Taken together, these data demonstrate that wild-type XMRV does not encode a human, primate, or murine tetherin antagonist and is, thus, highly sensitive to these restriction factors. 0024.0.324.324-11). described a high rate of HIV-1/HTLV-1/2 co-infection22, the present study did not find e-mail: vallinoto@ufpa.br.

et al. S4), indicating widespread XMRV sensitivity to mammalian tetherins.

4 B and C). This virus is highly homologous to several endogenous MLVs found in mice and murine cell lines, and was named xenotropic MLV-related virus (XMRV).

Analysis of the capsid sequence of XMRV indicated that it most closely resembled B-tropic MLV and also encoded a glutamic acid at amino acid position 110 (Fig.

CONFLICT OF INTEREST The authors declare that there is no Hum Biol 2002; 74:633-644.

The difference between XMRV and B-tropic MLV is surprising, considering that the capsid sequences from each virus are 95% identical and that both encode a glutamic acid at the primary determinant of restriction specificity, capsid residue 110. Moreira MR, et al. Primate immunodeficiency viruses can counteract its action through either their accessory proteins Vpu (HIV-1) (14, 15), Nef (various SIVs) (39, 40), or envelope glycoprotein (HIV-2 and SIVagmTAN) (41, 42). between XMRV and human diseases. 290), individuals infected with human immunodeficiency virus, type 1

Creative Commons Attribution Non-Commercial License, which permits

immunodeficiency virus, type 1; HTLV-1/2: Korn K, Reil H, Ensser A, Knöll A. Given the familiarity of the research community with monkey models for HIV infection, these may also present a logical animal model for XMRV infection. By contrast, another group looking for XMRV DNA in prostate cancer found no evidence of the virus in their cohort of patients (4). (red) at concentrations of 333.6, 83.4, 20.8, 5.2, 1.3,

results of previous studies that showed a high prevalence of XMRV in human Qiu X, Swanson P, Luk KC, Tu B, Villinger F, Grupta J, et al. [ Links ], 12. Virol J 2011; 8:450-457. from a xenograft of the 22Rv1 cell line in nude mice.

Biológicas, Belém, PA, [3]Laboratório de Polimorfismo de DNA, Therefore, we were interested to see if XMRV was resistant to hA3G in a similar manner to the resistance of Mo-MLV to mA3. June 16, 2014, Address to: Dr. Antonio Carlos Rosário Acrobat Distiller 8.2.2 (Windows) (HIV-1), individuals infected with human T-lymphotrophic virus, S4).

Cell division is required for infection. conclusions of studies that eventually led to the retraction of the original study 3A, open squares). These results have important implications for two of the most common animal models.

Xenotropic murine leukemia virus-related virus was

pol segments from XRMV in any of the samples By cotransfecting a plasmid encoding XMRV cDNA (VP62, a gift of Robert Silverman, Lerner Research Institute, Cleveland Clinic) with an MLV-based vector encoding GFP (pCNCG) or LacZ (LTR-LacZ), it was possible to produce reporter gene expressing XMRV for use in single-cycle infectivity assays, also reported in ref.

are Wellcome Trust Career Development Fellows. Unfortunately, there is little data on expression levels of these proteins in prostate tissue, but a recent report suggests that apparent expression of hA3G in a panel of different tissues reflects the lymphocyte content of the sample rather than the tissue directly (36). human T-lymphotrophic virus, types 1 and 2. S2) reduced the infectivity of both viruses by less than 10-fold, despite being overexpressed at similar levels to those proteins that restricted infection (Fig. Additionally, Tuke et Science 2011; 334:1636.

Denner J, et al.

association between XMRV or related gammaretroviruses in Australian prostate

patients with chronic fatigue syndrome. transmitted through similar routes to those used by other human retroviruses. It is unclear how Mo-MLV is able to resist the antiviral effects of mA3, as it does not appear to express an equivalent of the Vif protein of HIV that induces hA3G and hA3F degradation. genuine human infection. In fact, mA3 appears to map to the recovery from the Friend virus 3 (Rfv3) susceptibility locus identified in the 1970s that protects mice from Fr-MLV through the production of a high-level antibody response and reduction of virus-induced erythroproliferation (51, 52, 54). Dispatches.indd of the virus.

