Only a small portion of latently infected cells are reactivated by latency-reversing agents.
Recent findings challenge the current “shock and kill” approach to eliminating HIV, indicating the need to explore alternative options for treating the disease, according to a study published in the journal eLife.
The study found that the “shock and kill” approach proposes the use of latency-reversing agents (LRAs) to force infected cells to produce HIV again, while maintaining antiretroviral therapy (ART) to prevent the occurrence of new infections. As a result, the reactivation of HIV would cause the shocked cells to be killed directly or indirectly by ART. However, currently available LRAs have proven ineffective, according to the study.
Lead study author Emilie Battivelli, PhD, postdoctoral research scholar at the Buck Institute, aimed to investigate the ability of LRAs to reactivate HIV infection in latent cells. By developing a new dual-fluorescent HIV-1 reporter virus, called HIVGKO, the researchers were able to determine which latently infected cells are reactivatable by current candidate LRAs.
The authors discovered that only 5% of latently infected cells are reactivated by LRAs. Through sequencing analysis of reactivatable versus non-reactivatable cell populations, the authors determined that the integration sites were distinguishable between viruses that reactivate and those that do not in response to LRAs.
“Several obstacles can explain the failure of LRAs, but the biggest challenge to date is our inability to accurately identify the number of cells in the HIV latent reservoir — the group of cells that are infected with HIV but do not produce new infections,” Dr Battivelli said in a press release.
Although the “shock and kill” method may be helpful, the findings challenge its use in the less readily reactivatable population. The authors indicated that alternative strategies to control the latent HIV reservoir need to be explored.
“Perhaps this cell population should instead be ‘blocked and locked’ using latency-promoting agents, as previous research has suggested,” Eric Verdin, MD, senior author, president and CEO of the Buck Institute, said in the press release.
“For a functional cure, having non-reactivatable latent HIV genomes would surely be preferable to a lifetime of chronic active infection,” he concluded.
Battivelli E, Dahabieh MS, Abdel-Mohsen M, et al. Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4+ T Cells. eLife. 2018. Doi: 10.7554/eLife.34655