SEPTEMBER 1998

NUMBER ONE

HIV-Remission: The New Goal

With HIV rates skyrocketing worldwide, a new treatment strategy emerged at Geneva. The surprising secret weapon? Our immune system.

In recent months there's been no shortage of gloom and doom about HIV. After two years of hope and hype over the new protease drugs, headlines referred to the recent World AIDS Conference in Geneva as a grand "reality check"-a sobering hangover brought on by myriad reports of drug failure, drug resistance, and unusual side effects among those taking the newest therapies (see "Freak Fat"). The latest of these is the first case report of the transmission of a multiply drug-resistant strain of HIV, something we've been fearing.

Across the globe, the virus is raging out of control, threatening the future of Africa and Southeast Asia with no treatments and few prevention dollars to stem the tide. In Russia and war-torn places like Rwanda and Bosnia, the collapse of health-care infrastructures has spawned new mini-epidemics caused by mutant HIV strains. Current estimates show 40 million people will have HIV by 2000, and only the smallest fraction will have access to pricey HIV drugs.

Unfortunately, this very grim picture obscures real progress and exciting developments in HIV research. Many studies show that successful HAART therapy offers people with HIV a new lease on life by stopping active infection, preventing the onset of HIV-related infections, and slowly but steadily restoring depleted immune systems. The overall decline in HIV-related infections has prompted researchers to reconsider whether people on HAART whose sustained T-cell counts rise above 200 should continue to take prophylactic treatments (see "HIV Illnesses"). Early treatment has also worked in newly exposed people, preventing the virus from damaging their immune systems.

Remission: But the big news concerns HIV remission. Almost overnight, a new treatment strategy has emerged and ushered in a new arsenal against the virus. As top scientists reported in Geneva, some evidence suggests we may be able to control HIV without completely eradicating it. In a one-two punch, antiviral drugs could initially be used to stop active infection while immune boosters could bolster depleted immune defenses and help the immune system contain any virus escaping from latent reservoirs.

The approach signals a radical step in a new direction-immunology-one that has the theoretical potential to transform HIV into a chronic, latent infection similar to herpes. People won't get rid of HIV, but they'll learn to live with it-and stay healthy. As of July, 13 people have been identified who fit that general profile: After taking a combination of HIV drugs that fully suppressed active infection, they stopped their regimens and haven't seen the virus rebound. They're not HIV free, however: Traces of virus can be found lingering inside dormant, long-lasting immune T-cells in their bodies. Because the cells aren't active, the virus remains dormant as well. That's what scientists call remission.

Hydroxyurea: Some of these people in remission have added an unusual drug to their regimen: hydroxyurea, a 35-year-old cancer treatment that blocks cell enzymes rather than viral enzymes, like other HIV drugs. It also appears to act against latently infected T-cells.

"Can the immune system control HIV? We're gonna find out," said Dr. Franco Lori, the Italian researcher who first proposed using hydroxyurea to treat HIV and has hundreds of patients on the drug. "The data supports such an idea. But for me, the evidence is the experience of the patients. And that makes me optimistic."

Interestingly, many of Lori's patients are taking a combination of only two drugs-ddI and hydroxyurea-and have seen strong, sustained drops in viral load as well as a slow but steady regeneration of naive T-helper (CD4+) cells. The patients are tolerating the drug well and haven't experienced development of resistance. If anything, the cancer drug helps such other HIV drugs as ddI work better, even when HIV has become resistant. Best of all, it's far cheaper than protease inhibitors.

If successful, the goal of remission could help curb the growing problems of drug resistance and toxicity associated with long-term use of antiviral drugs. It also opens new doors to vaccine research at a time when current efforts to develop a safe preventive vaccine have failed. At Geneva, disappointed vaccine researchers reported that a promising vaccine candidate made of a weakened live strain of SIV had failed in monkey studies, causing a fast lethal disease instead. Prior to that news, lively debate had broken out over a proposed human trial of a live-attenuated vaccine, and up to 300 people-mostly physicians-had volunteered to try it. For now, such a trial is off. Recruitment for a large-scale trial of another preventive vaccine, called AIDSVAX, has begun, but scientists at Geneva expressed skepticism that it can generate the specific immune responses needed to stop HIV.

And what might those responses be?

Lymphoproliferative Response (LPR): refers to the ability of certain CD4 cells to recognize the virus and make copies of themselves to fight it. These CD4 cells then send a call to arms to a subset of CD8 cells called CTLs-cytotoxic (cell-killing) T-lymphocytes. To understand, think of different regiments in the immune system's defensive army: If the general, CD4, is attacked, he can't direct the troops, CD8, to fight the enemy. Many studies of long-term non-progressors indicate that they have very large levels of HIV-specific CD4 cells that are critical to controlling the virus. But in people who develop HIV infection, these specific immune responses are lost.

The current buzz about LPR, CTL, and the immune system actually began last fall, when Harvard researchers Bruce Walker and Spryos Kalams reported that individuals with acute HIV infection who were treated with HIV drugs developed HIV-specific CD4 responses exactly like those of long-term non-progressors. Lori's studies using hydroxyurea show a similar pattern. For the past year, he's been closely following a man known in AIDS circles as "the Berlin patient," a young man who developed acute HIV infection and began taking therapy 10 days later with a combination of ddI, Crixivan, and hydroxyurea. Three weeks later, he developed a testicular infection and stopped taking his drugs. He went back on therapy but only half-heartedly, then got hepatitis A, went off again, and eventually quit altogether after six months. To everyone's surprise, HIV didn't bounce back quickly after he abandoned therapy, as it has in most other patients. A year and a half later, the Berlin patient remains healthy with no detectable viral load. Supersensitive tests show that traces of HIV remain in his tissue, but his immune system appears to be controlling it.

What's his secret? LPR? Well, the Berlin patient has a strong HIV-specific CD4 response. A French doctor, Jorge Vila, had two patients with a similar profile; now he has another eight with no detectable HIV rebound. And Dr. David Ho, the man who has championed HIV eradication and continues to think it's possible, also has a few patients.

At Geneva, Dr. Lori reported with some excitement that the LPR strategy also works in people with chronic HIV infection-and does so with only a two-drug regimen. In a study that began almost three years ago, Lori started 12 patients-who had an average viral load of 50,000 and CD4 counts of 250-500-on a ddI/hydroxyurea combination. After 40 weeks, their average viral load had dropped to 2,000 copies; after 122 weeks, it was down to 200 copies and falling. More important, their naive T-cell levels were increasing-a good sign of improved immune response-and six of the 12 had recovered vigorous HIV-specific CD4 responses. "It is possible to reconstitute an immune response in patients who are chronically infected with HIV," Dr. Lori declared. While he's trying to temper his enthusiasm, he finds he can't: "This is the kind of proof we've been seeking. This is good news."

Remune: There was more. In a late surprise session at Geneva, New York University immunologist Fred Valentine revealed that a novel therapeutic vaccine called Remune (the renamed Salk vaccine) had successfully boosted HIV-specific CD4 responses in 43 volunteers on HAART with below-detectable viral loads. The vaccine had produced very strong specific immune responses to various HIV antigens.

As scientists rushed back to their labs after Geneva, plans were already under way to expand studies of Remune, hydroxyurea, and other combinations. There were also countless new agents being tested that can boost immune responses (see "What's in the Pipeline").

Whether remission can be achieved and will allow people to control HIV in the long-term remains a billion-dollar question. As we've seen with protease inhibitors, we should expect to encounter many obstacles in the months ahead. But these new findings offer renewed hope. And equally important, they show real insight into how we can slow, if not stop, the virus.