Intrinsic obstacles to human immunodeficiency virus type 1 coreceptor switching

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Human immunodeficiency virus type 1 (HIV-1) infection naturally evolves, often involving a late-stage switch in coreceptor preference from CCR5 to CXCR4.
• This coreceptor switch expands the virus's target cell range and is linked to a worse clinical prognosis.

Purpose of the Study:

• To investigate the obstacles that impede the natural CCR5-to-CXCR4 coreceptor switch in HIV-1 infection.
• To understand the reasons behind the significant delay in the emergence of CXCR4-using HIV-1 variants.

Main Methods:

• Selection of coreceptor switch variants through in vitro target cell replacement.
• Comparative analysis of replication efficiency between parental R5 isolates and switch variants.
• Assessment of sensitivity to CCR5 and CXCR4 inhibitors for parental, transitional, and final variants.
• Detailed mutational analysis of CXCR4-using viruses.

Main Results:

• Most CCR5-to-CXCR4 switch variants exhibited diminished replication fitness compared to their parental R5 isolates.
• Transitional intermediate variants showed increased sensitivity to both CCR5 and CXCR4 inhibitors.
• Mutations enabling CXCR4 use were nonrandom, favoring charged amino acid substitutions, altered N-linked glycosylation sites, and isolate-specific patterns, often arising from G-to-A transitions.

Conclusions:

• Diminished replication fitness, less-efficient coreceptor utilization, and specific mutational pathways collectively explain the prolonged delay in the emergence of CXCR4-using HIV-1.
• Understanding these obstacles provides insights into HIV-1 evolution and pathogenesis.