Adaptive mutations in a human immunodeficiency virus type 1 envelope protein with a truncated V3 loop restore...

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• A human immunodeficiency virus type 1 (HIV-1) clade B envelope protein with a truncated V3 loop regained function after adaptation.
• The adapted virus (TA1) retained V3 truncation, used CCR5 for entry, was sensitive to neutralization, and resistant to CCR5 antagonists.

Purpose of the Study:

• To investigate the mechanistic basis for the functional recovery and specific properties of the adapted HIV-1 TA1 clone.
• To identify the specific mutations responsible for enhanced envelope function and altered neutralization sensitivity.

Main Methods:

• Introduced individual and combined mutations from TA1 into the parental envelope.
• Assessed envelope function, CD4 binding, CCR5 utilization, and neutralization sensitivity.

Main Results:

• Single amino acid changes in C3, V3 loop, and fusion peptide restored envelope function.
• T342A mutation, losing a C3 glycosylation site, was primary.
• Mutations enhanced CD4 binding and responsiveness, increasing sensitivity to CD4 binding site antibodies.
• Mutations reduced CCR5 interaction efficiency and increased sensitivity to CCR5 N-terminal antibodies.

Conclusions:

• Enhanced CD4 utilization is a key mechanism for HIV-1 to compensate for V3 loop mutations affecting CCR5 interactions.
• The findings provide insights into HIV-1 adaptation, neutralization, and potential therapeutic targets.