-B's, and two class II markers with the appropriate TAP variant), but none carried more than four. Of the 139 men in the MACS cohort, 73 percent had at least one contributing marker.
A genetic score was calculated by adding the integers. Based on this score, each man was assigned to one of five relative risk categories (-2, -1, 0, 1, 2), and the investigators calculated the relationship between the resulting HLA profile and development of AIDS.
The authors write, "This search for immunogenetic determinants of progression of HIV-1 infection illustrates how exploration of HLA associations with disease may be enhanced by comprehensive and systematic methods. Such studies generally need to include larger numbers of carefully classified subjects than have customarily been assembled, and they should preferably aim from the beginning to identify important markers in one population and verify them in another."
The other authors on the paper are: Mary Carrington, Ph.D., James J. Goedert, M.D., Cheryl Winkler, Ph.D., Stephen J. O'Brien, Ph.D., William Blattner, M.D., and Dean L. Mann, M.D., of the National Cancer Institute, NIH, Bethesda, Md.; Raymond Apple, Ph.D., and Henry Erlich, Ph.D., of Roche Molecular Systems Inc., Alameda, Calif.; Lawrence Park, M.S., Alvaro Munoz, Ph.D., and Alfred J. Saah, M.D., M.P.H., of The Johns Hopkins School of Hygiene and Public Health, Baltimore, Md.; Charles Rinaldo, Ph.D., of the University of Pittsburgh; Roger Detels, M.D., M.S., of the UCLA School of Public Health; and John Phair, M.D., of Northwestern Medical School, Chicago, Ill.
NIAID and NCI are components of the National Institutes of Health. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NCI conducts and supports research on cancer, AIDS and related conditions. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
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Kaslow R, et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nature Medicine 1996;2:405-11.