Variation in Simian Immunodeficiency Virus<i>env</i>V1 Region in Simian AIDS-Associated Lymphoma

Fortgang, Ilana S.; Rege, Tanya A.; Baskin, Gary B.; Murphey‐Corb, Michael; Lévy, Laurence

doi:10.1089/088922201750102580

Cited by 5 publications

(4 citation statements)

References 27 publications

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“…The findings showed good agreement with previous studies describing the region corresponding to the V3 of HIV-1 is conserved in SIV [54] and the genetic variation of SIV is different from HIV-1 [55]. However, this study detected the V1 and V2 as the possible regions in the envelope glycoprotein to exhibiting the genetic variation of SIVsmE660 for selecting CCR6 as new coreceptor and our observation showed harmony to previous reports [56,57]. …”

Section: Discussionsupporting

confidence: 92%

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

et al. 2013

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More than 12 chemokine receptors (CKRs) have been identified as coreceptors for the entry of human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2), and simian immunodeficiency viruses (SIVs) into target cells. The expression of CC chemokine receptor 6 (CCR6) on Th17 cells and regulatory T cells make the host cells vulnerable to HIV/SIV infection preferentially. However, only limited information is available concerning the specific role of CCR6 in HIV/SIV infection. We examined CCR6 as a coreceptor candidate in this study using NP-2 cell line-based in-vitro studies. Normally, CD4-transduced cell line, NP-2/CD4, is strictly resistant to all HIV/SIV infection. When CCR6 was transduced there, the resultant NP-2/CD4/CCR6 cells became susceptible to HIV-1HAN2, HIV-2MIR and SIVsmE660, indicating coreceptor roles of CCR6. Viral antigens in infected cells were detected by IFA and confirmed by detection of proviral DNA. Infection-induced syncytia in NP-2/CD4/CCR6 cells were detected by Giemsa staining. Amount of virus release through CCR6 has been detected by RT assay in spent culture medium. Sequence analysis of proviral DNA showed two common amino acid substitutions in the C2 envelope region of HIV-2MIR clones propagated through NP-2/CD4/CCR6 cells. Conversely, CCR6-origin SIVsmE660 clones resulted two amino acid changes in the V1 region and one change in the C2 region. The substitutions in the C2 region for HIV-2MIR and the V1 region of SIVsmE660 may confer selection advantage for CCR6-use. Together, the results describe CCR6 as an independent coreceptor for HIV and SIV in strain-specific manner. The alteration of CCR6 uses by viruses may influence the susceptibility of CD4+ CCR6+ T-cells and dendritic cell subsets in vivo and therefore, is important for viral pathogenesis in establishing latent infections, trafficking, and transmission. However, clinical relevance of CCR6 as coreceptor in HIV/SIV infections should be investigated further.

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Section: Discussionsupporting

confidence: 92%

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

et al. 2013

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“…Our examination revealed the V1 and V2 regions of SIVsmE660 were not conserved as like the V3 region. These findings are also consistent with other reports describing sequence variation mostly in the V1 region of SIV infections [47,48]. Therefore, the V1 and V2 regions in the envelope glycoprotein may carry the potentiality in determining receptor tropism.…”

Section: Discussionsupporting

confidence: 92%

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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“…Each of these animals fit the criteria of rapid progression, lacking measurable SIV-specific antibody responses and exhibiting persistent antigenemia and increasing levels of viral RNA in plasma. The in vivo pathogenesis of SIVsmE543-3 in these animals has been described in detail previously (20,21). Tissues were collected at necropsy following deep anesthesia and saline perfusion to remove residual blood in tissues, and the samples were frozen and stored in liquid nitrogen until use.…”

Section: Methodsmentioning

confidence: 99%

“…Because these regions were defined for animals with robust immune responses, particularly neutralizing antibody responses, evolution of these regions is likely to be the result of viral mechanisms of immune evasion. The primary regions subject to genetic variation during the course of SIV infection in macaques are limited to the V1 and V4 regions of the envelope glycoprotein (3,20,55). Variation in the V1 region is characterized by substitutions and short, in-frame deletions and insertions.…”

mentioning

confidence: 99%

Unique Pattern of Convergent Envelope Evolution in Simian Immunodeficiency Virus-Infected Rapid Progressor Macaques: Association with CD4-Independent Usage of CCR5

Dehghani

Puffer

Doms

et al. 2003

J Virol

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The rate of disease development in simian immunodeficiency virus (SIV) infection of macaques varies considerably among individual macaques. While the majority of macaques inoculated with pathogenic SIV develop AIDS within a period of 1 to 2 years, a minority exhibit a rapid disease course characterized by absence or transience of humoral and cellular immune responses and high levels of virus replication with widespread dissemination of SIV in macrophages and multinucleated giant cells. The goal of this study was to examine viral evolution in three SIVsmE543-3-inoculated rapid progressors to determine the contribution of viral evolution to the development of rapid disease and the effect of the absence of immune pressure upon viral evolution. PCR was used to amplify and clone the entire SIV genome from tissues collected at necropsy, and the course of viral evolution was assessed by env sequences cloned from sequential plasma samples of one rapid progressor (RP) macaque. The majority of sequence changes in RP macaques occurred in the envelope gene. Substitutions were observed in all three animals at specific conserved residues in envelope, including loss of a glycosylation site in V1/V2, a D-to-N/V substitution in a highly conserved GDPE motif, and a P-to-V/H/T substitution in the V3 loop analog. A cell-cell fusion assay revealed that representative env clones utilized CCR5 as a coreceptor, independent of CD4. The selection of specific substitutions in envelope in RP macaques suggests novel selection pressures on virus in such animals and suggests that viral variants that evolve in these animals may play a role in disease progression.

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Variation in Simian Immunodeficiency VirusenvV1 Region in Simian AIDS-Associated Lymphoma

Cited by 5 publications

References 27 publications

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

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

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

Unique Pattern of Convergent Envelope Evolution in Simian Immunodeficiency Virus-Infected Rapid Progressor Macaques: Association with CD4-Independent Usage of CCR5

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