Virus-induced vesicular acidification enhances HIV immune evasion.
Yaple-Maresh, M. E.; Flores, G. G.; Zimmerman, G. E.; Gomez-Rivera, F.; Collins, K. L.
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To block endocytic viral entry, cells typically acidify endosomes via upregulated expression of the short isoform of human nuclear receptor 7 (NCOA7) which boosts vacuolar ATPase (V-ATPase) activity. In our study, primary T cells infected with HIV-1 triggered endosomal acidification, yet NCOA7 levels were only modestly altered. Instead, we observed a pronounced depletion of the 50 kDa form of the sodium/hydrogen exchanger 6 (NHE6). Remarkably, NHE6 overexpression or treating cells with low-dose concanamycin A, a V-ATPase inhibitor, selectively neutralized endosomal pH. This neutralization impaired Nef-driven MHC-I downmodulation by our wildtype HIV reporter virus. Mechanistically, NHE6 overexpression disrupted Nef-mediated MHC-I loss by reducing recruitment of Nef to recycling endosome (Rab11+) compartments and blocking Nef interactions with {beta}-COP, and ARF-1. Together, these findings reveal NHE6 as a critical regulator of endosomal pH and HIV immune evasion.
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