Researchers at George Washington University found a potential obstacle to discovering a cure for HIV. A “kick-and-kill” strategy using latency-reversing agents and natural killer CD8+ T cells to eliminate HIV reservoirs was unable to deplete replication-competent virus, they wrote in The Journal of Clinical Investigation.
Brad Jones, PhD, assistant professor of microbiology, immunology and tropical medicine at George Washington University, and colleagues found evidence that latent reservoirs are inherently resistant to CD8+ T cells — a hurdle that the researchers said may need to be overcome to cure HIV.
“We have identified a barrier,” Jones said in a press release. “It is difficult to understand the nature of that barrier right now. We used our most powerful combinations against these cells, and when the dust settled, we found that the virus was present at just as high levels as what we started with.”
Previous research has demonstrated that a fraction of CD4 cells in patients with HIV remain infected with a latent virus, even with the use of ART. It is believed that these cells do not express HIV antigens. Therefore, the immune system is unable to detect and fight against this latent reservoir. Although latency-reversing agents (LRAs) and CD8+ T cells have shown promise in eliminating infected cells during experiments with in vitro latency models, this kick-and-kill strategy has failed to reduce infectious viral reservoirs in clinical trials, according to the researchers.
“This lack of efficacy has generally been attributed to insufficient latency reversal and/or to suboptimal immune clearance, with substantial clinical efforts currently focused on enhancing these factors,” Jones and colleagues wrote. “The current study raises the alternative possibility that natural HIV reservoirs in ex vivo CD4+ T cells may possess additional barriers to CD8+ T cell-mediated elimination that are not reflected in latency models.”
For their study, the researchers used a standard quantitative viral outgrowth assay to measure viral reservoir in ex vivo CD4+ T cells from ART-treated patients with HIV. They found that cells treated with combinations of CD8+ T cells and LRAs had significant reductions in HIV DNA compared with untreated cells (P < .0001). However, there was no measurable decline in infectious viral reservoirs. Instead, there was an increasing trend in infectious units per million cells among CD4 cells that were treated with CD8+ T cells and LRAs or CD8+ T cells alone (P = 0.17).
Although CD8+ T cells were ineffective against lately infected cells, they recognized and eliminated cells that were newly infected with HIV, which suggests that their failure to reduce latent reservoir is not attributed to immune escape or CD8+ T cell dysfunction, according to the researchers.
“While the results are certainly not what we hope for, we have identified what might be an important barrier in killing HIV-infected cells,” Jones said in the release. “Now that we have a way to study it, there’s reason to think that we might be able to have more success than previous studies.” – by Stephanie Viguers
Disclosures: Two authors report being employees of Altor Bioscience Corporation, which manufactures a superantagonist used in the study.