Dynamics of Low-Level Viremia and Immune Activation after Switching to a Darunavir-Based Regimen.

There is an ongoing debate regarding whether low-level viremia (LLV), in particular persistent LLV, during HIV treatment with optimal adherence originates from low-level viral replication, viral production, or both. We performed an observational study in 30 individuals with LLV who switched to a boosted darunavir (DRV)-based therapy. In-depth virological analyses were used to characterize the viral population and the (activity) of the viral reservoir. Immune activation was examined using cell-bound and soluble markers. The primary outcome was defined as the effect on HIV-RNA and was categorized by responders (<50 cp/mL) or non-responders (>50 cp/mL). At week 24, 53% of the individuals were considered responders, 40% non-responders, and 7% could not be assigned. Sequencing showed no evolution or selection of drug resistance in the non-responders. Production of defective virus with mutations in either the protease (D25N) or RT active site contributed to persistent LLV in two individuals. We show that in about half of the study participants, the switch to a DRV-based regimen resulted in a viral response indicative of ongoing low-level viral replication as the cause of LLV before the switch. Our data confirm that in clinical management, high genetic barrier drugs like DRV are a safe choice, irrespective of the source of LLV.

Shock and kill within the CNS: A promising HIV eradication approach?

The most studied HIV eradication approach is the "shock and kill" strategy, which aims to reactivate the latent reservoir by latency reversing agents (LRAs) and allowing elimination of these cells by immune-mediated clearance or viral cytopathic effects. The CNS is an anatomic compartment in which (persistent) HIV plays an important role in HIV-associated neurocognitive disorder. Restriction of the CNS by the blood-brain barrier is important for maintenance of homeostasis of the CNS microenvironment, which includes CNS-specific cell types, expression of transcription factors, and altered immune surveillance. Within the CNS predominantly myeloid cells such as microglia and perivascular macrophages are thought to be a reservoir of persistent HIV infection. Nevertheless, infection of T cells and astrocytes might also impact HIV infection in the CNS. Genetic adaptation to this microenvironment results in genetically distinct, compartmentalized viral populations with differences in transcription profiles. Because of these differences in transcription profiles, LRAs might have different effects within the CNS as compared with the periphery. Moreover, reactivation of HIV in the brain and elimination of cells within the CNS might be complex and could have detrimental consequences. Finally, independent of activity on latent HIV, LRAs themselves can have adverse neurologic effects. We provide an extensive overview of the current knowledge on compartmentalized (persistent) HIV infection in the CNS and on the "shock and kill" strategy. Subsequently, we reflect on the impact and promise of the "shock and kill" strategy on the elimination of persistent HIV in the CNS.