Newly published research led by University of Washington scientists could one day lead to a laboratory test to predict when people infected with human immunodeficiency virus type 1 (HIV-1) are likely to progress to symptomatic AIDS.
Dr. James Mullins, professor and chair of the UW Department of Microbiology, Dr. Raj Shankarappa, UW senior fellow in microbiology, and colleagues at Johns Hopkins University and the University of Pittsburgh report results of their study in the December 1999 issue of the Journal of Virology.
"We have found that there is a previously unrecognized consistency in the evolution of the HIV virus in people who subsequently progress to full-blown AIDS," said Mullins. "This finding allows us to recognize preclinical stages of infection."
The researchers did a retrospective analysis of blood samples provided every six months, beginning in the mid-1980s, by nine HIV-positive gay men enrolled in the Multicenter AIDS Cohort Study.
"Analyzing these sequential blood samples, we found there is predictability in the development of AIDS," said Shankarappa. "It was true of all nine people in this study, and we think it will occur in most cases of AIDS."
As was known previously, immediately after infection with HIV there is an acute stage of a few weeks. Then comes an asymptomatic stage of variable length; finally, the infection progresses to the symptomatic stage of clinical AIDS.
Some people with HIV progress to AIDS within a year of initial infection; the average is about nine years. A few people may never progress to clinical AIDS.
The UW research used a sequential analysis of mutations in the HIV-1 envelope gene to recognize progression within the asymptomatic clinical stage, and thus, the timing of development of full-blown AIDS. The researchers studied the evolution of a region of the HIV-1 envelope gene and of T-cell subsets in the nine men, all of whom had a roughly moderate rate of disease progression. They were monitored for a period of six to 12 years, until development of advanced disease in seven of the men. (None of the participants was prevented from receiving the latest treatment available at the time; in fact, most of the blood samples date from the mid- and late 1980s when therapies such as protease inhibitors were not available.)
The researchers analyzed three factors at sequential time points: how much the virus had mutated from its original form, how diverse the virus population became, and the appearance of X4 viruses, capable of utilizing a T-cell receptor called CXCR4.
Analysis suggested the existence of three distinct phases within the asymptomatic phase of HIV infection: a phase prior to a peak in diversity and the appearance of X4 viruses; a second phase prior to peak representation of X4 viruses and maximal divergence from the original form of virus; and a third phase following those peaks.
"The phases describe a consistent pattern of viral evolution during the course of HIV-1 infection in moderate progressors," report the researchers. "Recognition of this pattern may help explain previous conflicting data on the relationship between viral evolution and disease progression and may provide a useful framework for evaluating immune damage and recovery in untreated and treated HIV infection."
"We think we can now predict the progression of the disease three of four years before the onset of clinical symptoms of AIDS," said Mullins. "This capability is important, because by the time it is recognized that someone has entered the clinical phase, it may be too late to treat effectively. Furthermore, current treatments greatly suppress but do not eliminate HIV from the body. Hence, treatments need to be taken throughout the lifespan of the infected person. However, these drugs may produce serious side effects, and financial costs of these therapies are too great for many individuals to even consider, especially in developing countries. The ability to predict the onset of disease may therefore eventually help target therapies to the time that they might be most effective at blocking the onset of clinical AIDS.
"However, the considerable challenge now is to create a viable lab test based on this research, so that it can be useful in clinical application."
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