FeaturePerspective

‘Like insects in amber’: ART ‘freezes’ latent HIV reservoir

Rowena Johnston, PhD
Rowena Johnston

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 in Science Translational Medicine.

“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 people with HIV are on ART, HIV can persist in resting CD4+ T cells as a latent reservoir, despite the effective suppression of HIV-1 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.

However, much is still unknown about the formation of the HIV-1 latent reservoir, inhibiting progress toward a cure. Understanding when it forms may inform future research.

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 (CAPRISA) 002 cohort. The women were originally enrolled into the cohort during acute/primary HIV-1 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.

Abrahams and colleagues assessed the genetic makeup the replicating viruses found right before ART initiation and the viruses induced from the post-therapy latent reservoir. They 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.”

The researchers noted a standing hypothesis that through untreated infection, the latent reservoir is continuously being formed. However, these findings 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.

Abrahams and colleagues 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.” – by Marley Ghizzone

Reference:

Abrahams MR, et al. Sci Transl Med. 2019;doi:10.1126/scitranslmed.aaw5589.

Disclosures: Abrahams and Johnston report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Rowena Johnston, PhD
Rowena Johnston

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 in Science Translational Medicine.

“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 people with HIV are on ART, HIV can persist in resting CD4+ T cells as a latent reservoir, despite the effective suppression of HIV-1 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.

However, much is still unknown about the formation of the HIV-1 latent reservoir, inhibiting progress toward a cure. Understanding when it forms may inform future research.

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 (CAPRISA) 002 cohort. The women were originally enrolled into the cohort during acute/primary HIV-1 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.

Abrahams and colleagues assessed the genetic makeup the replicating viruses found right before ART initiation and the viruses induced from the post-therapy latent reservoir. They 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.”

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The researchers noted a standing hypothesis that through untreated infection, the latent reservoir is continuously being formed. However, these findings 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.

Abrahams and colleagues 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.” – by Marley Ghizzone

Reference:

Abrahams MR, et al. Sci Transl Med. 2019;doi:10.1126/scitranslmed.aaw5589.

Disclosures: Abrahams and Johnston report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Paul A. Volberding

    Paul A. Volberding

    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. To date, attempts to activate the latent virus without causing potentially dangerous inflammatory reactions have had at best modest success. 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.

    The current study adds 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.

    • Paul A. Volberding, MD
    • Infectious Disease News Chief Medical Editor
      Professor of medicine
      Director of the AIDS Research Institute
      University of California, San Francisco

    Disclosures: Volberding reports serving as a chair of a data management committee for Merck.