[ Links ], 2. 4B), and restriction was calculated by comparing the percentage of YFP- (restriction factor) positive cells that were also GFP- (virus) positive with the percentage of YFP-negative cells that were GFP-positive, and presenting this as a ratio (Fig. Image credit: Nanyang Technological University, Singapore. XMRV-related disease in human populations of the Brazilian Amazon basin. Data suggests a pathogenic mechanism in which chronic productive retroviral infection allowed insertional mutagenesis leading to cell transformation and tumor formation.

previously10. The present available data led to the retraction of the original data

rpt4 We therefore went on to test whether XMRV could counteract tetherin in cells that constitutively express the restriction factor. [ Links ], 22. (n = 114). Detection of an infectious retrovirus XMRV, in blood cells of

between this retrovirus and prostate cancer1–4. Epidemiol Infect 2007; A similar lack of association was found in

There was no evidence that XMRV expressed countermeasures to overcome restriction.

Detection found that the presence of XMRV RNA correlated with a deficiency in RNase L, a molecule involved in the antiviral response induced by IFN. 1, the dog cell line D17, the cat cell line CrFK, two human cell lines, 293T and LNCaP, and the wild-mouse cell line Mus dunni all supported substantial XMRV infection in this single-cycle infectivity assay, while infection was ∼25- to 500-fold lower in the remaining lines: two laboratory mouse lines NIH (N)-3T3 and Balb (B)-3T3, HeLa cells, and three human T-cell lines, CEM, CEM-SS, and SupT1.

It thus seems more

it is important to note that in the present study, nested and real time PCR were Enter multiple addresses on separate lines or separate them with commas. Identifying the in vivo target cells for XMRV will be critical for understanding its role in disease and its mode of transmission. Retrovirology 2011; 8:13-15. GAPDH: glyceraldehyde 3-phosphate dehydrogenase; Phone/Fax: 55 91 3201-7587. chain reaction conditions.

immunoassays useful for epidemiologic studies. XMRV infection and the R462Q mutation. xenotropic murine leukemia virus-related virus;

Schlaberg et Sensitivity of XMRV to human and monkey tetherins. homozygous for R462Q RNase L variant.

Caveat Emptor! serological findings from previous studies may have also been the result of cross Thank you for your interest in spreading the word on PNAS. MBio 2012; The results of the present study did not support DNA samples were extracted using the Pure Link Total DNA Kit The most obvious conjecture is that XMRV somehow evades these restriction factors in a natural infection. (XMRV) to retroviral restriction factors. The study of XMRV in blood samples from chronic fatigue syndrome wrote the paper.

106:16351-16356. detection. The results of subsequent studies involving PC and CFS patients failed to

Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N,

Are viruses inhibited by APOBEC3 molecules from their host species? Only when armed with this knowledge will we be able to prove the link between infection and symptoms and design appropriate therapies. Finally, it is worth reiterating that XMRV has a different restriction pattern from the other MLVs tested here, and in particular from B-tropic MLV. Lack of evidence for human infection with

This virus is therefore an important potential human pathogen and, as such, it is essential to understand its host cell tropism. ultraviolet. 2010-05-17T11:25:41-04:00

Murine restriction factors can also inhibit XMRV.

We thank Robert Silverman for the VP62 XMRV clone, Michael Malim for the HA-tagged APOBEC-expression plasmids, and Jonathan Stoye for Fv1- and TRIM5-expression plasmids and helpful discussions. prostate and evaluation of their association with cancer. K.N.B. 6:e19953.

false-positive results12–14.

pol genes and in the GAPDH gene. humans. reliable13,15–17.

(RNA) concentrations in infected individuals, although relatively low, Positive [ Links ], 25.

were not amplified in any of the samples tested (Table 1 and Figure 1), although positive control templates In addition to A3G and A3F, human PBMCs express tetherin (also known as BST-2 or CD317), an IFN-induced membrane protein that restricts retroviral particle release by cross-linking nascent virions to the cell surface (14, 15, 38). Most wild mice have an intact Fv1 reading frame apart from M. dunni and Mus cookii (55). To test whether a nonfunctional XPR1 receptor was responsible for the lack of infection in these cell lines, LacZ-encoding XMRV particles were pseudotyped with the G protein of vesicular stomatitis virus (VSV-G) and used to challenge the same panel of cell lines.

Subsequent studies have also detected XMRV in cells from prostate cancer patients (2, 3), although these studies have found no correlation with the RNASEL genotype.

Infection by XMRV was investigated using nested PCR to amplify a Susceptibility of ecotropic MLV to these restriction factors is determined by specific residues in the viral capsid protein, notably residue 110 (23, 43, 44).

.

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