New Approaches in HIV Cure Research: functional or sterilizing?

The failure of antiretroviral therapy (ART) to eradicate HIV infection lies in the fact that HIV remains quiescent in latent reservoirs. Latently infected resting CD4+ cells carry transcriptionally silent HIV-1 and represent the predominant viral reservoir in patients on suppressive ART. Other cells may also act as reservoirs such as macrophages, dendritic cells and astrocytes.

HIV is a retrovirus that integrates into the host genome and as such, on cell division will be automatically present in both daughter cells. The mechanisms involved in the maintenance of HIV reservoirs are progressively deciphered.

An HIV cure could be envisaged as either sterilizing, equivalent to HIV eradication, or functional, equivalent to HIV remission.

The concept of a functional cure implies to deplete virus reservoirs to such an extent that a “controller” status is achieved. In this way, HIV is maintained at low levels for long periods of time in the absence of ART, equivalent to that observed in known HIV “Elite controllers”.

Approaches to deplete HIV reservoirs include “purging” these reservoirs by selective activation of latently infected cells (such as memory cells) in the presence of ART such that released virus may not infect and replicate in neighboring cells. Agents include histone deacetylase (HDAC) inhibitors, cytokines, as IL-15, and bryostatin, a protein kinase C activator.

In order to demonstrate a sustained virological response (functional cure), ART will ultimately need to be stopped in order to show that virus levels remain undetectable.

The current skepticism regarding treatment interruption means that inclusion criteria for patients in such studies will take in to consideration both pre ART and nadir CD4+ T-cell counts.

It is likely that a cocktail of potent anti-latency compounds will be needed in concert with intensified ART regimen to reach an HIV cure. This implies assessing the ratio between benefit and risk and clearly informing patients about ethical issues.

The next edition of the “International Workshop on HIV Persistence, Reservoirs and Eradication Strategies” will take place in Miami, Florida, 3-6 December 2013. Meanwhile, the scientists that met together at the last meeting will keep regular ties in order to implement the first proof-of-concept trials of HIV functional cure.