The Effect of Latency Reversal Agents on Primary CD8 + T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication

• Latency reversal agents can reactivate HIV-1 expression in latently infected cells.
• CD8 T cells from HIV-1 infected patients did not eliminate reactivated latently infected cells.
• This finding can partially be explained by our data showing that latency reversal agents affect the function of CD8 + T cells.Latently infected CD4 + T cells are a major barrier to the cure of HIV-1 infection. One strategy of eliminating these cells involves inducing viral transcription with small molecules (latency reversal agents or LRAs) which would result in the recognition of these cells by the immune system. We show here that CD8 + T cells were not able to eliminate CD4 + T cells from HIV-1-infected patients following stimulation with LRAs. Our data suggests that this may be partially because some LRAs affect the function of CD8 + T cells. Thus it will be critical to select LRAs that do not cause immune suppression.

Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4 + T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4 + T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8 + T cells were not able to eliminate autologous resting CD4 + T cells that had been reactivated with these drugs. We tested the hypothesis that the drugs affected primary CD8 + T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8 + T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8 + T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies.