By David N. Leff

Science Editor

In the barracks, they still tell the story of the tough, burly Marine sergeant who was training his raw recruits in armed, hand-to-hand combat. All of a sudden, he found himself pinned to the ground by one of his boot-camp trainees. "So you see, men," the sergeant barked, "now and then the enemy overpowers YOU!"

A similar surprise effect occurs in AIDS therapy. By now, the anti-HIV, multi-drug cocktail widely and optimistically known as HAART - highly active antiretroviral therapy - with its "profound suppression of plasma viremia in HIV-infected individuals," observed virologist/immunologist Tae-Wook Chun, "has resulted in a highly beneficial clinical effect and a dramatic decrease in the death rate attributable to AIDS in the U.S. and other developed countries."

That's the upside. One of the downsides - that now and then the enemy does the overpowering - "is the persistence," Chun continued, "of reservoirs of HIV [which have] posed a sobering challenge to the long-term control or eradication of HIV in infected individuals receiving HAART."

Other drawbacks to the multidrug regimen include its very high cost to the patient, the cumbersome complexity of popping handfuls of varied pills on a strict daily schedule, and the buildup of toxic side effects. (See BioWorld Today, June 2, 1999, p. 1; and July 21, 1998, p. 1.)

Little wonder that so many HIV-positive people give up on HAART, once they see the threat of AIDS dwindling. The more so that the treatment often drives down the number of viral particles in their blood "to below the level of detectability." But that doesn't mean zero. Once HAART lowers the patient's blood count - as well as his guard - the replication-competent virus hibernates doggo inside memory T cells, sequestered and safe from those antiretroviral and protease drugs.

Chun and Anthony Fauci, director of NIAID, the National Institute of Allergy and Infectious Diseases in Bethesda, Md., are co-authors of a "Perspective" essay in today's Proceedings of the National Academy of Sciences (PNAS), dated September 28, 1999. Its crisp title: "Latent reservoirs of HIV: Obstacles to the eradication of virus."

Plea Bargaining Over Doing Time On HAART

"There is no question," the authors point out, "that the latent HIV reservoir in the pool of resting CD4⁺ T cells persists in HIV-infected individuals receiving HAART for considerable periods of time. [But] the precise duration of the half-life of this viral reservoir has been debated." Their paper cites two contradictory studies, one of which concludes that a HAART compliance verdict should run for at least seven to 10 years on those pills; the other, for 60 years to life. These throw-away-the-key sentences derive from findings that the half-life of the latent virus is 6.2 months (meaning seven to 10 years time served) to 44 months (60 years or more). Both estimates assume that the latency safe-house reservoir contains only 100,000 infected cells and that no other viral reservoirs exist in the subject's body.

But the co-authors make the point that "other potential tissue reservoirs of HIV [do] exist and include the brain, gut-associated lymphoid tissue, bone marrow and genital tract, among other organs." Hence, the virus is quick to rebound when a person drops out of HAART.

What revives and reactivates this dormant virus, they point out, "is a natural occurrence" - the interleukin-2, interleukin-6 and tumor necrosis factor released by the immune system to counteract inflammation. They "speculated that induction of HIV by this combination of cytokines may in part explain the commonly observed reappearance of detectable plasma viremia in HIV-infected individuals in whom HAART has been discontinued."

Seeking to reprieve that life sentence, Chun and Fauci propose a string of latency-curbing strategies, notably:

• The use of immune enhancers to partially reconstitute immune competency.

• Therapeutic HIV-specific vaccines.

• Intermittent IL-2 administration, along with HAART.

Is 100 Percent Viral Extirpation Doable?

Proving somehow, some day, the truly total eradication of latent HIV from its reservoir, the PNAS paper observed, "will only come from clinical trials in which therapy is discontinued in individuals who have become aviremic on [HAART] therapy." Meanwhile, they suggest "regimens of structured drug holidays," as respites from the multi-pill ordeal. But in the long run, the outlook for 100 percent viral eradication, the co-authors reiterate, is "problematic."

A companion paper in today's PNAS bears the title: "An anti-CD45RO [memory T cell] immunotoxin eliminates T cells latently infected with HIV-1 in vitro." Its senior author is cancer immunologist Ellen Vitetta, at the University of Texas Southwestern Medical Center in Dallas.

She and her co-authors constructed their T-cell-killing agent from a sequence of the powerful ricin toxin chain, harnessed to monoclonal antibodies. Then after exposing peripheral blood mononuclear cells from healthy donors to a two-hour session in vitro with HIV-1 virus, they sicced their immune toxin on the cells.

The major results from these experiments, Vitetta reported, "indicate that the anti-CD45RO immune toxin eliminates more than 99 percent, of either M-tropic or T-tropic virus produced by the latently infected cells."

She then posed "a key question emerging from our findings - whether this immune toxin also will eliminate the more 'conventionally defined' latent cells from patients on HAART. ... at the expense of significantly compromising the immune system?"