Selective elimination of myeloid HIV reservoirs by targeting pro-survival pathways

OBJECTIVES: HIV reservoirs in myeloid cells, including tissue-resident macrophages, persist despite antiretroviral therapy, hindering viral eradication. We have tested an approach for HIV clearance through selective elimination of host cells harboring replication-competent HIV (SECH), by inhibition of autophagy and anti-apoptotic molecules during viral reactivation. Whether the SECH approach can effectively target reservoirs of the myeloid lineage is investigated.

METHODS: We examined whether SECH treatments could deplete HIV-infected macrophages from HIV + donors ex vivo, and in humanized mice in vivo. We also performed spatial transcriptome analyses of myeloid HIV reservoirs in the brains of humanized mice that escaped SECH treatments.

RESULTS: SECH treatments can eliminate HIV-infected macrophages from HIV + donors ex vivo, and in a portion of humanized mice in vivo. Spatial transcriptome analyses showed increases in epigenetic repressors for HIV transcription, as well as elevated autophagy and glycolysis genes in brain myeloid cells resistant to SECH treatments, while counteracting these molecular mechanisms sensitized the myeloid reservoirs to cell death.

CONCLUSIONS: Our data suggest that myeloid HIV reservoirs resistant to depletion display limited HIV gene expression by epigenetic repressors, and express more pro-survival genes, while targeting these mechanisms helps to promote the clearance of myeloid HIV reservoirs.