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‘Like insects in amber’: ART ‘freezes’ latent HIV reservoir
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The latent HIV reservoir is mostly formed soon after the initiation of treatment, suggesting that ART indirectly affects the host environment to favor the establishment of latently infected long-lived cells, researchers reported — a finding that could help guide future research into a cure for HIV.
“These researchers are proposing that the virus cycles in and out of the reservoir, and that it is the introduction of antiretroviral therapy that freezes the reservoir viruses in place, like insects in amber,” Rowena Johnston, PhD, vice president and director of research at amfAR, told Infectious Disease News.
While patients with HIV are on ART, HIV can persist in resting CD4+ T cells as a latent reservoir, despite the effective suppression of HIV replication. Even with early ART initiation, the reservoir can form, and discontinuation of ART usually results in the “rapid rebound of virus, indicating that although therapy suppresses viral replication, HIV-1 is able to persist in an infectious state for years,” Melissa-Rose Abrahams, MSc(Med), PhD, a research officer in the division of medical virology at the University of Cape Town’s Institute of Infectious Disease and Molecular Medicine, and colleagues wrote in Science Translational Medicine.
However, much is still unknown about the formation of the HIV latent reservoir, inhibiting progress toward a cure.
“The existence of a pool of T cells latently infected with HIV has proven a major barrier to attempts to cure the infection. These cells are not recognized as infected by the immune system and seem very long-lived, thus outlasting the effects of conventional HIV treatment,” said Infectious Disease News Chief Medical Editor Paul A. Volberding, MD, professor of medicine and director of the AIDS Research Institute at the University of California, San Francisco.
“To date, attempts to activate the latent virus without causing potentially dangerous inflammatory reactions have had at best modest success,” said Volberding, who was not involved in the study. “It is of importance to better characterize the cells and virus in the reservoir to design approaches to eliminate the reservoir and eventually effect a cure.”
Small study conducted among women
Abrahams and colleagues studied blood samples from nine women with HIV receiving ART who participated in the Centre for the AIDS Programme of Research in South Africa 002 cohort. The women were originally enrolled into the cohort during acute/primary HIV infection.
“It’s refreshing to see these researchers look at an understudied population — namely women — and in the region of the world most affected by HIV,” said Johnston, who was not involved in the study. “Even though more than half of all people in the world living with HIV are women, only a small fraction are represented in HIV cure research.”
According to the study, the researchers compared sequences of replication-competent viruses from resting peripheral CD4+ T cells with viral sequences circulating in blood that was collected longitudinally prior to therapy. They assessed the genetic makeup the replicating viruses found right before ART initiation and the viruses induced from the post-therapy latent reservoir and reported that, on average, 71% of the post-therapy viruses were genetically similar to the pretreatment viruses.
“A reservoir of HIV is formed within days of initial infection, and this reservoir cannot be cleared by antiretroviral therapy,” Johnston noted. “What is as yet unknown is whether that virus cycles in and out of the reservoir, or whether it enters the reservoir and stays for the duration of the person’s life.”
Findings can guide new strategies
Abrahams and colleagues noted a standing hypothesis that through untreated infection, the latent HIV reservoir is continuously being formed. However, the findings in their study suggest that this may not be the case because the proportion of genetical similarity is “far greater than would be expected if the reservoir formed continuously and was always long lived,” they wrote.
The researchers suggested that ART provides an opportunity for the “formation or stabilization” of the latent reservoir, and that these findings will provide a guide for new strategies targeting the reservoir formation near the time of ART initiation.
“More research is needed, but if these results are borne out, they suggest that introducing a curative intervention at the time of antiretroviral therapy initiation may have a profound effect on the reservoir, and may one day even eliminate the reservoir and cure HIV,” Johnston said. “While these data using a laboratory assay are thought-provoking, the real test will be to see what happens when a person living with HIV stops antiretroviral therapy. Will the viruses that emerge from the reservoir and reignite infection be the same as the ones present right before antiretroviral therapy? Time, and more research, will tell.”
Volberding said the study added “fascinating insight into the nature of HIV in the latent reservoir, suggesting that most of this pool of cells are infected during the initiation of ART, rather than at the time of initial infection.”
“This observation opens new areas of research that could well fundamentally change our attempts to eliminate this barrier to a cure,” he said. – by Marley Ghizzone
Reference:
Abrahams MR, et al. Sci Transl Med. 2019;doi:10.1126/scitranslmed.aaw5589.
Disclosures: Volberding reports serving as a chair of a data management committee for Merck. Abrahams and Johnston report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.