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
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
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
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
"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.
NIAID, a component of the National Institutes of Health (NIH),
supports research on AIDS, malaria and other infectious diseases, as
well 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 are
available on the Internet via the NIAID home page at
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.