Abstract
BackgroundHuman immunodeficiency virus 1 and 2 (HIV-1 and HIV-2) use cellular receptors in distinct ways. Besides a more promiscuous usage of coreceptors by HIV-2 and a more frequent detection of CD4-independent HIV-2 isolates, we have previously identified two HIV-2 isolates (HIV-2MIC97 and HIV-2MJC97) that do not use the two major HIV coreceptors: CCR5 and CXCR4. All these features suggest that in HIV-2 the Env glycoprotein subunits may have a different structural organization enabling distinct - although probably less efficient - interactions with cellular receptors.ResultsBy infectivity assays using GHOST cell line expressing CD4 and CCR8 and blocking experiments using CCR8-specific ligand, I-309, we show that efficient replication of HIV-2MIC97 and HIV-2MJC97 requires the presence of CCR8 at plasma cell membrane. Additionally, we disclosed the determinants of chemokine receptor usage at the molecular level, and deciphered the amino acids involved in the usage of CCR8 (R8 phenotype) and in the switch from CCR8 to CCR5 or to CCR5/CXCR4 usage (R5 or R5X4 phenotype). The data obtained from site-directed mutagenesis clearly indicates that the main genetic determinants of coreceptor tropism are located within the V1/V2 region of Env surface glycoprotein of these two viruses.ConclusionsWe conclude that a viral population able to use CCR8 and unable to infect CCR5 or CXCR4-positive cells, may exist in some HIV-2 infected individuals during an undefined time period, in the course of the asymptomatic stage of infection. This suggests that in vivo alternate molecules might contribute to HIV infection of natural target cells, at least under certain circumstances. Furthermore we provide direct and unequivocal evidence that the usage of CCR8 and the switch from R8 to R5 or R5X4 phenotype is determined by amino acids located in the base and tip of V1 and V2 loops of HIV-2 Env surface glycoprotein.
Highlights
Human immunodeficiency virus 1 and 2 (HIV-1 and Human Immunodeficiency Virus (HIV)-2) use cellular receptors in distinct ways
We addressed the determinants of chemokine receptor usage at the molecular level, and deciphered the amino acids involved in the usage of CCR8 and in the switch from CCR8 to CCR5 or to CCR5/CXCR4 usage
HIV-2MIC97 and HIV-2MJC97 uses CCR8 to infect GHOST cell lines and peripheral blood mononuclear cells (PBMC) Our previous results showed that both HIV-2MIC97 and HIV-2MJC97 are unable to infect GHOST-CD4 cell lines expressing several coreceptors including CCR5 and CXCR4 [7,28,29,30,31]
Summary
Human immunodeficiency virus 1 and 2 (HIV-1 and HIV-2) use cellular receptors in distinct ways. Besides a more promiscuous usage of coreceptors by HIV-2 and a more frequent detection of CD4-independent HIV-2 isolates, we have previously identified two HIV-2 isolates (HIV-2MIC97 and HIV-2MJC97) that do not use the two major HIV coreceptors: CCR5 and CXCR4 All these features suggest that in HIV-2 the Env glycoprotein subunits may have a different structural organization enabling distinct - probably less efficient - interactions with cellular receptors. Several other GPCRs have been implicated as coreceptors [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21], revealing that HIV-1 and HIV-2 isolates can exploit alternate molecules in vitro as co-factors for viral entry, raising the possibility that they might contribute to HIV infection of natural target cells in vivo. The importance of CCR5 and CXCR4 as HIV coreceptors emanates from (i) the apparent selection of CCR5using (R5) variants during or soon after HIV-1 mucosal transmission [22]; (ii) the almost exclusive presence of R5 HIV-1 variants during chronic infection; and (iii) the emergence and predominance of CXCR4-using (X4) variants in some patients with advanced HIV-1 disease [23]
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