Coreceptor usage by HIV-1 and HIV-2 primary isolates: The relevance of CCR8 chemokine receptor as an alternative coreceptor

Abstract

The human immunodeficiency virus replication cycle begins by sequential interactions between viral envelope glycoproteins with CD4 molecule and a member of the seven-transmembrane, G-protein-coupled, receptors' family (coreceptor). In this report we focused on the contribution of CCR8 as alternative coreceptor for HIV-1 and HIV-2 isolates. We found that this coreceptor was efficiently used not only by HIV-2 but particularly by HIV-1 isolates. We demonstrate that CXCR4 usage, either alone or together with CCR5 and/or CCR8, was more frequently observed in HIV-1 than in HIV-2 isolates. Directly related to this is the finding that the non-usage of CXCR4 is significantly more common in HIV-2 isolates; both features could be associated with the slower disease progression generally observed in HIV-2 infected patients. The ability of some viral isolates to use alternative coreceptors besides CCR5 and CXCR4 could further impact on the efficacy of entry inhibitor therapy and possibly also in HIV pathogenesis.

Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8

“…CCR8 is a beta chemokine receptor with a known role in induction of chemotaxis in Th2 cells via its two ligands CCL1 and CCL18 [50], and functions as a co-receptor for enveloped viruses including HIV [51,52]. The CCR8 axis has been found to be activated in urothelial and renal carcinomas resulting in immune response impairment, and it is responsible for apoptosis inhibition in lymphoma [53,54].…”

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic than HIV-1

“…Recently we have studied the contribution of CCR8 as an effective coreceptor for HIV-1 and HIV-2 primary isolates [89]. A major and interesting finding arise from this report: a minor coreceptor such as CCR8 was used much more frequently by HIV-1 than by HIV-2 primary isolates, regardless the clinical stage, the plasma viral load or the CD4+ T-cell counts of patients.…”

“…After the initial identification of CXCR4 and CCR5 in 1996 [86,87], several other GPCRs have been described as being able to act as coreceptors for HIV-1, HIV-2 and SIV: CCR1, CCR2b, CCR3, CCR4, CCR5, CCR8, CCR9, CCR10, CXCR2, CXCR4, CXCR5, CXCR6, CX3CR1, XCR1, FPRL1, GPR1, GPR15, APJ, ChemR23, CXCR7/ RDC1, D6, BLTR and US28 [88][89][90][91][92]. Despite this extensive array of potential HIV entry coreceptors, only CCR5 and CXCR4 have been considered important for HIV-1 infection in vivo [93,94].…”

“…This notion stems from studies reporting: (i) the apparent selection of CCR5-using (R5) variants during mucosal transmission; (ii) the predominance of R5 population during asymptomatic stage of infection; and (iii) the arise and eventual predominance of CXCR4-using (X4) variants in late stages of HIV-1 infection. However, several exceptions to this simplistic R5/X4 dichotomy have been reported [89,91,[95][96][97][98][99][100][101][102][103][104], revealing that some HIV-1 and HIV-2 isolates can exploit other coreceptors in vitro, raising the possibility that these alternate molecules can in vivo contribute to HIV infection of natural target cells, at least under certain circumstances.…”

In VitroPhenotypic Susceptibility of HIV-2 Clinical Isolates to CCR5 Inhibitors

“…The new class of CCR5 inhibitors, including maraviroc (7), is the first one to have a cellular target, and so, it is expected not to be impacted by HIV genetic diversity and may provide a new therapeutic opportunity for HIV-2 infection. However, previous studies showed that HIV-2 isolates can use a broad range of coreceptors in vitro, including CCR5 and CXCR4 as well as alternative coreceptors, as follows: CCR1-5, GPR15 (BOB), CCR8, and CXCR6 (BONZO) (5,8,10,12). The in vivo role of these alternative coreceptors is still under question (2,9,11,22); however, it suggests that HIV-2 clinical isolates may be able to access more coreceptors than those of HIV-1, a mechanism that might impact the antiviral activity of maraviroc against HIV-2.…”