In the largest study of its kind, a group of investigators from the Johns Hopkins School of Public Health in Baltimore and Washington University in St. Louis have found distinct patterns of human immunodeficiency virus (HIV) evolution in individuals with different rates of disease progression. The findings, which appeared in the October 1998 Proceedings of the National Academy of Science, USA, suggested that the course of disease is determined by factors within the infected individual that affect how the virus evolves, and that the level of HIV genetic diversity in a group of infected individuals was predictive of that group's deterioration over the next year. The study also suggested that, when developing ways to combat the virus, scientists must develop means to stimulate the immune system to fight multiple genetic variants of the virus simultaneously.
Lead author Richard B. Markham, associate professor, Molecular Microbiology and Immunology, the Johns Hopkins School of Public Health, said, "In HIV infection, the problem with directly studying the effect of host factors on the course of the disease is that the virus is evolving so rapidly. When you attempt to measure the individual's immune response to the virus, for example, you don't know to which of the many different HIV viruses in the individual he or she might be responding. But instead of viewing that viral variation as a complicating factor, we used the pattern of variation to analyze how the host might be influencing the virus' evolution."
The researchers studied the genetic sequence patterns in over 800 viruses obtained from the study subjects, examining how HIV was evolving in 15 HIV-infected injection drug users at six-month intervals, from the time of seroconversion over a period of up to four years later. Rapid progressors were defined as those subjects whose CD4 T cell levels--a measure of how robust the immune system is--had fallen to fewer than 200 within two years of seroconversion; moderate progressors, as those whose CD4 T cell levels declined to 200-650 by four years; and nonprogressors, as those whose CD4 T cell levels remained above 650 throughout the four-year observation period.
The study found that the HIV virus followed a different pattern of genetic evolution in HIV-infected individuals whose disease was progressing moderately or rapidly compared to those defined as nonprogressors. In the study group as a whole, those individuals in whom the virus showed the greatest genetic diversity were likely to experience significantly greater declines in immune system health over the next year, and thus faster progression of the disease. Although the most prevalent strain of the viruses at a given point in the disease would usually be eliminated over time, those individuals with more rapidly progressive disease were able to eliminate only a small proportion of the diverse range of viruses present in the host. Hence, the viral population continued to become more heterogeneous.
Continuing viral evolution was also observed in individuals with slow or non-progressive disease, but the immune systems of these individuals apparently inhibited the appearance of more diverse strains, a finding that led the investigators to speculate that these slowly progressing individuals were launching a broader immune attack against the virus.
Dr. Markham said, "With current drug therapy, we are able to slow virus growth but not eradicate HIV infection. These studies provide direction to future therapeutic efforts by suggesting that the failure to eliminate the virus results from host defenses that are directed against only a limited portion of the viruses that infect an individual. As we think about how to intervene, one of our goals should be to broaden the range of viruses that are targeted by the host immune response."
This work was supported by the National Institute on Drug Abuse (National Institutes of Health).
Materials provided by Johns Hopkins School Of Public Health. Note: Content may be edited for style and length.
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