Abstract

The latent reservoir of HIV-infected CD4+ T-cells presents challenges for finding an effective strategy to eradicate HIV. HIV latency occurs after the reverse transcription and integration of HIV-DNA into the host cell genome. After HIV-DNA integrates, the proviruses may produce trans-activator of transcription proteins (Tat) that bind to the promoters located in the long terminal repeats (5’LTRs), initiating HIV-DNA transcription. In contrast, when Tat is absent, the CD4 T-cells enter a state of latency without HIV-DNA transcription. Latent-reversal agents (LRAs) can “shock and kill” infected and latent CD4 T-cells but without fully reactivating and eliminating all dormant cells. Many LRAs fail to eliminate the latent reservoir because deficient levels of Tat reduce LRA potency. LRAs that could modify the epigenetics of HIV genomic promoters, located in LTR regions, may not reduce latency due to the unstable availability of Tat, which produces “bipolar” LTRs. Because many existing LRAs fail to reduce HIV latency, we need to identify alternative novel LRAs. It may be possible to find novel LRAs through examining potential LRA targets in cellular signaling pathways initiated by HIV viral entry. Currently, we know the binding between HIV-gp120 and the CD4-T-cell CCR5 co-receptor induces cellular signaling pathways that differ from signaling cascades stimulated by conventional CCR5 ligands. However, further research is needed to fill this gap in the literature, concerning the early impact of viral entry on HIV latency. To enhance our understanding of HIV latency this commentary recommends exploring the cellular signaling pathways formed by HIV viral entry.