STRL33, A Novel Chemokine Receptor–like Protein, Functions as a Fusion Cofactor for Both Macrophage-tropic and T Cell Line–tropic HIV-1

Abstract

The chemokine receptors CXCR4, CCR2B, CCR3, and CCR5 have recently been shown to serve along with CD4 as coreceptors for HIV-1. The tropisms of HIV-1 strains for subgroups of CD4+ cells can be explained, at least partly, by the selective use of G protein–coupled receptors (GPCRs). We have identified a novel human gene, STRL33, located on chromosome 3 that encodes a GPCR with sequence similarity to chemokine receptors and to chemokine receptor–like orphan receptors. STRL33 is expressed in lymphoid tissues and activated T cells, and is induced in activated peripheral blood lymphocytes. When transfected into nonhuman NIH 3T3 cells expressing human CD4, the STRL33 cDNA rendered these cells competent to fuse with cells expressing HIV-1 envelope glycoproteins (Envs). Of greatest interest, STRL33, in contrast with CXCR4 or CCR5, was able to function as a cofactor for fusion mediated by Envs from both T cell line–tropic and macrophage-tropic HIV-1 strains. STRL33-transfected Jurkat cell lines also supported enhanced productive infection with HIV-1 compared with control Jurkat cells. Despite the sequence similarities between STRL33 and chemokine receptors, STRL33-transfected cell lines did not respond to any in a panel of chemokines. Based on the pattern of tissue expression of the STRL33 mRNA, and given the ability of STRL33 to function with Envs of differing tropisms, STRL33 may play a role in the establishment and/or progression of HIV-1 infection.

Genetic influence of CXCR6 chemokine receptor alleles on PCP-mediated AIDS progression among African Americans

“…16 As the HIV-1 virus shifts from R5 to X4 in the late stages of infection, the envelope glycoprotein may interact with CXCR6 and use it as a coreceptor since it can mediate fusion by both macrophage and T-cell line tropic HIV-1 strains. 8 Although no specific mechanism for CXCR6 in PCP or HIV-1 pathogenesis has been determined, this study suggests some role for this chemokine receptor. The high allele frequency (44%) among African Americans and the significant protective influence on progression to death after PCP requires further investigation, especially in other African-American or native African cohorts that may have similar allele frequencies.…”

“…Overall, there were 351 deaths (228 AIDS related and 123 non-AIDS related) among CXCR6-genotyped individuals. The AIDS-related deaths included AIDS-defining complication (181), sepsis (23), bacterial pneumonia (12), endocarditis (8), and pulmonary disease (3). There were 123 non-AIDS-related causes of death, including 49 owing to drug overdose and 17 owing to trauma.…”

“…[7][8][9][10] CXCR6, is a secondary coreceptor for HIV that can mediate fusion of HIV-1 to CD4 + cells with HIV-1 envelope from M-tropic and dualtropic strains, and CXCR6 enhances HIV-1 infectivity, suggesting a potential role in progression of HIV-1. 8 Additionally, the chemokine and ligand for CXCR6, CXCL16 is highly expressed in lung and chemotactic to CD4 + T cells. 11 Furthermore, CXCR6+ T cells are prevalent in tissue sites of inflammation and preferentially expressed by Th1 cells, making it a candidate gene for OIs and malignancies.…”

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

“…Assuming that the CXCR6 E3K mutant struggles to traffic to the cell surface, just as the E3Q mutant we describe here, it can be hypothesised that HIV-1 utilises CXCR6 as a co-receptor for viral entry during the later stages of infection and that reduced expression of CXCR6 conferred by the CXCR6 G1469A allele is protective. Such a scenario is plausible, as CXCR6 has previously been shown to facilitate the entry of both macrophage-and T cell line-tropic strains of HIV-1 [31].…”

Adaptation of the Fluorogenic 5′-Nuclease Chemistry to a PCR-Based Reverse Transcriptase Assay

“…The cationic surfactant Catrimox-14 ™ (Iowa Biotechnology, Oakdale, IA, USA) is becoming a method of choice for extracting RNA from mammalian cells, tissues and biopsy samples (2)(3)(4)(5)(6)(7)(8). It rapidly lyses cells and complexes nucleic acids in a form that is not degradable by RNases.…”