Virus-induced vesicular acidification enhances HIV immune evasion

Area of Science:

• Cell Biology
• Virology
• Immunology

Background:

• Cellular endosomes are acidified by vacuolar ATPase (V-ATPase) to block viral entry.
• Upregulated nuclear receptor 7 (NCOA7) typically enhances V-ATPase activity for this process.

Purpose of the Study:

• To investigate the role of endosomal pH regulation in HIV-1 infection and immune evasion.
• To identify key regulators of endosomal pH beyond NCOA7 in primary T cells.

Main Methods:

• Primary T cells infected with HIV-1 reporter virus.
• Analysis of NCOA7 and sodium/hydrogen exchanger 6 (NHE6) expression.
• Overexpression of NHE6 and treatment with V-ATPase inhibitor (concanamycin A).
• Assessment of endosomal pH and major histocompatibility complex class I (MHC-I) downregulation.
• Investigation of Nef protein interactions and localization.

Main Results:

• HIV-1 infection induced endosomal acidification but only modestly altered NCOA7 levels.
• A significant depletion of the 50 kDa form of NHE6 was observed.
• NHE6 overexpression or V-ATPase inhibition selectively neutralized endosomal pH.
• Neutralized endosomal pH impaired Nef-driven MHC-I downregulation.
• NHE6 overexpression disrupted Nef-mediated MHC-I loss by altering Nef recruitment and interactions.

Conclusions:

• NHE6 is a critical regulator of endosomal pH in T cells during HIV-1 infection.
• NHE6 plays a key role in HIV-1 immune evasion by modulating Nef function.
• Targeting NHE6 may offer a novel strategy to combat HIV-1 immune evasion.