Abstract
The variable V1V2 and V3 regions of the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein (gp120) can influence viral coreceptor usage. To substantiate this we generated isogenic HIV-1 molecularly cloned viruses that were composed of the HxB2 envelope backbone containing the V1V2 and V3 regions from viruses isolated from a patient progressing to disease. We show that the V3 amino acid charge per se had little influence on altering the virus coreceptor phenotype. The V1V2 region and its N-linked glycosylation degree were shown to confer CXCR4 usage and provide the virus with rapid replication kinetics. Loss of an N-linked glycosylation site within the V3 region had a major influence on the virus switching from the R5 to X4 phenotype in a V3 charge-dependent manner. The loss of this V3 N-linked glycosylation site was also linked with the broadening of the coreceptor repertoire to incorporate CCR3. By comparing the amino acid sequences of primary HIV-1 isolates, we identified a strong association between high V3 charge and the loss of this V3 N-linked glycosylation site. These results demonstrate that the N-linked glycosylation pattern of the HIV-1 envelope can strongly influence viral coreceptor utilization and the R5 to X4 switch.
Highlights
Many seven-transmembrane chemokine receptors, in conjunction with the CD4 molecule, have been shown to facilitate entry of human immunodeficiency virus type-1 (HIV-1)[1] into the various cell types that it infects (1–9)
Effect of V3 Charge on Coreceptor Utilization—Our starting material for this study was a panel of molecularly cloned chimeric viruses that consisted of the HxB2 envelope in the LAI viral backbone
We found that all viruses were strong users of the CCR5 receptor, and none were capable of utilizing CXCR4 (Fig. 1A)
Summary
Many seven-transmembrane chemokine receptors, in conjunction with the CD4 molecule, have been shown to facilitate entry of human immunodeficiency virus type-1 (HIV-1)[1] into the various cell types that it infects (1–9). We demonstrate that the loss of an N-linked glycosylation event within the V3 region of the envelope was significant in determining strong CXCR4 utilization and in the virus switching from the R5 to X4 phenotype.
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