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

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...

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Bibliographic Details
Published in:EBioMedicine 2020-09, Vol.59, p.102853-102853, Article 102853
Main Authors: Mann, Jamie F.S., Pankrac, Joshua, Klein, Katja, McKay, Paul F., King, Deborah F.L., Gibson, Richard, Wijewardhana, Chanuka N., Pawa, Rahul, Meyerowitz, Jodi, Gao, Yong, Canaday, David H., Avino, Mariano, Poon, Art F.Y., Foster, Caroline, Fidler, Sarah, Shattock, Robin J., Arts, Eric J.
Format: Article
Language:English
Subjects:
Activator vector (ACT-VEC)
Adult
Antiretroviral Therapy, Highly Active
Biomarkers
CD4 Lymphocyte Count
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
CD4-Positive T-Lymphocytes - virology
Female
Gene Expression Regulation, Viral - drug effects
Gene Order
Genetic Vectors - genetics
High-Throughput Nucleotide Sequencing
HIV Infections - drug therapy
HIV Infections - immunology
HIV Infections - virology
HIV-1 - physiology
HIV-1 Cure
HIV-1 Latency
Humans
Immunophenotyping
Immunotherapy
Male
Middle Aged
Monocytes - immunology
Monocytes - metabolism
Monocytes - virology
Research Paper
RNA, Viral
Transcriptional reactivation
Viral Load
Virus Activation
Virus Latency
Virus Replication - genetics
Virus-Like Particles
Young Adult
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Summary: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. 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. 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. 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. NIH and CIHR
ISSN:2352-3964
2352-3964
DOI:10.1016/j.ebiom.2020.102853