Combination antiretroviral therapy (cART) has led to a major reduction in HIV-related mortality and morbidity but HIV can still not be cured and treatment must be continued for life. The most significant barrier to curing HIV is the establishment of a latent or “silent” infection in resting CD4+ T cells. In latent HIV infection, the virus is able to integrate into the host cell genome, but does not proceed to active replication. One potential approach to eliminate latently infected cells is to promote viral production in these cells. If this is done in a patient on cART, subsequent rounds of viral replication will be inhibited and the infected cell will die by either virus induced cytolysis or immune mediated clearance. 

We have successfully demonstrated that latency can be established via direct infection of resting CD4+ T-cells following incubation with chemokines such as CCL19. Using this model, we have screened compounds that may potentially activate latency and confirmed that histone deacetylase inhibitors (HDACi), alone or in combination, are potent activators of latency. Given these in vitro findings, we recently examined the effects of multiple doses of the HDACi, vorinostat, on activating latency in HIV-infected patients receiving cART (n=20). In a single arm, single site observational study, we demonstrated that vorinostat induced a significant increase in cell associated HIV RNA (a marker of HIV transcription) but no significant changes in cell associated HIV DNA (a marker of the number of infected cells). 

Taken together, these data demonstrate that activation of latent HIV is possible both in vitro and in vivo. Although the HDACi vorinostat can activate HIV latent infection in the majority of patients on cART, it is likely that additional strategies will be required to eliminate latently infected cells. These strategies could potentially include a combination of activating agents or alternatively the combination of an HDACi with immune modulation using a therapeutic vaccine or interventions that reduce antigen-specific T-cell exhaustion. 

Successfully eradicating HIV latency is complex and will likely require multiple combined strategies. If successful, this will allow patients the opportunity to cease cART which will have a profound impact on individual lives as well as managing the broader HIV epidemic.