Virus-induced vesicular acidification enhances HIV immune evasion.

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 major histocompatibility complex class I (MHC-I) downmodulation by our wild-type 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 β-COP and ARF-1. Together, these findings reveal NHE6 as a critical regulator of endosomal pH and HIV immune evasion.