A chronic, survivable condition is better than a death sentence, but it isn’t a cure. This limbo is what HIV patients endure while they are on combined antiretroviral therapy (cART). Unfortunately, cART has no effect on latent HIV reservoirs, which can always support a resurgence of HIV, so HIV patients must stay on treatment to ensure that HIV remains suppressed.
To help bring about cART-free remission—a cure—scientists based at the University of Western Ontario and the University of Bristol (United Kingdom) have developed a latency reversal agent that consists of a multivalent HIV-1-derived virus-like particle (HLP). They describe it as a “shock and kill” biotherapeutic that targets and activates CD4+ T cells through their HIV-1-specific T cell receptor.
The scientists demonstrated the effectiveness of their HLP in a new study. Using blood samples from 32 participants who were living with chronic HIV from the United States, Uganda, and Canada, and who were on stable cART for a median of approximately 13 years, the scientists found that their HLP was able to specifically target just the immune cells containing latent HIV reservoir and purge these cells of their HIV, a critical step toward an HIV-1 cure.
The scientists detailed their findings in the journal Emerging Microbes and Infections, in an article titled, “Effective and targeted latency reversal in CD4+ T cells from individuals on long term combined antiretroviral therapy initiated during chronic HIV-1 infection.”
“Even after 5–20 years on stable cART, HLP could target CD4+ T cells harboring latent HIV-1 reservoir resulting in 100-fold more HIV-1 release into culture supernatant than by common recall antigens, and 1,000-fold more than by chemotherapeutic LRAs,” the article’s authors wrote. “HLP induced release of a divergent and replication-competent HIV-1 population from people living with HIV-1 on cART.
“These findings suggest HLP provides a targeted approach to reactivate the majority of latent HIV-1 proviruses among individuals infected with HIV-1.… HLP represents a cost-effective antigen-driven biotherapeutic, administered by intramuscular injections, that eliminates the HIV-1 latent reservoir and provides a potential cure (or remission) for the 25-plus million living with HIV-1 and receiving stable cART.”
The scientists, who were led by Eric J. Arts, PhD, professor of microbiology and immunology at the University of Western Ontario, and Jamie F.S. Mann, PhD, senior lecturer vaccinology and immunotherapies at the University of Bristol, suggest that their HLP approach could bring us closer to meeting a goal set by the World Health Organization (WHO), the Global Fund, and UNAIDS. This goal is to end the HIV and AIDS epidemic by 2030.
HLPs are dead HIV particles hosting a comprehensive set of HIV proteins that increase immune responses without infecting a person. When compared with other potential cure approaches, HLP is an affordable biotherapeutic and can be administered by intramuscular injection—similar to the seasonal flu vaccine.
“The development of this HIV cure was 10 years in the making,” Arts said. “With strong support from our collaborators in the United States, Canada, and Uganda, we have observed a striking ability of HLP to drive out the last remnants of HIV-1, which we hope will provide an affordable cure for all.”
About 39 million people are infected with HIV, which is a retrovirus that attacks the body’s immune system. Approximately 95% of people living with HIV have chronic HIV—where the virus is slowly causing a slow destruction of the patients’ immune systems when they initiated lifelong cART.
While cART is effective at treating HIV, it has been unable to completely eliminate the virus from the body. This is because of the virus’ ability to create a latent reservoir—where it hides dormant inside of cells, safe from detection.
“Over time, the virus grows more diverse within a single individual that is not on treatment which makes it more difficult to target,” said co-lead author Ryan Ho, a master’s student in the department of microbiology and immunology. “This formulation we’ve crafted covers the theoretical diversity so it can reach the HIV-1 in all those people living with HIV.”
Minh Ha Ngo, PhD, lead author and postdoctoral scholar in the department of microbiology and immunology, says one concern expressed among people living with HIV for years is that continued use of cART could lead to the virus becoming unreachable and unable to be eliminated. The results of this study, by contrast, demonstrate that combining HLP with cART is still able to trigger the latent reservoir, even in chronic cases. If these dormant latent reservoirs can be awakened, then they can be eliminated from the body.
“Owing to its high mutation rate, HIV exhibits remarkable genetic diversity, resulting in different viral subtypes; some of which predominate in particular regions of the globe,” Mann said. “We were excited to see preliminary evidence that our HLP cure therapy reverses latency irrespective of the subtype of the individual’s infection. Whilst this needs to be explored further, it hints at the global applicability of our approach.”
In the future, researchers plan to test HLP on a larger representative HIV cohort with subtype C infections, which includes people living in South Africa, Ethiopia, Vietnam, and India. This would help determine if the treatment strategy is effective for most people living with acute and chronic HIV.
Current studies involve confirming a lack of toxicity in preparation for human clinical trials.
