In vitro modeling of HIV-1 latency in distinct primary memory CD4+ T cell subsets

Currently, more than 33 million people are infected with human immunodeficiency virus type 1 (HIV-1) or living with acquired immunodeficiency syndrome (AIDS). Specifically, the existence of latent HIV-1 proviruses in memory CD4⁺T lymphocytes poses the greatest barrier towards viral eradication. In vivo, memory CD4⁺ T lymphocytes can be categorized as either central memory (T_CM) or effector memory (T_EM), subsets that display distinct homing capacities and effector function. T_CM harbor the majority of latent HIV proviruses in vivo. However, a substantial latent reservoir was also found to exist within transitional memory CD4⁺ T lymphocytes (T_TM), a poorly characterized memory subset that has an intermediate phenotype between those of T_CM and T_EM. Using naïve T cells from healthy donors, we have been able to generate a heterogeneous population of cultured T_CM and T_TM through the use of select cytokine cocktails and antigenic stimulation.  We have found that these cultured cells phenotypically look and functionally behave like their ex vivo counterparts.Furthermore, when these cells reach an activated state, they can be infected with HIV-1. Upon their return to quiescence, a viral latent reservoir is established, containing a polyclonal population of integrated viruses. Using this novel HIV-1 latency model, we are currently investigating the potential differences among T_CM and T_TM regarding (a) permissivity to the establishment of a latent infection; and (b) the ability to reactivate virus in response to a broad panel of stimuli. Our studies will therefore be an essential component towards the rational design and screening of anti-latency drugs.