Murine leukemia virus glycosylated Gag (gPr80 gag ) facilitates interferon-sensitive virus release through lipid rafts

182

327

Chronic fatigue syndrome (CFS) is a serious systemic illness of unknown cause. A recent study identified DNA from a xenotropic murine leukemia virus-related virus (XMRV) in peripheral blood mononuclear cells (PBMCs) from 68 of 101 patients (67%) by nested PCR, as compared with 8 of 218 (3.7%) healthy controls. However, four subsequent reports failed to detect any murine leukemia virus (MLV)-related virus gene sequences in blood of CFS patients. We examined 41 PBMC-derived DNA samples from 37 patients meeting accepted diagnostic criteria for CFS and found MLV-like virus gag gene sequences in 32 of 37 (86.5%) compared with only 3 of 44 (6.8%) healthy volunteer blood donors. No evidence of mouse DNA contamination was detected in the PCR assay system or the clinical samples. Seven of 8 gag -positive patients tested again positive in a sample obtained nearly 15 y later. In contrast to the reported findings of near-genetic identity of all XMRVs, we identified a genetically diverse group of MLV-related viruses. The gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs and were even less closely related to those of ecotropic MLVs. Further studies are needed to determine whether the same strong association with MLV-related viruses is found in other groups of patients with CFS, whether these viruses play a causative role in the development of CFS, and whether they represent a threat to the blood supply.

Section: Discussionsupporting

confidence: 77%

RETRACTED: Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors

Pripuzova²,

Li³

et al. 2010

182

327

“…Glyco-Gag is incorporated into MLV virions (4,14), and we found that glyco-Gag mutant viruses have less stable capsids. Although it is possible that capsid stability and resistance to restriction are unlinked, our data suggest that by increasing the stability of the capsid, glyco-Gag renders these viruses more Fig.…”

Section: Discussionmentioning

confidence: 80%

“…Glyco-Gag mutant M-MLV buds differently from WT virus and contains less membrane cholesterol (13,14). To determine whether these changes affected stability of viral cores, we treated equal amounts of WT and glyco-Gag mutant virions isolated from NIH 3T3 cells with 0.5% Triton X-100, followed by sucrose density gradient centrifugation; the virion preparations contained the p30 CA only found in mature virions.…”

Section: Glyco-gag Mutant and Wt MLV Produced In Vivo Contains Apobec3mentioning

confidence: 99%

“…We found that glyco-Gag is important for late stage virus budding/release from infected fibroblasts and that mutant virus-infected cells show aberrant tubelike structures at the surface (13). Moreover, glyco-Gag appears to direct virus budding through lipid rafts, which results in high cholesterol content in the virus (13,14). Pizzato (15) reported that MLV glyco-Gag can complement an infectivity defect for nef-negative HIV-1 that is specific for lymphocytes and does not affect virus release.…”

mentioning

confidence: 90%

See 1 more Smart Citation

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Stavrou

Nitta

Kotla

et al. 2013

Self Cite

194

Pathogenic retroviruses have evolved multiple means for evading host restriction factors such as apolipoprotein B editing complex (APOBEC3) proteins. Here, we show that murine leukemia virus (MLV) has a unique means of counteracting APOBEC3 and other cytosolic sensors of viral nucleic acid. Using virus isolated from infected WT and APOBEC3 KO mice, we demonstrate that the MLV glycosylated Gag protein (glyco-Gag) enhances viral core stability. Moreover, in vitro endogenous reverse transcription reactions of the glyco-Gag mutant virus were substantially inhibited compared with WT virus, but only in the presence of APOBEC3. Thus, glyco-Gag rendered the reverse transcription complex in the viral core resistant to APOBEC3. Glyco-Gag in the virion also rendered MLV resistant to other cytosolic sensors of viral reverse transcription products in newly infected cells. Strikingly, glycoGag mutant virus reverted to glyco-Gag-containing virus only in WT and not APOBEC3 KO mice, indicating that counteracting APOBEC3 is the major function of glyco-Gag. Thus, in contrast to the HIV viral infectivity factor protein, which prevents APOBEC3 packaging in the virion, the MLV glyco-Gag protein uses a unique mechanism to counteract the antiviral action of APOBEC3 in vivonamely, protecting the reverse transcription complex in viral cores from APOBEC3. These data suggest that capsid integrity may play a critical role in virus resistance to intrinsic cellular antiviral resistance factors that act at the early stages of infection.intrinsic immunity | trex1 | virus restriction factors

“…The mechanisms engaged by gPr80 to promote virus replication remain largely unknown. However, a recent report has revealed that gPr80 affects release of both MLV and HIV-1 by facilitating budding from lipid rafts (48).…”

mentioning

confidence: 99%

MLV glycosylated-Gag is an infectivity factor that rescues Nef-deficient HIV-1

Pizzato

2010

102

Optimal infectivity of HIV-1 virions requires synthesis of the HIV-1 regulatory protein Nef in some producer cells but not others. A survey of 18 lymphoid cell lines found that Nef was dispensable in three, each of which harbored gammaretroviruses. Nef-dependent cell lines were rendered Nef-independent by a cell-free supernatant from the independent lines or by transfection of cloned murine leukemia virus (MLV). Analysis of MLV deletion mutations identified glycosylated gag (glycogag) as the factor that rescues Nef-defective HIV-1 virions. Glycogag was also demonstrated to be required for the infectivity of MLV virions produced in lymphoid cells. Direct comparison of Nef and glycogag revealed identical dependence for activity on Env-pseudotype and producer cell type. The two proteins colocalize within cells, and both increase the yield of viral cDNA in target cells. The functional similarity of Nef and glycogag is a compelling example of convergent evolution in which two structurally unrelated proteins provide a function necessary for virion infectivity in lymphoid cells.