This is a tale of two men, exposed years ago to HIV infection, but who have never progressed to full-blown AIDS.

The first is a hemophiliac who 18 years ago, when a university student, received infusions of donor blood clotting factors. Then the Red Cross advised him that these had been contaminated with HIV, to which he was ipso facto exposed.

The patient, a professional person, and something of a local public figure, contacted immunologists Eric Rosenberg and Bruce Walker, at Massachusetts General Hospital (MGH) in Boston. Walker directs the hospital's Partners AIDS Research Center, in Charlestown, Mass., where Rosenberg is a clinical and research fellow. (See BioWorld Today, Oct. 21, 1997, p.1.)

"We don't know exactly why this individual hasn't progressed," Rosenberg told BioWorld Today. "What we do know is that he has what we consider to be several key immunological responses to HIV. We think," he added, "that these are going to be highly associated with his non-progression."

The first such response, Rosenberg went on, "was from a very vigorous HIV-specific CTL (cytotoxic T lymphocyte). We're certain that was helping him to control the amount of virus that he has. Yet he never had a detectable viral load and registers a healthy CD4 helper-cell count of 1,440."

Rosenberg surmises that "this helper-cell response is the second key thing, aiding his immune system in containing viral replication."

There's been a spate of genetic evidence indicating that a mutation in the CCR5 cytokine that helps HIV break and enter its target cells may account for the ability of some infected individuals to remain asymptomatic for long periods. (See BioWorld Today, March 4, 1997, p. 1.)

But Rosenberg's and Walker's hemophiliac non-progressor is "genetically wild type. His chemokine receptors are not mutants, which would make him uninfectable. They're the normal type, which make him infectable."

Heightened Immune Response May Be Key

The MGH investigators can only speculate as to what's behind his non-progression. "It's possible," surmised Rosenberg, "that he's got a defective virus, which is stimulating a very robust immune response, but not hurting him. Yet we've never been able to isolate virus from him to look at. I see him every couple of weeks, letting us draw his blood."

The first time they did so, they observed an unexpected upsurge in helper-cell response, "the first such response we have ever seen to HIV," Walker said.

Their second non-progressor has a different, but equally baffling, tale to tell.

"Now in his mid-30s," Rosenberg recounted, "he has had HIV, via sexual infection, for at least 14 years that we know of, but has never been clinically ill in any way. He has a stable, normal CD4+ count and a very low but detectable load of replicating virus in his blood, last read at 700 copies per cubic milliliter."

The MGH clinician ascribes this person's non-progression too to a high-powered immune response. "Both of these men have CD4 helper cells that are able to recognize different viral proteins and proliferate," Rosenberg pointed out. "They're present in those two men, but virtually absent in everybody else that we look at who's got chronic infection."

From this he concluded: "There's got to be some association with the way that their immune system is dealing with the virus."

Rosenberg is first author, and Walker senior author, of a paper in today's Science, dated Nov. 21, 1997, titled: "Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia."

They report analyzing eight chronically infected individuals, plus their two prime non-progressors. "The thing those 10 had in common," Rosenberg observed, "is that none of them have ever been on any kind of antiviral drugs."

The MGH team counted their viral load, and on the same blood draw looked to see if their cells proliferate HIV. They found "a direct correlation between a robust immune response and a low viral load. Inversely, those people with high viral loads had absent immune capacity."

Rosenberg made the point that "this confirmed the obvious, but it had never been shown before," and observed: "The things you can extrapolate from that, although clearly not proven, are that if you were a vaccine maker, and you wanted to design a vaccine, inducing this type of immune response would probably be an important thing to do."

Way To Go: Drug Therapy, Then Vaccine

"We want to look at potential vaccines," he added, "that can be used therapeutically to induce these immune responses in people who have undetectable viral loads on therapy."

Rosenberg suggested tentatively how to go about it: "This would be a therapeutic, not a preventative, vaccine. First, I'd treat chronically infected people with triple-drug therapy. Drive their viral loads below detection, then immunize them with some antigen that was capable of inducing a proliferative response."

He ventured that "the most important cohort are the people who had acute HIV infection. Who were just infected a few weeks prior to seeking medical attention. And then they came in with high fevers and the whole primary clinical syndrome; they were actually quite ill.

"Such candidate subjects knew just when they were exposed to HIV. When asked, all got it sexually, had unprotected sex this particular day within the past couple of weeks. When an individual comes in two weeks after exposure," he continued, "his or her immune system is already beginning to decline.

"In HIV, which makes it unique from other viral infections, what we think is happening is that those very T cells that are proliferating are subsequently becoming targets of infection and possibly getting infected, making more virus, and then getting killed off.

"But if it looks like their immune system is up and running, then if the patients are willing, we might give them the option to come off of the therapy and see if their immune system will take over and do the job begun by the drugs. So that would be kind of the ultimate test to see if these responses mean anything."

Then Rosenberg voiced his prime take-home message: "Start that regimen immediately after exposure. Don't delay a day!" *