AIDSWEEKLY Plus, Monday, 3 November 1997
Daniel J. DeNoon, Senior Editor

Latent, replication-competent HIV persists in memory cells long after highly active antiretroviral therapy (HAART) has essentially ended virus production.

Should drug treatment stop for any reason, the residual virus appears capable of restoring high-level HIV replication and progressive disease if HAART is not resumed.

"Latently infected CD4(+) T cells represent the last hurdle to overcome in eradicating virus by antiretroviral therapy," said Robert Siliciano of Johns Hopkins University, Baltimore, Maryland. "It is important to reach these cells because their biologic function is to persist."

Siliciano spoke during the opening session of the American Society for Microbiology's 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 28 to October 1, 1997, in Toronto, Ontario, Canada.

HAART - combination therapy that typically includes an HIV protease inhibitor and two HIV reverse-transcriptase inhibitors - can reduce HIV viral load to undetectable levels. This effect can continue indefinitely for the great majority of patients who are able to maintain treatment despite its side effects and demanding schedule.

The most pressing issue in antiretroviral therapy is whether continued HAART can eventually eliminate HIV so that all treatments can be stopped. This depends on the size and persistence of the reservoir of latently infected cells, as HIV or the immune system kills actively infected cells.

Siliciano and others have theorized that latently infected cells come from CD4(+) T cells that have become infected with HIV but that survived long enough to develop into inactive, memory cells. Such cells would carry the HIV DNA preintegration complex. Upon activation, they would produce infectious HIV.

"Our ability to eliminate HIV by antiretroviral therapy depends upon the frequency of these cells and their decay rate," Siliciano said.

Experiments underway at Johns Hopkins confirm that resting T cells from HIV infected patients carry integrated viral DNA and can produce replication-competent virus when activated. Other data from the experiments:

* The frequency of HIV infected cells is very low: fewer than one in 10,000 resting cells. "The low frequency was surprising to many," Siliciano said.

* Similar levels of HIV infected resting cells are found in the plasma and in the lymph nodes.

* Resting cells bearing HIV DNA have a memory phenotype.

* Cells don't tend to accumulate in the reservoir of latently infected cells.

Although cells bearing HIV DNA produced HIV upon activation, the researchers found that only a very small percentage of these HIV(+) resting cells were actually replication competent.

"Only 10(7) cells in the body have latent HIV infection," Siliciano said. "Only a fraction of these produce HIV."

The researchers then sought to detect this reservoir of infection in patients receiving HAART. They enrolled a cohort of "fanatically compliant" patients and considered for evaluation only those whose viral load levels remained below the limit of detection (<200 copies/mL).

Replication-competent virus could be detected and isolated from activated latent cells from all of the patients.

"These results suggest that replication-competent virus can persist," Siliciano said. "The question is how long? The answer is we still don't know. Analysis suggests that to do longitudinal studies will take quite a long time."

The studies showed no relationship between the frequency of latently infected cells and time on HAART. There were no appreciable differences in the size of the reservoir between long-term HAART patients and patients who had never received HAART.

"These results suggest that this is a relatively stable reservoir," Siliciano said.

Interestingly, the virus produced by the latent cells derived from the HAART patients showed no sign of resistance to drugs included in the HAART regimen.

"This reservoir represents archival virus from earlier periods of infection," Siliciano said. "Virus elimination may be accelerated by strategies that directly target this viral reservoir."

Other research groups have initiated clinical studies in which interleukin 2 is added to the HAART regimen. It is hoped that the cytokine will activate latently infected cells, effectively flushing out this viral reservoir.

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