CKR-L3, a deletion version CCR6-isoform shows coreceptor-activity for limited human and simian immunodeficiency viruses

BMC Infectious Diseases

Hiroo Hoshino⁵  Atsushi Tanaka⁴  Atsushi Jinno-Oue⁵  Takahiro Ohtsuki²  Nobuaki Shimizu⁵  Katsuaki Kanbe³  Salequl Islam¹ 

[1] Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA;Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;Department of Orthopaedic Surgery, Tokyo Women’s Medical University, Tokyo 116-8567, Japan;Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;Department of Virology and Preventive Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan

关键词: CCR6 and CKR-L3;    G protein-coupled receptors (GPCRs);    Chemokine receptors (CKRs);    Coreceptors;    HIV/SIV;   

Others  :  1127470
DOI  :  10.1186/1471-2334-14-354

 received in 2013-12-30, accepted in 2014-06-26,  发布年份 2014

【 摘 要 】

Background

The chemokine receptors (CKRs), mainly CCR5 and CXCR4 function as major coreceptors in infections caused by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). Approximately 20 G protein-coupled receptors (GPCRs) have been identified as minor coreceptors, alike CCR6 that we reported recently. Since CKR-L3 is indentified as a natural isoform of CCR6, we attempted in this study to explore the coreceptor function of CKR-L3.

Methods

NP-2 cells transduced with CD4-receptor (NP-2/CD4) normally remain resistant to HIV or SIV infection. However, the introduction of functional coreceptors can make these cells susceptible to these viruses. NP-2/CD4/CKR-L3 cells were produced to examine the coreceptor activity of CKR-L3. Likely, CCR6-isoform and the major coreceptors, CCR5 and CXCR4 were also examined in parallel. Presence of viral antigen in infected NP-2/CD4/coreceptor cells was detected by indirect immunofluorescence assay (IFA). The results were validated by detection of syncytia, proviral DNA and by measuring reverse transcriptase (RT) activities.

Results

HIV-2MIR and SIVsmE660 were found to infect NP-2/CD4/CKR-L3 cells, indicative of the coreceptor function of CKR-L3. Viral antigens appeared faster in NP-2/CD4/CKR-L3 cells than in NP-2/CD4/CCR6, indicating that CKR-L3 is a more efficient coreceptor. Moreover, syncytia formation was more rapid and RT release evidenced earlier and at higher levels with CKR-L3 than with CCR6. Sequence analysis in the C2-V3 envelope region of HIV-2MIR replicated through CKR-L3 and CCR6 coreceptor showed two and three amino acid substitutions respectively, in the C2 region compared to the CCR5-variant. The SIVsmE660-CKRL3 variant showed three amino acid substitutions in the V1 region, one change in the V2 and two changes in the C2 region. The SIVsmE660-CCR6 variant produced two changes in the V1 region, and three in the C2 region.

Conclusions

Isoform CKR-L3 exhibited coreceptor activity for limited primary HIV and SIV isolates with better efficiency than the parent CCR6-isoform. Amino acid substitutions in the envelope region of these viruses may confer selective pressure towards CKR-L3-use. CKR-L3 with other minor coreceptors may contribute to HIV and SIV pathogenesis including dissemination, trafficking and latency especially when major coreceptors become compromised. However, further works will be required to determine its clinical significance in HIV and SIV infection.

【 授权许可】

   
2014 Islam et al.; licensee BioMed Central Ltd.

【 图 表 】

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