Genetic characteristics of the V3 region associated with CXCR4 usage in HIV-1 subtype C isolates

• Published in: Virology (New York, N.Y.) Vol. 356; no. 1; pp. 95 - 105
• Main Authors: Coetzer, Mia, Cilliers, Tonie, Ping, Li-Hua, Swanstrom, Ronald, Morris, Lynn
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2006
• Subjects: Amino Acid Sequence; CXCR4 usage; Heteroduplex Analysis - methods; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - genetics; HIV-1 - classification; HIV-1 - genetics; HIV-1 - isolation & purification; HIV-1 - metabolism; HIV-1 subtype C; Human immunodeficiency virus 1; Humans; Molecular Sequence Data; Peptide Fragments - chemistry; Peptide Fragments - genetics; Receptors, CCR5 - metabolism; Receptors, CXCR4 - metabolism; Sequence Analysis, DNA; V3 region; V3-HTA; V3-HTA; CXCR4 usage; HIV-1 subtype C; V3 region
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2006.07.030

CXCR4 coreceptor usage appears to occur less frequently among HIV-1 subtype C viruses. The aim of this study was to investigate the genetic determinants within the V3 region of subtype C isolates able to use CXCR4. Thirty-two subtype C isolates with known phenotypes (16 R5, 8 R5X4 and 8 X4 isolates) were assessed. A subtype C-specific V3 heteroduplex tracking assay (HTA) was used to determine sample complexity, and nucleotide sequencing analysis was used to compare characteristics associated with CCR5 and CXCR4-using isolates. There were sufficient genetic differences to discriminate between R5 viruses and those able to use CXCR4. In general, R5 isolates had an HTA mobility ratio >0 .9 whereas CXCR4-using isolates were usually < 0.9. Multiple bands were more frequently seen among the dualtropic isolates. Sequence analysis of the V3 region showed that CXCR4-using viruses were often associated with an increased positive amino acid charge, insertions and loss of a glycosylation site, similar to HIV-1 subtype B. In contrast, where subtype B consensus V3 has a GPGR crown motif irrespective of coreceptor usage, all 16 subtype C R5 viruses had a conserved GPGQ sequence at the tip of the loop, while 12 of the 16 (75%) CXCR4-using viruses had substitutions in this motif, most commonly arginine (R). These findings were confirmed using a larger published data set. We therefore suggest that changes within the crown motif of subtype C viruses might be an additional pathway to utilise CXCR4 and thus GPGQ may limit the potential for the development of X4 viruses.