Latency Reversal 2.0: Giving the Immune System a Seat at the Table.

The HIV reservoir is primarily composed of latently infected CD4+ T cells carrying integrated, replication-competent provirus that can give rise to rebound viremia if ART is stopped. Myeloid lineage cells also contribute to HIV latency in certain tissues; we focus here on CD4+ T cells as a sufficient body of evidence regarding latency reversal in myeloid cells is lacking. The immunomodulatory LRA 2.0 approaches we describe include pattern recognition receptor agonists, immune checkpoint inhibitors, non-canonical NF-kB stimulation, and transient CD8+ lymphocyte depletion, along with promising combination strategies. We highlight recent studies demonstrating robust latency reversal in nonhuman primate models. While significant strides have been made in terms of virus reactivation from latency, initial hopes for latency reversal alone to result in a reduction of infected cells, through viral cytopathic effect or an unboosted immune system, have not been realized and it seems clear that even effective latency reversal strategies will need to be paired with an approach that facilitates immune recognition and clearance of cells containing reactivated virus.