Early- and Intermediate-Stage Variants of Simian Immunodeficiency Virus Replicate Efficiently in Cells Lacking CCR5

Forte, Serene; Harmon, Mary Elizabeth; Pineda, Mario Javier; Overbaugh, Julie

doi:10.1128/jvi.77.17.9723-9727.2003

Cited by 10 publications

(8 citation statements)

References 24 publications

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“…recently showed that a mutated CCR5 gene encoding a truncated molecule that is not expressed on the cell surface does not protect sooty mangabeys from infection with the “R5-tropic” SIVsmm virus in vivo (Riddick et al, 2010). This, together with our data, support previous studies (Forte et al, 2003) suggesting that other surface molecules may also serve as co-receptors for SIV. SIV Env has been shown to mediate target cell entry in cell-to-cell fusion assays via interaction with chemokine receptor-like orphan receptors such as CXCR6 (STRL33/Bonzo) and GPR15 (BOB) (Edinger et al, 1998; Lauren et al, 2006; Pohlmann et al, 1999).…”

Section: Discussionsupporting

confidence: 93%

TCR triggering transcriptionally downregulates CCR5 expression on rhesus macaque CD4+ T-cells with no measurable effect on susceptibility to SIV infection

et al. 2011

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Studies using transformed human cell lines suggest that most SIV strains use CCR5 as co-receptor. Our analysis of primary rhesus macaque CD4+ T-cell clones revealed marked differences in susceptibility to SIVmac239 infection. We investigated whether different levels of CCR5 expression account for clonal differences in SIVmac239 susceptibility. Macaque CD4+ T cells showed significant CCR5 downregulation 1-2 days following CD3 mAb stimulation, which gradually recovered at resting state, 7-10 days after activation. Exposure of clones to SIVmac239 during their CCR5low or CCR5high expression states revealed differences in SIV susceptibility independent of surface CCR5 levels. Furthermore, a CCR5 antagonist similarly reduced SIVmac239 infection of clones during their CCR5low or CCR5high expression states. Our data suggest a model where i) very low levels of CCR5 are sufficient for efficient SIV infection, ii) CCR5 levels above this threshold do not enhance infection, and iii) low level infection can occur in the absence of CCR5.

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Section: Discussionsupporting

confidence: 93%

TCR triggering transcriptionally downregulates CCR5 expression on rhesus macaque CD4+ T-cells with no measurable effect on susceptibility to SIV infection

et al. 2011

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“…Figure 4 lists and plots the data which have been used here to measure the rate of SIV-induced cell death in such experiments. The results from these measurements are quite consistent across different experiments and publications (Forte et al 2003;Ilyinskii and Desrosiers 1996;Reitter and Desrosiers 1998). The death rate of SIV-infected PBMC in culture tends to be around a=0.3 days −1 (Figure 4) This corresponds to a half life of infected cells which is slightly greater than 2 days.…”

Section: Siv Dynamicssupporting

confidence: 76%

“…However, these experiments did not provide an estimate of the virus-induced death rate of infected cells, a, because the relative amounts of virus-induced and immune-mediated cell killing could not be distinguished in this study. However, it is possible to obtain a general idea about how fast SIV kills its cells from in vitro experiments in which SIV growth is monitored over time in PBMC (Forte et al 2003;Ilyinskii and Desrosiers 1996;Reitter and Desrosiers 1998). In such experiments, the virus first grows exponentially to a peak, and then declines exponentially (Figure 3b).…”

Section: Siv Dynamicsmentioning

confidence: 99%

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On the relative fitness of early and late stage Simian immunodeficiency virus isolates

Wodarz

2007

Theoretical Population Biology

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Simian immunodeficiency virus (SIV) has been shown to evolve from a relatively slowly replicating and mildly cytopathic virus early in the infection (SIVMneCL8) to a faster replicating and more cytopathic virus at later stages of the infection (SIVMne170). It has recently been demonstrated that the early and mildly cytopathic variant SIVMneCL8 out-competed the late and highly cytopathic strain SIVMne170 in cell culture experiments, because the fitness disadvantage derived from the higher cytopathicity was not matched by a sufficient increase in the viral replication rate. However, in another set of experiments where the life span of cells in culture was artificially limited, the late and more cytopathic virus won the competition, because under this condition cytopahticity was not an important determinant of viral fitness. It was hypothesized that the limited life span experiment reflected the immune-mediated high turnover environment in vivo more accurately, and that the presence of immune responses accounts for the selection of the cytopathic strain SIVmne170 during later stages of the infection. This paper investigates the effect of immune responses, in particular cytotoxic T lymphocyte (CTL) responses, on the competition dynamics between these two SIV strains with the help of mathematical models. Model analysis and parameter estimates derived from previously published data on SIV growth kinetics suggest that the SIV-specific CTL response might not be the driving force that leads to the selection of the cytopathic strain SIVMne170 during later stages of the infection. This implies that more complex evolutionary mechanisms might have to be invoked in order to explain the emergence of these strains in vivo. One possibility is that the ability of multiple virus particles to infect the same cell (coinfection) might be a pre-requisite for the emergence of the cytopathic strain SIVMne170 as the disease progresses.

