A targeted reactivation of latent HIV-1 using an activator vector in patient samples from acute infection.

EBioMedicine

Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5C1, Canada; Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States. Electronic address:

Published: September 2020

AI Article Synopsis

  • A latent reservoir of HIV in resting memory CD4 T cells persists during anti-retroviral treatment, leading to potential viral resurgence when treatment stops.
  • Previous attempts to activate this reservoir using latency reversing agents (LRAs) have not effectively reduced the latent HIV population or achieved sustained remission without ongoing treatment.
  • The study shows that a new formulation called Activator Vector (ACT-VEC) can more effectively reactivate latent HIV in CD4 T cells than existing LRAs, suggesting potential new strategies for targeted HIV cure approaches.

Article Abstract

Background: During combined anti-retroviral treatment, a latent HIV reservoir persists within resting memory CD4 T cells that initiates viral recrudescence upon treatment interruption. Strategies for HIV-1 cure have largely focused on latency reversing agents (LRAs) capable of reactivating and eliminating this viral reservoir. Previously investigated LRAs have largely failed to achieve a robust latency reversal sufficient for reduction of latent HIV pool or the potential of virus-free remission in the absence of treatment.

Methods: We utilize a polyvalent virus-like particle (VLP) formulation called Activator Vector (ACT-VEC) to 'shock' provirus into transcriptional activity. Ex vivo co-culture experiments were used to evaluate the efficacy of ACT-VEC in relation to other LRAs in individuals diagnosed and treated during the acute stage of infection. IFN-γ ELISpot, qRT-PCR and Illumina MiSeq were used to evaluate antigenicity, latency reversal, and diversity of induced virus respectively.

Findings: Using samples from HIV patients diagnosed and treated at acute/early infection, we demonstrate that ACT-VEC can reverse latency in HIV infected CD4 T cells to a greater extent than other major recall antigens as stimuli or even mitogens such as PMA/Iono. Furthermore, ACT-VEC activates more latent HIV-1 than clinically tested HDAC inhibitors or protein kinase C agonists.

Interpretation: Taken together, these results show that ACT-VEC can induce HIV reactivation from latently infected CD4 T cells collected from participants on first line combined antiretroviral therapy for at least two years after being diagnosed and treated at acute/early stage of infection. These findings could provide guidance to possible targeted cure strategies and treatments.

Funding: NIH and CIHR.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502668PMC
http://dx.doi.org/10.1016/j.ebiom.2020.102853DOI Listing

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