Treating latent HIV reservoirs with latency-reversing agents and autologous CD8 + T cells fails to eliminate the replication-competent virus, a new study, published in the Journal of Clinical Investigation , reports.

The existence of a reservoir of latently infected resting CD4 + T cells is thought to be a major barrier impeding viral eradication. During a quiescent state, they do not appear to express HIV antigens and, therefore, are not targeted by the immune system.

The recent kick-and-kill paradigm aims to combine latency-reversing agents (LRAs) with immune effectors, such as CD8 + T cells, to overcome this quiescent state and eliminate infected cells. This approach has failed to achieve hoped-for reductions in infectious viral reservoirs.

Dr. Bruce D. Walker – from Massachusetts Institute of Technology, Massachusetts General Hospital, and Harvard University – and colleagues investigated whether the coculture of potent CD8 + T cells in combination with LRAs could reduce latent HIV reservoirs from ex vivo CD4 + T cells of HIV- infected, antiretroviral drug-treated individuals.

Their approach significantly reduced cell-associated HIV DNA, but it failed to deplete replication-competent virus. The CD8 + T cells recognized and eliminated CD4 + T cells that were newly infected with autologous reservoirs, excluding both immune escape and CD8 + T-cell dysfunction as explanations.

"The elimination of cells harboring defective HIV proviruses is needed to account for the magnitude of these reductions, given that these outnumber intact proviruses by approximately 20 to 1," the researchers noted.

"Our results suggest the elimination of a subset of cells harboring defective HIV proviruses, while those harboring infectious proviruses displayed a resistance to CD8 + T cell-mediated killing that have not been observed in latency models, and which may have to be overcome to cure infection," they wrote.

"We suggest that the unexpected complexity raised by the current study should prompt more widespread testing of kick-and-kill strategies against ex vivo patient CD4 + T cells, despite the challenges involved," the authors concluded.

"The identification of successful cases of reservoirs reductions in the HIVE assay would provide clues into the nature of potential novel mechanisms of resistance reported in this study that, in turn, would open up novel angles from which to target the therapeutic elimination of infectious viral reservoirs in people living with HIV, "the researchers noted.

Dr. Jintanat Ananworanich from Walter Reed Army Institute of Research, Silver Spring, Maryland, said, "Most striking is the discovery that proves how clever HIV is in ensuring its own survival. Even under the optimal experimental conditions, the CD8 + T cell that forms our core immune defense against virus is unable to get rid of cells that have live or replicating HIV. In fact, these cells appear resistant to immune defense, and our inability to get rid of them is a major obstacle to HIV cure. "

"The best way to limit the amount of HIV in the body is to start HIV medications soon after infection," she said. "Physicians have a big role in encouraging their patients to get regular HIV testing, and if they have HIV, to start treatment immediately and take it regularly."