May 16, 2003 ROCHESTER, Minn. -- Mayo Clinic researchers have identified a naturally occurring "good guy" for patients infected with HIV. It is a helpful gene mutation that impairs the HIV virus' cell-killing machinery, thus preserving immune system function. Moreover, Mayo's experiments in mice suggest that the presence or absence of this mutation in the gene known as Vpr may play a central role in determining which HIV-infected patients develop full-blown, fatal AIDS.
If these findings hold up, this "good guy" mutation could lead to new AIDS therapies based upon Vpr inhibitors to reduce immune-system cell death during HIV infection. By preserving these immune system cells -- known as T cells -- the body would then not be defenseless against the many infections from which AIDS patients eventually die.
Says Andrew Badley, M.D., senior author of the study that appears in the May 15th Journal of Clinical Investigation, "For seven years our lab has been studying how HIV infection causes T cells to die. We had come to suspect that the patients who live with the replicating virus -- who are referred to as long-term nonprogressive HIV patients because they don't die from this normally fatal disease -- had abnormalities of the programmed cell-death response. In this study we found that, in fact, they have a mutation on the Vpr gene that impairs the cell-killing mechanism of the HIV virus."
Significance of Mayo's Research
The Mayo Clinic work provides laboratory evidence that confirms a hypothesis long held by many researchers around the world about how HIV infection progresses to finally overwhelm the body with the opportunistic infections that characterize AIDS. Mayo Clinic's conclusion: The principal mechanism by which HIV infection breaks down the body's immune system is by a biological process called "apoptosis" (a-pop-TOW-sis) or, programmed cell death.
Background: Why Vpr?
It has been an intriguing mystery since the beginning of the AIDS epidemic: How do some HIV-infected patients -- approximately 25-30 percent -- naturally thwart the development of Aids? These patients get infected with HIV and stay infected, but don't get AIDS. Says Dr. Badley, "Clearly, something is going on to help these long-term nonprogressors survive the infection -- but what? Previous studies have explained some of it -- but not all."
The Mayo Clinic group focused on a Vpr gene associated with the HIV virus because it was known to play a role in programmed cell death. When researchers compared the Vpr genes from some of their typical AIDS patients with the Vpr genes of long-term nonprogressors, they discovered the long-term nonprogressors' Vpr was, in fact, different: mutated. But what was the function of the mutation? This led to their next level of inquiry.
Discovering the Role of the Mutant Vpr
In the lab, Mayo Clinic researchers engineered HIV virus and tested two versions. One contained normal Vpr and one contained the mutant Vpr. Then they infected cultured cells grown in laboratory glassware with the two strains, paying special attention to how the mutant Vpr initiated cell death. "Lo and behold," says Dr. Badley, "the mutant doesn't kill as well as the normal, or wild type, Vpr. That was neat to find."
Earlier experiments by other investigators had shown how normal Vpr causes cell death. So the Mayo Clinic researchers examined mutant Vpr on a molecular level to see if it works the same way. It binds to the same target as normal Vpr, but doesn't trigger the same cell death cascade.
This provocative finding led to a final series of experiments: looking at the protein product that the mutant gene makes. Researchers first measured cell death caused by the protein in cell culture, then in live mice. Results in both lab dish and in mice were the same: impaired cell-death mechanism in the presence of the mutant-gene's protein.
Says Dr. Badley, "This particular experiment ends here, but our work continues because Mayo Clinic has a multidisciplinary HIV clinic and a number of investigators interested in novel treatment approaches and strategies toward HIV disease. By further exploring the role of Vpr we may be looking at a mechanism by which patients with long-term nonprogressive HIV disease are able to stay disease free. That information could eventually translate into new treatments."
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