Immunophilin Ligands Modulate Phagocytosis and Viral 2 Replication in HIV-Infected Macrophages

Abstract (1) Background: HIV-associated neurocognitive disorders (HAND) can occur as a result of HIV-mediated neuroinflammation and affect people living with HIV (PWH) despite advances in combination antiretroviral therapy (cART). Brain macrophages have been implicated as a source of virus and neurotoxic factors. In this study, we examined the potential role of the immunophilin ligands rapamycin and FK506 in modulating neuroinflammation caused by infected macrophages. (2) Methods: Monocytes were isolated from blood samples from three different blood donors and were differentiated into macrophages (MDMs). These cells were subsequently infected with HIV and treated with combinations of an antiretroviral (ARV) cocktail (raltegravir, emtricitabine, and tenofovir), FK506, and rapamycin. Immunocytochemistry and RT-qPCR were used to analyze the phagocytosis of amyloid beta and the expression of macrophage phenotype-associated markers such as Iba1, TREM2, and IL-6. Viral replication was measured using p24 ELISA. (3) Results: Viral replication among infected MDMs as indicated by p24 levels was positively correlated with Iba1 levels and negatively correlated with IL-6 expression. However, infected MDMs showed lower Iba1 levels than non-infected cells. Rapamycin treatment appeared to lower p24 levels across all donors. Phagocytosis was associated with higher Iba1 levels and was impaired in rapamycin-treated MDMs. (4) Conclusions: Rapamycin seemed to protect against viral replication. However, decreased replication was correlated with a decrease in phagocytic activity. Iba1 may be involved in phagocytosis and HIV infection while IL-6 appeared to indicate protective effects against replication.