New Weapon Attacks Latent HIV Reservoirs

November marked one year since the war against HIV took another frightening twist. It was learned that, like guerrillas sneaking into a sleeping army command post, the virus could conceal itself from combination drug therapy by hiding in resting CD4+ T cells--the immune cells that order destruction of such foreign invaders, yet themselves are primary targets of HIV. But November also marked the emergence of a new weapon in the fight against these latent viral reserves, a fight still far from won. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., announced during the 35th annual meeting of the Infectious Diseases Society of America, Nov. 12-15 at the Denver Convention Center, that his research group had significantly reduced the number of latently infected T cells in several subjects. The as-yet-unpublished study involved 26 HIV-infected patients. All received highly active antiretroviral therapy (HAART), generally a combination of at least three antiretroviral drugs including a protease inhibitor, which reduced viral load in their blood to undetectable levels. Twelve of the subjects continued to receive HAART, and the other 14 were given HAART plus interleukin-2 (IL-2), a regulatory protein of the immune system. "It's a very provocative and insightful thing to try." --Barton F. Haynes Fauci explains that the IL-2 activates the resting T cells, which then spit out the hidden virion, to be destroyed by HAART before it can replicate. After this treatment, no replication-competent virus could be found in resting T cells of three of the 14 subjects. A lymph-node biopsy performed on one of the three also failed to isolate replication-competent HIV. As encouraging as these preliminary findings are for at least some patients, they do not mean that other lymphatic beds are devoid of the virus, Fauci points out. Nor has the durability of the treatment been demonstrated. "We can't be lulled into thinking that's the end point," he cautions. "In fact, I would say we're not likely to eradicate the virus." Instead, he believes it may be possible to force the viral load low enough that the immune system could then contain it. "I hope IL-2 works," says Robert F. Siliciano, associate professor of molecular biology and genetics at Johns Hopkins University School of Medicine. He praises the approach as "courageous" but adds, "You've got to be sure you're getting every latently infected T cell." Even an extremely small number of latent viral cells can cause a resurgence of the infection. And toxicity can be associated with the release of cytokines during activation of all such cells, he notes. Douglas D. Richman, a pathology professor at the University of California, San Diego, says of the new work, "It's intriguing preliminary data, but in practice, it has created problems with patients." Misreporting of the results has brought patients into the clinics asking to be cured, he explains. Warning that the battle isn't over, Richman hopes for the development of safer and more potent drug regimens. and Infectious Diseases Tel: (301) 496-2263 www.niaid.nih.gov The Body: An AIDS and HIV Information Resource www.thebody.com Siliciano and Richman were senior authors on two papers published simultaneously last year that determined the existence of latent viral reservoirs among patients receiving combination therapy (J.K. Wong et al., Science, 278 :1291-5, 1997, and D. Finzi et al., Science, 278 :1295-1300, 1997). Fauci was senior author of a similar paper published just days later (T.W. Chun et al., Proceedings of the National Academy of Sciences, 94 :13193-7, 1997). The latter paper also showed that some of the hidden virus may not be latent, but very slowly replicating. Other viral reservoirs also may exist, particularly in cerebral spinal fluid and in semen (O. Bagasra et al., AIDS, 10 :573-85, 1996, and R.A. Byrn et al., Lancet, 350 :1141, 1997). Siliciano suggests that these pools may contain proviral DNA not susceptible to purgation by IL-2. Fauci acknowledges, "It's entirely conceivable, possibly even likely, that the virus is in compartments that we don't have access to." All the scientists agree that the worth of IL-2 plus HAART must be determined over many months, or even years, after the subjects discontinue therapy. However, Frederick L. Altice, assistant professor of medicine and director of the HIV in Prisons Program at Yale University School of Medicine, believes the new results from Fauci's group suggest an accelerating decay of the latent reservoirs. Siliciano says his team is preparing a paper on whether the reservoirs decay at all. Barton F. Haynes, chairman of the department of medicine at Duke University School of Medicine, assesses Fauci's method: "It's a very provocative and insightful thing to try, based on the pathophysiology of HIV infection. It's an important step along the way." Steve Bunk is a contributing editor for The Scientist.

New Weapon Attacks Latent HIV Reservoirs

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Steve Bunk

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December 1998

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