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April 27, 1999

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"Silent" HIV Infection Lasts A Lifetime

Hopkins Physicians Urge Patients to Keep Taking Anti-HIV Medication

In 1995, researchers at Johns Hopkins discovered HIV (human immunodeficiency virus) evades anti-viral drugs by hiding in the immune system, infecting certain white blood cells, called T cells, and then going to sleep, or turning off. In the May Nature Medicine, the same team reports this silent infection persists for a lifetime.

"This doesn't mean a cure for HIV is impossible, but it is an obstacle," says Robert Siliciano, M.D., Ph.D., senior author on the report. "And it emphasizes that patients need to stay on their medication, possibly for the rest of their lives."

However, not all news from the study was bleak. The study patients, who kept to their strict drug regimens under supervision from physicians at the Johns Hopkins Moore HIV Clinic, all had undetectable levels of HIV in their blood and no signs of AIDS (acquired immune deficiency syndrome).

"The good news is that patients who comply with their therapy are able to keep the virus suppressed for long periods," says Joel Gallant, M.D., who directs the Moore Clinic. "We have assumed that therapy for HIV patients would have to be long-term or even lifelong. This study suggests that is still the case. But the study also suggests that HIV-infected patients can still live long, healthy lives without symptoms, provided they are rigorous about taking their medications." When taken as prescribed, combination therapy (the so-called "drug cocktails") of older anti-HIV drugs like AZT and newer protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs), reduces the amount of circulating virus to undetectable levels in most patients. The immune system remains relatively healthy and the collection of diseases that signal AIDS is staved off.

But the latent form of HIV can wait out even decades of anti-HIV therapy. First, it integrates its genetic code into the DNA of dormant, or resting, T cells. While the cells are in their resting phase, the HIV genes inside them remain switched off a silent infection. When the dormant cells are reactivated, say by a simple infection like the flu, the HIV genes reemerge, co-opting the cell machinery to make millions of copies of the virus.

Anti-HIV medication suppresses this flood of virus. But without medication to stop it, the virus can replicate out of control, eventually causing AIDS.

"We've seen patients without detectable virus in their blood come off their medication, and within a few weeks or months they experience a rebound, with high levels of virus in their blood," says Gallant. "Now we know that this reservoir of dormant T cells is responsible."

To measure how long the reservoir survives, the team followed 34 patients for two years, periodically drawing blood samples. Using a sophisticated cell-sorting technique developed at Hopkins, they siphoned off the dormant T cells that carried HIV genes and counted them. They found the number of silently infected cells remained stable, or declined very little. A statistical projection showed the reservoir lasting 60 years or more.

Siliciano added that because so few T cells only one in one million harbor the silent infection, they are impossible to detect without extremely precise methods. In the Nature Medicine article the team reports finding the infected T cells in 32 of 34 patients. Since writing the article, they have found silently infected cells in the other two patients.

Diana Finzi, a graduate student in Siliciano's lab, is lead author on the paper and did much of the work isolating the dormant T cells. Researchers from Harvard University, Cornell University, and the National Institute of Allergy and Infectious Diseases contributed to the study. The work was funded by the National Institute of Allergy and Infectious Diseases.

Relevant Web sites:
Hopkins AIDS Service: http://www.hopkins-aids.edu/
Siliciano lab: http://www.med.jhu.edu/bcmb/faculty/siliciano.html

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