1-21-2002
Scientists
have found that people who carry one copy of a mutation that protects cells
against HIV infection may be partially resistant to the virus causing AIDS. The
new finding is reported in a study by a multi-center research consortium that
included institutions in New York City, Boston, Seattle, and San Francisco.
"We looked for this mutation in a large cohort of high-risk people who were HIV-negative. We found that bisexual and homosexual Caucasian men with one copy of the mutation had a 70% reduced risk of HIV infection compared with men who didn't carry the mutation at all," says Michael Marmor, Ph.D., Professor of Environmental Medicine and Medicine at New York University School of Medicine, the first author of the study.
In
previous studies it had been established that men with two mutant copies of the
CCR5 gene had even stronger resistance to HIV infection
"Our
finding suggests that strategies to prevent HIV infection by blocking receptors
used by the virus need not block all of the receptors," says Dr. Marmor.
"Reducing the number of receptor sites per cell may be adequate to provide
an imperfect but important degree of protection."
There
are thousands to tens of thousands of CCR5 receptors on the surface of a subset
of immune cells called T-helper cells. In people with two copies of the delta-32
mutation there are no functional CCR5 receptors on these cells.
In order for HIV, the virus causing AIDS, to enter cells it usually must fuse with a receptor called CCR5 that sits on the surface of T-helper immune cells. The delta-32 mutation in the gene encoding the CCR5 protein results in a defective receptor site that blocks entry of the virus.
People
who carry two copies of the mutation, one from each parent, are resistant to HIV
infection despite repeated exposures to the virus. People who carry one copy of
the mutation, the study concludes, also may be substantially resistant.
Every
gene has two alleles, or forms, one inherited from each parent. People who carry
a gene with the same alleles are called homozygotes for a particular trait.
People who carry a gene with two different alleles are called heterozygotes.
It has been known for several years that around one percent of Caucasians are genetically resistant to HIV because they are homozygous for the CCR5 mutation, meaning they have inherited two copies of the mutation, one from each parent.
"These
people, however, are not resistant to all strains of HIV," warns Dr. Marmor.
"They should avoid behaviors that might expose them to relatively uncommon
HIV strains that use receptors other than CCR5 to gain entry into cells."
Prior
research had established that HIV-infected people who are heterozygous for the
mutation progress to full-blown AIDS more slowly than people with no copies of
the mutation. But it was unclear to what extent people with one copy of the
mutation were protected against HIV infection.
The
new study suggests that people with one copy of the mutation do have some
protection against infection. It prospectively monitored a large cohort of
bisexual and homosexual men to see how their CCR5 status correlated with the
incidence of HIV infections.
The
study, published in the current issue of the Journal of Acquired Immune
Deficiency Syndromes, helps fill in the missing information about resistance to
HIV infection among men at high risk of infection. The report also contained
data on injection-drug users and women at sexual risk of HIV infection.
The study analyzed the prevalence of homozygotes and heterozygotes for the CCR5 mutation among 2,996 individuals, including 1,892 gay men, 474 male injection drug users, 283 female drug users, and 347 women at heterosexual risk of HIV infection.
The
men in the study were followed for 18 months. They had their blood tested for
HIV every six months, and they responded to questionnaires that asked about
their behaviors during the course of the study. The women were followed for 24
months, but too few were enrolled to yield statistically significant results.
Among
the men, the study found that 40, or 1.3 percent, were homozygous, 387, or 12.9
percent, were heterozygous for the CCR5-delta-32 mutation, and 2,569 had no
copies of the mutation. Men who were heterozygotes had a 70 percent reduced risk
of HIV infection compared with men who did not carry the mutation. A total of 45
individuals during the course of the study became infected with HIV.
The data also revealed that 10.5 percent of white gay men in the study who were age 45 or older and who lived in San Francisco or New York City, and were HIV negative in 1995, were homozygous for the CCR5-delta-32 mutation.
This
observation, says Dr. Marmor, underscores the survival advantage provided by the
homozygous mutation. Only one percent of Caucasians in the general population
would be expected to be homozygous for the mutation.
The
study cohort is culled from the larger HIVNET Vaccine Preparedness Study, which
enrolled 4,892 people who were HIV negative, but had histories of behaviors that
placed them at high risk of infection. Study sites were in Boston, Chicago, New
York City, Philadelphia, Providence, San Francisco, and Seattle.