CCR6 Functions as a New Coreceptor for Limited Primary Human and Simian Immunodeficiency Viruses

Islam, Salequl; Shimizu, Nobuaki; Hoque, Sirajul; Jinno-Oue, Atsushi; Tanaka, Atsushi; Hoshino, Hiroo

doi:10.1371/journal.pone.0073116

Cited by 18 publications

(15 citation statements)

References 56 publications

(60 reference statements)

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“…We have described the coreceptor-role of CCR6 in detail previously [13]. The present report highlights the superior coreceptor-role of CKR-L3 relative to its native counterpart, CCR6.…”

Section: Resultssupporting

confidence: 52%

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

et al. 2014

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BackgroundThe 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.MethodsNP-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.ResultsHIV-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.ConclusionsIsoform 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.

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“…We have described the coreceptor-role of CCR6 in detail previously [13]. The present report highlights the superior coreceptor-role of CKR-L3 relative to its native counterpart, CCR6.…”

Section: Resultssupporting

confidence: 52%

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

et al. 2014

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“…Very recently, SIVsmm and SIVagm strains were reported to utilize CXCR6 as a coreceptor (Elliott et al, 2015; Riddick et al, 2016). It has also been reported that CCR6 and CRK-L3, a natural isoform of CCR6, can act as a coreceptor for both primary HIV and SIVsmm isolates (Islam et al, 2013, 2014). This suggests that some SIVs may have an expanded cell tropism besides CD4 + CCR5 + T-cells or an expanded range of potential target cells (Elliott et al, 2015; Riddick et al, 2016).…”

Section: Post-transmission Features That May Impact Siv Pathogenesmentioning

confidence: 99%

The well-tempered SIV infection: Pathogenesis of SIV infection in natural hosts in the wild, with emphasis on virus transmission and early events post-infection that may contribute to protection from disease progression

Raehtz

Pandrea

Apetrei

2016

Infection, Genetics and Evolution

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African NHPs are infected by over 40 different simian immunodeficiency viruses. These viruses have coevolved with their hosts for long periods of time and, unlike HIV in humans, infection does not generally lead to disease progression. Chronic viral replication is maintained for the natural lifespan of the host, without loss of overall immune function. Lack of disease progression is not correlated with transmission, as SIV infection is highly prevalent in many African NHP species in the wild. The exact mechanisms by which these natural hosts of SIV avoid disease progression are still unclear, but a number of factors might play a role, including: (i) avoidance of microbial translocation from the gut lumen by preventing or repairing damage to the gut epithelium; (ii) control of immune activation and apoptosis following infection; (iii) establishment of an anti-inflammatory response that resolves chronic inflammation; (iv) maintenance of homeostasis of various immune cell populations, including NK cells, monocytes/macrophages, dendritic cells, Tregs, Th17 T-cells, and γδ T-cells; (v) restriction of CCR5 availability at mucosal sites; (vi) preservation of T-cell function associated with down-regulation of CD4 receptor. Some of these mechanisms might also be involved in protection of natural hosts from mother-to-infant SIV transmission during breastfeeding. The difficulty of performing invasive studies in the wild has prohibited investigation of the exact events surrounding transmission in natural hosts. Increased understanding of the mechanisms of SIV transmission in natural hosts, and of the early events post-transmission which may contribute to avoidance of disease progression, along with better comprehension of the factors involved in protection from SIV breastfeeding transmission in the natural hosts, could prove invaluable for the development of new prevention strategies for HIV.

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“…CCR6 is an independent HIV/SIV co-receptor may promote HIV transmission and disease progression in part, when other major co-receptors are affected [19]. CCL20/MIP-3α is responsible for the chemo-attraction of iDCs, effector/memory B cells and T cells.…”

Section: Introductionmentioning

confidence: 99%

Macrophage Inflammatory Protein-3 Alpha (MIP-3α)/CCL20 in HIV-1- Infected Individuals

et al. 2016

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Objective Uncontrolled HIV infection progresses to the depletion of systemic and mucosal CD4 and AIDS. Early HIV infection may be associated with increases in the concentration of MIP-3α in the blood and gut fluids. MIP-3α/CCL20 is the only chemokine known to interact with CCR6 receptors which are expressed on immature dendritic cells and both effector and memory CD8+ and CD4+ T cells. The role and prognostic value of blood levels of MIP-3α in HIV-infected individuals has yet to be described. Methods We determined the serum levels of MIP-3α, and IFN-γ, in 167 HIV-1-infected and 27 HIV-1-uninfected men participating in the Multicenter AIDS Cohort Study (MACS). The blood biomarkers were measured using enzyme-linked immunosorbent assays (ELISA) and the cell phenotypes using flow cytometry. Results Median serum levels of MIP-3α in HIV-1-infected and uninfected men was significantly different (p<0.0001) and were 21.3 pg/mL and 6.4 pg/mL respectively. The HIV-1-infected men with CD4+ T cell count <200 cells/μL showed the highest median serum MIP-3α (23.1 pg/mL). Serum levels of MIP-3α in HIV-1 infected (n=167) were negatively correlated with absolute number of CD4+ T cell (p=0.01) and were positively correlated with CD38 molecules on CD8+ T cells (p=0.0002) and with serum levels of IFN-γ (0.006). Conclusion Serum levels of MIP-3α concomitantly increase with plasma levels of IFN-γ, CD38 expression on CD8+ T cells, and decreased of absolute CD4+ T cells in HIV-1-infected men. A higher blood level of MIP-3α may be representation of locally high level of MIP-3α and more recruitment of immature dendritic cell at site of infection. Involvement of CCR6/CCL20 axis and epithelial cells at the recto-colonel level may enhance sexual transmission of HIV-1 in MSM and may be useful as a prognostic marker in HIV-1-infection and AIDS.

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CCR6 Functions as a New Coreceptor for Limited Primary Human and Simian Immunodeficiency Viruses

Cited by 18 publications

References 56 publications

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

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

The well-tempered SIV infection: Pathogenesis of SIV infection in natural hosts in the wild, with emphasis on virus transmission and early events post-infection that may contribute to protection from disease progression

Macrophage Inflammatory Protein-3 Alpha (MIP-3α)/CCL20 in HIV-1- Infected Individuals

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