A defining characteristic of the human immunodeficiency virus is its ability to permanently integrate into the genome of an infected cell. Since a subset of viruses become latent shortly after infection, a reservoir of HIV persists that is not impacted by antiretroviral therapy (ART), yet retains the ability to restart viremia should ART be discontinued. This viral trick creates a life-long requirement for ART in most individuals in order to maintain virologic control, and no cure.
Latent HIV shares many of the characteristics of a genetic disease, so it was no coincidence that HIV became an early target for gene therapy. Despite the complexity of these procedures, the potential for long-lasting effects, especially if stem cells could be modified, was appealing when measured against life-long ART. Initial studies focused on the idea of protecting uninfected cells by adding anti-HIV factors, and early trials established a portfolio of anti-HIV candidates and safety, although they stopped far short of demonstrating efficacy.
More recently, applications of gene therapy have been expanded to include consideration of a cure. However similar to ART, gene therapies aimed at simply protecting uninfected cells are not expected to impact the latent reservoir. Therefore approaches being considered combine transient drug treatments to ‘shock’ HIV awake with engineering HIV-specific immune cells that would deplete the infected cells so revealed. Other strategies under development are taking advantage of our deeper understanding of the biology of the host-virus interaction. Recent advances in genome editing based on targeted nucleases are allowing for the possibility of removing host dependency factors, such as the CCR5 coreceptor, or editing anti-viral restriction factors to shift the balance in favor of the host. Finally, the HIV genome itself is a tantalizing target for disruption, since nucleases can also be engineered to specifically recognize and disable this genetic parasite, if only the significant challenges of in vivo delivery could be met.
Antiretroviral drugs have made extraordinary progress over the last 30 years, turning HIV into a chronic and medically managed disease, but they have reached a limit in the latent HIV reservoir. Gene, immune and cell-based therapies may yet prove to be part of the final push that is needed to achieve a cure.