Mutant Gene Not Sole Explanation for HIV Non-Progression
A recently described genetic mutation does not fully explain why a small proportion of people infected with the human immunodeficiency virus (HIV) remain completely well for a decade or more, according to investigators at the National Institute of Allergy and Infectious Diseases (NIAID).
Instead, the researchers say, the good health of such "long-term nonprogressors" probably is due to multiple factors, which may vary from individual to individual.
Oren Cohen, M.D., a medical officer in NIAID's Laboratory of Immunoregulation (LIR); LIR Lab Chief and NIAID Director Anthony S. Fauci, M.D.; and their colleagues report their findings in the Sept. 15, 1997 issue of The Journal of Clinical Investigation. The study involved 33 patients from LIR's cohort of long-term nonprogressors, the NIAID-supported Multicenter AIDS Cohort Study, and the San Francisco City Clinic Cohort.
"This study fortifies the concept that HIV long-term nonprogressors represent a diverse group," says Dr. Fauci. "Multiple immune system factors, genetic and other host factors, and viral factors contribute to the clinical profiles of these patients, who usually have preserved immune function and low levels of HIV in their bodies."
Recent research has shown that most infecting strains of HIV use a cellular receptor called CCR5, in addition to the CD4 molecule, to enter certain of its target cells. HIV-infected people with a specific mutation in one of their two copies of the gene for this receptor generally have a slower disease course than people with two normal copies of the gene. People with two mutant copies of the CCR5 gene appear -- in most cases -- to be completely protected from HIV infection.
Several epidemiological studies have shown that individuals with one mutant copy of the CCR5 gene are disproportionately represented among long-term nonprogressors. The LIR defines long-term nonprogressors as people who have been HIV-infected for more than seven years, have stable CD4+ T cell counts above 600 per cubic millimeter (mm3) of blood, have no history of HIV-related symptoms, and who have not taken antiretroviral drugs.
Drs. Cohen, Fauci and their team began recruiting long-term nonprogressors five years ago to determine the specific factors that protect these people from HIV disease progression. Soon after the discovery of the role of CCR5 in HIV disease and the association of the mutant CCR5 gene with slower disease progression, the LIR team found that people with one copy of the mutant gene (and one copy of the normal gene) were over-represented in their cohort of long-term nonprogressors.
With that information in hand, they asked the question, do long-term nonprogressors with one copy of the mutant CCR5 gene have less virus in their bodies and higher CD4+ T cell counts compared with long-term nonprogressors with two normal copies of the CCR5 gene -- a situation that would help explain the association of the CCR5 mutation and long-term nonprogression?
The answer, Dr. Cohen says, "was a resounding no." The investigators found that nonprogressors with one copy of the mutant CCR5 gene were indistinguishable from nonprogressors with two normal copies of the gene with regard to all immunologic and virologic parameters they measured, including CD4+ T cell counts and viral load in the bloodstream and lymph nodes.
"Although an HIV-infected individual who carries one copy of the mutant CCR5 gene has an increased chance of becoming a long-term nonprogressor, other factors in the complex interaction between HIV and the body allow individuals with normal copies of the gene to maintain similar immunologic status."
What explains the epidemiological data that show many people with the CCR5 gene mutation in cohorts of long-term nonprogressors?
"Around the time of initial infection with HIV, people with the specific mutation in the CCR5 gene have lower levels of virus in their blood and a smaller initial decline in CD4+ T cells, as compared to other patients," says Dr. Cohen. (See Huang, et al. Nature Medicine 1996;2:1240-1243). "This lower 'set point' probably has an important influence on the subsequent rate of disease progression."
The LIR continues its studies of long-term nonprogressors, and will report important new data from their cohort at the upcoming Interscience Conference on Antimicrobial Agents and Chemotherapy later this month.
"Studies of long-term nonprogressors have contributed greatly to our understanding of the HIV disease process, and provide perhaps the best evidence that protective immunity may exist in HIV infection," says Dr. Fauci. "We owe an enormous debt to the many patients who have come to Bethesda to take part in our studies. The contribution that these individuals have made to science and the fight against AIDS is immeasurable."
Dr. Cohen's and Fauci's collaborators include Mauro Vaccarezza, M.D., Gordon K. Lam, Barbara F. Baird, Kathryn Wildt, Philip M. Murphy, M.D., Ph.D., Peter A. Zimmerman, Ph.D., Thomas B. Nutman, M.D., Cecil H. Fox, Ph.D., Shelley Hoover, Joseph Adelsberger, Michael Baseler, Ph.D., James Arthos, Ph.D., Richard T. Davey, Jr., M.D., Robin L. Dewar, Ph.D., Julia Metcalf, Douglas J. Schwarzentruber, Ph.D., Jan M. Orenstein, M.D., Ph.D., Susan Buchbinder, M.D., Alfred J. Saah, M.D., Roger Detels, M.D., John Phair, M.D., Charles Rinaldo, Ph.D., Joseph B. Margolick, M.D., Ph.D., and Giuseppe Pantaleo, M.D.
Reference: Cohen OJ, et al. Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long term non-progressors. Journal of Clinical Investigation 1997;100(7):1581-1589.
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