A recently described genetic mutation does not fully explainwhy a small proportion of people infected with the humanimmunodeficiency virus (HIV) remain completely well for a decade ormore, according to investigators at the National Institute of Allergyand Infectious Diseases (NIAID).
Instead, the researchers say, the good health of such "long-term nonprogressors" probably is due to multiple factors, which mayvary from individual to individual.
Oren Cohen, M.D., a medical officer in NIAID's Laboratory ofImmunoregulation (LIR); LIR Lab Chief and NIAID Director AnthonyS. Fauci, M.D.; and their colleagues report their findings in the Sept.15, 1997 issue of The Journal of Clinical Investigation. The studyinvolved 33 patients from LIR's cohort of long-term nonprogressors,the NIAID-supported Multicenter AIDS Cohort Study, and the SanFrancisco City Clinic Cohort.
"This study fortifies the concept that HIV long-termnonprogressors represent a diverse group," says Dr. Fauci. "Multipleimmune system factors, genetic and other host factors, and viralfactors contribute to the clinical profiles of these patients, who usuallyhave preserved immune function and low levels of HIV in theirbodies."
Recent research has shown that most infecting strains of HIVuse a cellular receptor called CCR5, in addition to the CD4 molecule,to enter certain of its target cells. HIV-infected people with a specificmutation in one of their two copies of the gene for this receptorgenerally have a slower disease course than people with two normalcopies of the gene. People with two mutant copies of the CCR5 geneappear -- in most cases -- to be completely protected from HIVinfection.
Several epidemiological studies have shown that individualswith one mutant copy of the CCR5 gene are disproportionatelyrepresented among long-term nonprogressors. The LIR defines long-term nonprogressors as people who have been HIV-infected for morethan seven years, have stable CD4+ T cell counts above 600 percubic 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-termnonprogressors five years ago to determine the specific factors thatprotect these people from HIV disease progression. Soon after thediscovery of the role of CCR5 in HIV disease and the association ofthe mutant CCR5 gene with slower disease progression, the LIR teamfound that people with one copy of the mutant gene (and one copy ofthe normal gene) were over-represented in their cohort of long-term nonprogressors.
With that information in hand, they asked the question, dolong-term nonprogressors with one copy of the mutant CCR5 genehave less virus in their bodies and higher CD4+ T cell countscompared with long-term nonprogressors with two normal copies ofthe CCR5 gene -- a situation that would help explain the associationof the CCR5 mutation and long-term nonprogression?The answer, Dr. Cohen says, "was a resounding no." Theinvestigators found that nonprogressors with one copy of the mutantCCR5 gene were indistinguishable from nonprogressors with twonormal copies of the gene with regard to all immunologic and virologicparameters they measured, including CD4+ T cell counts and viralload in the bloodstream and lymph nodes.
"Although an HIV-infected individual who carries one copy ofthe 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 manypeople with the CCR5 gene mutation in cohorts of long-termnonprogressors?
"Around the time of initial infection with HIV, people with thespecific mutation in the CCR5 gene have lower levels of virus in theirblood 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 upcomingInterscience Conference on Antimicrobial Agents and Chemotherapylater this month.
"Studies of long-term nonprogressors have contributed greatlyto our understanding of the HIV disease process, and provideperhaps the best evidence that protective immunity may exist in HIVinfection," says Dr. Fauci. "We owe an enormous debt to the manypatients who have come to Bethesda to take part in our studies. Thecontribution that these individuals have made to science and the fightagainst 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., SusanBuchbinder, M.D., Alfred J. Saah, M.D., Roger Detels, M.D., JohnPhair, M.D., Charles Rinaldo, Ph.D., Joseph B. Margolick, M.D.,Ph.D., and Giuseppe Pantaleo, M.D.
NIAID, a component of the National Institutes of Health (NIH),supports research on AIDS, malaria and other infectious diseases, aswell as allergies and asthma. NIH is an agency of the U.S.Department of Health and Human Services. ###Press releases, fact sheets and other NIAID-related materials areavailable on the Internet via the NIAID home page athttp://www.niaid.nih.gov.
Reference:Cohen OJ, et al. Heterozygosity for a defective gene for CCchemokine receptor 5 is not the sole determinant for the immunologicand virologic phenotype of HIV-infected long term non-progressors. Journal of Clinical Investigation 1997;100(7):1581-1589.
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