Expression of noncoding RNAs (ncRNAs) is more tissue and cell type-specific than expression of protein-coding genes. Understanding the mechanisms of action of ncRNAs and their roles in HIV replication and latency may inform targets for the latent HIV reservoir reactivation or elimination with high specificity to CD4+ T cells latently infected with HIV.

While the number of studies in the field of ncRNAs and HIV is limited, evidence points to complex interactions between different ncRNAs, protein-coding RNAs, and proteins. Latency-reversing agents modulate the expression of ncRNAs, with some effects being inhibitory for HIV reactivation. An important limitation of basic research on the ncRNA mechanisms of action is the reliance on cell lines. Because of cell type specificity, it is uncertain whether the ncRNAs function similarly in primary cells.

Comprehensive functional screens to uncover all ncRNAs that regulate HIV expression and the detailed exploration of their mechanisms of action in relevant cell types are needed to identify promising targets for HIV reservoir clearance. Classes of ncRNAs as a whole rather than individual ncRNAs might represent an attractive target for reservoir elimination. Compound screens for latency reversal should factor in the complexity of their effects on ncRNAs.