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

Addressing an HIV cure in LMIC

“…These APCs will ultimately present HIV-1 antigens on MHC class II to CD4 + T cells with TCR specific to these HIV-1 antigens, leading to activated CD4 + T cells, which are now susceptible to HIV-1 infection and replication [ 168 ]. We hypothesize that this cycle of HIV-1 antigen presentation and activation of HIV-specific T cells leads to a skewing of the antigen-specificity of latently infected cells towards HIV-1 antigens [ 169 ]. This hypothesis is supported by the observation that most variants in the reservoir arose from strains circulating immediately prior to ART initiation [ 10 , 81 , 82 ]: once ART is initiated and HIV-1 antigens are cleared HIV-specific T cells will revert to a resting state en masse .…”

“…This hypothesis is supported by the observation that most variants in the reservoir arose from strains circulating immediately prior to ART initiation [ 10 , 81 , 82 ]: once ART is initiated and HIV-1 antigens are cleared HIV-specific T cells will revert to a resting state en masse . The use of HIV-1 antigens as an immunogen could specifically reactivate and eliminate this substantial portion of the reservoir [ 169 ], We have recently developed heterogenous virus-like particle (VLP) derived from the quasi-species of five HIV-1 infected patients [ 169 , 170 ]. This VLP formulation contains all the HIV-1 proteins and is morphologically identical to wild type HIV-1 but lacks genomic RNA and has additional mutations to ensure it is not replication-competent and can be tested as a cure therapeutic [ 170 ].…”

“…However, for this therapeutic to be useful in LMIC, the effect of subtype congruency between VLP and patient must be ascertained. Additionally, while activation of the latent HIV-1 pool in response to VLP has been observed using cells form patients treated during both acute/early [ 169 ] and chronic infection, it must be ascertained if the reservoir of individuals treated during chronic infection is as heavily skewed towards HIV-specific T cells. Individuals who initiated ART soon after infection will have been exposed to fewer non-HIV antigens while viremic, but only a minority of PLWH in LMIC initiated treatment during acute infection.…”

Quantifying the clonality and dynamics of the within-host HIV-1 latent reservoir

“…An example of this was demonstrated by Simonetti et al (2016) who observed extensive clonal expansion in the presence of cancer metastases, suggesting that an infected cells harboring a replication-competent sequence variant proliferated in response to a cancer antigen. Similarly, others have hypothesized that a chronic state of immune activation, caused by the continuous activation of infected cells leading to the release HIV-1 antigens, drives the clonal expansion of HIV-1 targeting reservoir cells ( Mann et al. 2020 ).…”

Shock and kill, but don't miss the target

“…Mann et al study describes a “shock and kill” strategy that employs the activator vector termed ACT-VEC, a polyvalent virus like particle (VLP) formulation combining HIV quasi-species from five chronic HIV-infected volunteer's plasma samples taken immediately prior to cART initiation [ 7 ]. ACT-VEC are viral-like particles similar to human papillomavirus (HPV) VLPs used in multivalent HPV vaccines, with the advantages of increased antigenic breadth and generation a broader immune response, along with a suitable margin of safety and efficiency.…”