Novel envelope determinants for CCR3 use by human immunodeficiency virus

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Human immunodeficiency virus type 1 (HIV-1) utilizes coreceptors CCR5 and CCR3 for cellular entry.
• Understanding HIV-1 coreceptor usage is crucial for developing effective antiviral therapies.

Purpose of the Study:

• To investigate the molecular mechanisms underlying HIV-1 coreceptor switch.
• To identify specific amino acid residues in HIV-1 envelopes responsible for altered coreceptor tropism.

Main Methods:

• Analysis of HIV-1 envelope phenotypes during coreceptor switch.
• Mapping of envelope determinants for CCR3 and CXCR4 usage.
• Site-directed mutagenesis to assess the role of specific amino acids.

Main Results:

• HIV-1 envelopes can acquire novel phenotypes, including R5-only and R3/R5/X4-using tropisms.
• Three amino acids in conserved regions 3 and 4 were identified as critical for CCR3 binding.
• N356, a potential glycosylation site, was newly associated with coreceptor use, while R440 and N448 influenced CCR5 binding proximity.

Conclusions:

• Coreceptor switch in HIV-1 involves significant alterations in envelope tropism.
• Specific amino acid substitutions, including novel sites like N356, dictate HIV-1 coreceptor usage.
• These findings provide insights into HIV-1 evolution and potential therapeutic targets.