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“…Interestingly, a number of studies revealed that various strains of SIV were able to infect and replicate in CCR5-null human PBMC as well as in CEMx174 cells, which lack CCR5 expression (62)(63)(64). These findings indicate that coreceptors other than CCR5 can support SIV entry and replication ex vivo.…”

Section: Discussionmentioning

confidence: 81%

Simian Immunodeficiency Virus SIVagm Efficiently Utilizes Non-CCR5 Entry Pathways in African Green Monkey Lymphocytes: Potential Role for GPR15 and CXCR6 as Viral Coreceptors

Riddick

Matsuda

et al. 2016

J Virol

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African green monkeys (AGM) are natural hosts of simian immunodeficiency virus (SIV), and infection in these animals is generally nonpathogenic, whereas infection of nonnatural hosts, such as rhesus macaques (RM), is commonly pathogenic. CCR5 has been described as the primary entry coreceptor for SIV in vivo, while human-derived CXCR6 and GPR15 also appear to be used in vitro. However, sooty mangabeys that are genetically deficient in CCR5 due to an out-of-frame deletion are infectible with SIVsmm, indicating that SIVsmm can use alternative coreceptors in vivo. In this study, we examined the CCR5 dependence of SIV strains derived from vervet AGM (SIVagmVer) and the ability of AGM-derived GPR15 and CXCR6 to serve as potential entry coreceptors. We found that SIVagmVer replicated efficiently in AGM and RM peripheral blood mononuclear cells (PBMC) in the presence of the CCR5 antagonist maraviroc, despite the fact that maraviroc was capable of blocking the CCR5-tropic strains SIVmac239, SIVsmE543-3, and simian-human immunodeficiency virus SHIV-AD8 in RM PBMC. We also found that AGM CXCR6 and AGM GPR15, to a lesser extent, supported entry of pseudotype viruses bearing SIVagm envelopes, including SIVagm transmitted/founder envelopes. Lastly, we found that CCR5, GPR15, and CXCR6 mRNAs were detected in AGM and RM memory CD4 ؉ T cells. These results suggest that GPR15 and CXCR6 are expressed on AGM CD4 ؉ T cells and are potential alternative coreceptors for SIVagm use in vivo. These data suggest that the use of non-CCR5 entry pathways may be a common feature of SIV replication in natural host species, with the potential to contribute to nonpathogenicity in these animals. IMPORTANCEAfrican green monkeys (AGM) are natural hosts of SIV, and infection in these animals generally does not cause AIDS, whereas SIV-infected rhesus macaques (RM) typically develop AIDS. Although it has been reported that SIV generally uses CD4 and CCR5 to enter target cells in vivo, other molecules, such as GPR15 and CXCR6, also function as SIV coreceptors in vitro. In this study, we investigated whether SIV from vervet AGM can use non-CCR5 entry pathways, as has been observed in sooty mangabeys. We found that SIVagmVer efficiently replicated in AGM and RM peripheral blood mononuclear cells in the presence of the CCR5 antagonist maraviroc, suggesting that non-CCR5 entry pathways can support SIVagm entry. We found that AGMderived GPR15 and CXCR6 support SIVagmVer entry in vitro and may serve as entry coreceptors for SIVagm in vivo, since their mRNAs were detected in AGM memory CD4 ؉ T cells, the preferred target cells of SIV.

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Early- and Intermediate-Stage Variants of Simian Immunodeficiency Virus Replicate Efficiently in Cells Lacking CCR5

Cited by 10 publications

References 24 publications

TCR triggering transcriptionally downregulates CCR5 expression on rhesus macaque CD4+ T-cells with no measurable effect on susceptibility to SIV infection

TCR triggering transcriptionally downregulates CCR5 expression on rhesus macaque CD4+ T-cells with no measurable effect on susceptibility to SIV infection

On the relative fitness of early and late stage Simian immunodeficiency virus isolates

Simian Immunodeficiency Virus SIVagm Efficiently Utilizes Non-CCR5 Entry Pathways in African Green Monkey Lymphocytes: Potential Role for GPR15 and CXCR6 as Viral Coreceptors

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