Virus-induced vesicular acidification enhances HIV immune evasion

Area of Science:

• Virology
• Cell Biology
• Molecular Biology

Background:

• Cells utilize endosomal acidification, mediated by vacuolar ATPase (V-ATPase) and nuclear receptor 7 (NCOA7), to restrict viral entry.
• Human Immunodeficiency Virus type 1 (HIV-1) infection influences cellular processes, including endosomal pH, which can affect viral replication and host cell interactions.

Purpose of the Study:

• To investigate the role of endosomal acidification and its regulators, NCOA7 and sodium/hydrogen exchanger 6 (NHE6), in HIV-1 infection.
• To determine the impact of modulating endosomal pH on HIV-1 Nef-mediated MHC-I downmodulation.

Main Methods:

• Analysis of NCOA7 and NHE6 expression in HIV-1 infected primary T cells.
• Manipulation of NHE6 levels and V-ATPase activity using overexpression and concanamycin A.
• Assessment of endosomal pH changes and their effect on MHC-I downmodulation by HIV-1 reporter viruses.

Main Results:

• HIV-1 infection led to endosomal acidification, with marginal changes in NCOA7 but significant reduction in 50 kDa NHE6 levels.
• Overexpression of NHE6 or inhibition of V-ATPase reversed endosomal acidification and reduced Nef-dependent MHC-I downmodulation.
• NHE6 overexpression disrupted Nef-mediated MHC-I downmodulation by interfering with Nef-Rab11, Nef-β-COP, and Nef-ARF-1 interactions.
• HIV-1 Vif protein was essential for NHE6 downmodulation and endosomal acidification but not for Nef-dependent MHC-I downmodulation.

Conclusions:

• HIV-1 infection actively manipulates endosomal pH by reducing NHE6 levels, a process influenced by Vif.
• Modulating endosomal pH through NHE6 or V-ATPase offers a potential strategy to counteract viral mechanisms like MHC-I downmodulation.
• NHE6 plays a critical role in regulating endosomal pH and viral protein interactions essential for HIV-1 pathogenesis.