Conserved determinants of enhanced CCR5 binding in the human immunodeficiency virus subtype D envelope third variable...

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Human immunodeficiency virus 1 subtype D (HIV-1D) is prevalent in Africa and linked to faster disease progression.
• HIV-1D envelope V3 sequences show high divergence and are understudied.
• CCR5 is a key co-receptor for HIV-1 entry.

Purpose of the Study:

• To investigate residues in the HIV-1D envelope V3 region critical for CCR5 usage.
• To understand how sequence variability affects CCR5 binding and viral entry.

Main Methods:

• Alanine-scanning mutagenesis of the HIV-1D 94UG114 envelope V3 and bridging sheet residues.
• Assessment of CCR5 binding affinity and viral fusion/entry mediated by mutants.

Main Results:

• Most single alanine mutations abolished CCR5 binding, indicating high sensitivity to changes.
• Mutants with abolished CCR5 binding largely maintained wild-type fusion levels.
• Three mutations enhanced CCR5 binding and were conserved across subtypes, suggesting conformational constraints.

Conclusions:

• HIV-1D V3 loop residues are crucial for CCR5 binding, yet the virus can maintain entry.
• Conserved residues suggest structural constraints on the V3 loop conformation across subtypes.
• Understanding these interactions is vital for targeting HIV-1D entry mechanisms.