UCSF Researchers Investigate Mystery Of People Who Remain Uninfected With HIV Despite Multiple Exposures To The Virus

July 01, 1998

GENEVA, Switzerland--People repeatedly exposed to HIV but not infected may have some kind of immune protection that allows their cells to resist invasion by the virus.

What exactly this protection factor is remains a mystery, but researchers from the University of California San Francisco AIDS Research Institute may have some insight into the protection phenomenon: it may be suppression of the virus by the immune system, triggered by prior exposures. Sharon Stranford, PhD, postdoctoral researcher in the lab of Jay Levy, MD, UCSF professor of medicine, presented her findings today (July 1) at the 12th World AIDS Conference.

"We're guessing that a low dose exposure to HIV induces a form of cellular immunity in some people," said Stranford. "Repeated exposures may provide a boost to the immune system without infecting the cells, like a natural vaccine."

Stranford and her colleagues screened for people with "high risk" exposures to HIV, which they defined as someone who has either shared needles or had unprotected sex on multiple occasions with a person known to be HIV-positive. The researchers identified 60 people meeting these conditions.

"In the beginning, I didn't believe in protection," Stranford said. "I thought some people were just lucky and would seroconvert later, but after studying them for two and a half years, only one out of 60 has seroconverted."

"These are people who have beat the odds for many years," said Stranford. "They have a history of high-risk behavior. Some are in long-term relationships, and sometimes the infected partners do not even realize they are infected until they come down with AIDS. Some of our subjects are gay men who had unprotected sex with men who have died from AIDS, so they assumed they were infected and later found out they were not."

The researchers found that despite their repeated exposures to HIV, these people did not have antibodies to HIV, and did not have any virus that could be detected, even by the most sensitive methods available. They did, however show unique immune responses in their CD8+ T cells.

The two types of T cells are distinguished by different protein receptors on their surface, abbreviated to CD4 and CD8. The CD4+ T cells are a prime target for HIV infection, and the loss of them is what causes the opportunistic infections that make up AIDS. CD8+ cells are known for their ability to kill virus-infected cells.

"We studied CD8+ cells that can suppress virus replication without killing infected cells," Stranford said. "The reason we were looking for this CD8+ response is that it is seen in HIV-infected people who are clinically healthy, or ?long-term survivors.' It probably helps people who are already infected from rapidly losing CD4+ T cells."

If this type of response could occur early, before systemic infection, she speculated that this might be the process of protection in the high risk, uninfected people.

Stranford and her colleagues first wanted to exclude genetic differences that might account for the lack of infection. They screened for a defect in the gene that makes a receptor that assists HIV in entering the CD4+ cells. If someone is missing both copies of the gene, they are protected from infection by some virus strains, but if they have one copy, the receptor is made and the person has no noticeable protection. Only two out of the 60 had both defective copies, so the other 58 have some other process protecting them.

The researchers also demonstrated that the CD4+ cells of these people could be infected with HIV, ruling out the possibility that these cells were shielded from infection.

In a series of experiments looking at the CD8+ cells of high risk individuals--using those of HIV-infected and uninfected, unexposed people for comparison--they found that CD8+ cells from the high risk people mounted a response against HIV, as did the cells from most of the HIV-infected people. None of the cells of the uninfected, unexposed people showed anti-HIV activity.

The CD8+ cell response seen in those exposed to HIV suppressed replication of the virus. In the case of the high risk people, the researchers saw a reduced amount of virus replication compared with unexposed individuals.

"We are observing this CD8+ activity against HIV in uninfected but exposed individuals," said Levy, "and this provides great encouragement for the ultimate development of a vaccine to HIV. If such an immune response can be induced, we expect protection from HIV infection will result."

Co-investigators on this project are Dennis Osmond, PhD, UCSF associate professor of epidemiology and biostatistics; Joan Skurnick, PhD, and Donald Louria, MD, from New Jersey Medical School; Sheng-Yung Chang, MS and John Sninsky, PhD, from Roche Molecular Systems of Alameda, CA; Guido Ferrari, MD, and Kent Weinhold, PhD, of Duke University surgery department; and Craig Lindquist, MD, PhD, of Marin County Specialty Clinic in Greenbrae, CA. The UCSF ARI is an institute without walls that encompasses all UCSF AIDS programs under a single umbrella. Thomas Coates, PhD, is the director. The UCSF ARI includes a dozen research institutes, a wide range of clinical, behavioral science, and policy programs, and nearly 1,000 investigators.

University of California - San Francisco

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