» Articles » PMID: 32654992

A Targeted Reactivation of Latent HIV-1 Using an Activator Vector in Patient Samples from Acute Infection

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.

Citing Articles

Effective and targeted latency reversal in CD4 T cells from individuals on long term combined antiretroviral therapy initiated during chronic HIV-1 infection.

Ngo M, Pankrac J, Ho R, Ndashimye E, Pawa R, Ceccacci R Emerg Microbes Infect. 2024; 13(1):2327371.

PMID: 38444369 PMC: 10967673. DOI: 10.1080/22221751.2024.2327371.


A Canadian Survey of Research on HIV-1 Latency-Where Are We Now and Where Are We Heading?.

Abdalla A, Guajardo-Contreras G, Mouland A Viruses. 2024; 16(2).

PMID: 38400005 PMC: 10891605. DOI: 10.3390/v16020229.


Proviral location affects cognate peptide-induced virus production and immune recognition of HIV-1-infected T cell clones.

Dragoni F, Kwaa A, Traut C, Veenhuis R, Woldemeskel B, Camilo-Contreras A J Clin Invest. 2023; 133(21).

PMID: 37698927 PMC: 10617777. DOI: 10.1172/JCI171097.


Targeted shock-and-kill HIV-1 gene therapy approach combining CRISPR activation, suicide gene tBid and retargeted adenovirus delivery.

Klinnert S, Schenkel C, Freitag P, Gunthard H, Pluckthun A, Metzner K Gene Ther. 2023; 31(3-4):74-84.

PMID: 37558852 PMC: 10940146. DOI: 10.1038/s41434-023-00413-1.


Addressing an HIV cure in LMIC.

Ismail S, Pankrac J, Ndashimye E, Prodger J, Abrahams M, Mann J Retrovirology. 2021; 18(1):21.

PMID: 34344423 PMC: 8330180. DOI: 10.1186/s12977-021-00565-1.


References
1.
Bruner K, Murray A, Pollack R, Soliman M, Laskey S, Capoferri A . Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med. 2016; 22(9):1043-9. PMC: 5014606. DOI: 10.1038/nm.4156. View

2.
Gunthard H, Wong J, Spina C, Ignacio C, Kwok S, Christopherson C . Effect of influenza vaccination on viral replication and immune response in persons infected with human immunodeficiency virus receiving potent antiretroviral therapy. J Infect Dis. 2000; 181(2):522-31. DOI: 10.1086/315260. View

3.
Gay C, DeBenedette M, Tcherepanova I, Gamble A, Lewis W, Cope A . Immunogenicity of AGS-004 Dendritic Cell Therapy in Patients Treated During Acute HIV Infection. AIDS Res Hum Retroviruses. 2017; 34(1):111-122. PMC: 5771540. DOI: 10.1089/aid.2017.0071. View

4.
Deeks S . HIV: Shock and kill. Nature. 2012; 487(7408):439-40. DOI: 10.1038/487439a. View

5.
Mbonye U, Karn J . Transcriptional control of HIV latency: cellular signaling pathways, epigenetics, happenstance and the hope for a cure. Virology. 2014; 454-455:328-39. PMC: 4010583. DOI: 10.1016/j.virol.2014.02.008. View