Work

BCL-2 inhibitor sensitizes the latent HIV reservoir to elimination by CTLs

Year: 2017

Type: article

Abstract: Background: 'Kick-and-kill' strategies have shown promise in primary-cell models of latency, but have yet to show broad success in ex vivo patient samples.Our studies have found that latent reservoirs resist elimination, despite treatment with combinations of CTLs targeting non-escaped HIV epitopes and strong LRAs.Cummins et al recently observed elevated levels of the anti-apoptotic protein BCL-2 in CD4+ TCM-cells from HIV-infected individuals, which may increase infected cell resistance to elimination.Here, we investigate the ability of BCL-2 inhibitor 'venetoclax' to remove this barrier.Methods: Reservoir reduction was assessed in an HIV eradication assay using various CTL immune effectors in combination with/without venetoclax and the following lras: bryostatin, PMA/Ionomycin, and CD3/CD28 antibodies.Resting CD4+ T-cells were co-cultured with lras and ctls for 3 days with arvs, and then measured for cell-associated HIV DNA (ddpcr) and replication competent virus by quantitative viral outgrowth assay (QVOA).Results: Treatment of a primary cell model of latency model (Cultured TCM model), with either bryostatin alone or bryostatin with venetoclax, led to significant decreases in HIV DNA and replication competent reservoir.In ex vivo samples from ARV-treated participants, treatment with LRAs in combination with CTL immune effectors led to significant decreases in HIV DNA (p<0.0001,n=9), but no decreases in replication competent virus were observed (trend towards increase, p<0.13, n=9).Treatment with CTL clones, CD3/CD28 antibodies, and venetoclax together led to significant decreases in HIV DNA and in replication competent virus (HIV DNA: p<0.001,IUPM: p=0.0009, 4-fold decrease).Conclusions: HIV eradication assays utilizing potent CTL immune effectors in combination with strong LRAs significantly depleted HIV DNA, but venetoclax was necessary (but not sufficient) to significantly deplete the replication competent reservoir from ex vivo CD4+ T-cells.These data indicate that some latent reservoirs may exhibit BCL-2mediated resistance to elimination by CTLs.Further study is needed to explore venetoclax as an adjunct to kick-and-kill therapies.

Source: Journal of Virus Eradication

DOI: 10.1016/s2055-6640(20)30549-5