The Intact Noninducible Latent HIV-1 Reservoir Is Established in an In Vitro Primary TCM Cell Model of Latency.

The establishment of HIV-1 latency has hindered an HIV-1 cure. "Shock and kill" strategies to target this reservoir aim to induce the latent provirus with latency- reversing agents (LRAs). However, recent studies have shown that the majority of the intact HIV-1 viral reservoir found in antiretroviral therapy (ART)-suppressed HIV-infected individuals is not inducible. We sought to understand whether this noninducible reservoir is established, and thus able to be studied, in an in vitro primary TCM cell model of latency. Furthermore, we wanted to expand this model system to include R5-tropic and non-B-subtype viruses. To that end, we generated our TCM cell model of latency with an R5 subtype B virus, AD8, and an R5 subtype C virus, MJ4. Our results demonstrate that both intact and defective proviruses are generated in this model. Less than 50% of intact proviruses are inducible regardless of viral strain in the context of maximal stimulation through the T cell receptor (TCR) or with different clinically relevant LRAs, including the histone deacetylase (HDAC) inhibitors suberoylanilide hydroxamic acid (SAHA) and MS-275, the protein kinase C (PKC) agonist ingenol 3,20-dibenzoate, or the second mitochondria-derived activator of caspase (SMAC) mimetic AZD-5582. Our findings suggest that current LRA strategies are insufficient to effectively reactivate intact latent HIV-1 proviruses in primary CD4 TCM cells and that the mechanisms involved in the generation of the noninducible HIV-1 reservoir can be studied using this primary in vitro model. [ABSTRACT FROM AUTHOR]