Origins of XMRV Deciphered, Undermining Claims for a Role in Human Disease
[Excerpted from a 31 May 2011 press release by the National Cancer Institute.]
Delineation of the origin of the retrovirus known as XMRV from the genomes of laboratory mice indicates that the virus is unlikely to be responsible for either prostate cancer or chronic fatigue syndrome in humans, as has been widely published. The virus arose because of genetic recombination of two mouse viruses. Subsequent infection of lab experiments with XMRV formed the basis of the original association.
Reporting in Science, Vinay Pathak, Ph.D., and his research team from the National Cancer Institute (NCI), part of the National Institutes of Health, in collaboration with other researchers, described experiments that provide an understanding of when and how XMRV arose and explain the original, incorrect association. XMRV stands for xenotropic murine leukemia virus–related virus.
This study is being reported in the same issue of Science as another study of XMRV (Knox et al.) that finds a lack of association between the virus and CFS even in the same patients from a 2009 study. "Taken together, these results essentially close the door on XMRV as a cause of human disease," said John Coffin, Ph.D., special advisor to the NCI director, and professor at Tufts University School of Medicine, a coauthor of the paper with Pathak.
Murine leukemia viruses are retroviruses that cause cancers and other diseases in mice. They are divided into different classes, one of which is xenotropic murine leukemia viruses. Although viruses in this class cannot grow in or infect cells from most mice, in the laboratory they can infect cells from other species, including human cells.
XMRV was first reported in samples from a human prostate tumor in 2006, and has been reported to be present in 6 percent to 27 percent of human prostate cancers. Later research reported XMRV in the blood of 67 percent of people with CFS.
The assertion that XMRV is circulating in the human population has been challenged by several studies that have failed to detect XMRV in multiple sets of specimens from people with prostate cancer or CFS and healthy controls.
To try to resolve the degree of association between XMRV and human disease, Pathak, who led these studies at NCI in its Viral Mutation Section, Coffin, and their colleagues examined human prostate cancer cells which contained XMRV, as well as the tumors from which these prostate cell specimens arose after they were grafted into mice. Grafting human tumors, called xenografts, into mice is a common way to study disease when it might be unsafe to test new treatments or methods in humans.
Upon careful examination in this new study, it was shown that initial prostate tumor xenografts did not contain XMRV but later tumors that had been derived from them did, demonstrating that XMRV was not present in the original human tumor as previously supposed. Instead, the virus appears to have infected tumor cells while they were in mice. In addition, the mice that were used for xenografting the prostate tumor cells contained two previously undescribed viruses, PreXMRV-1 and PreXMRV-2. Each of these viruses has a stretch of over 3,200 nucleotides, the basic building blocks of DNA, which is nearly identical to XMRV, differing by only a single nucleotide.
Genetic comparison of the PreXMRV-1 and PreXMRV-2 sequences revealed that each one has non-overlapping stretches that are nearly identical to XMRV. Pathak, Coffin, and their colleagues postulate that recombination between these viruses generated XMRV in human cells while the cells were being grown in a mouse sometime between 1993 and1996 and infected the prostate tumor cells. Recombination between virus genomes in a cell infected by more than one virus is common.
Based on this genetic analysis, the scientists concluded that XMRV was not present in the original prostate tumor samples but arose only after they had been put into mice. The probability that an identical recombination event occurred independently is about 1 in 1 trillion, making it extremely unlikely that XMRV arose from another source. The researchers concluded that the association of XMRV with human disease is due to contamination of samples with virus originating from this recombination event.
"After the reports of XMRV in human prostate cancer, and later of XMRV in people with CFS, retrovirologists all over the world were excited to explore its role in human infection and disease. The results published today are not what we would have expected, but due to the time and resources dedicated to the understanding of this virus by researchers at NCI and NIH as well as others, scientists can now concentrate on identifying the real causes of these diseases," said Pathak.
Paprotka, T., Delviks-Frankenberry, K.A., Cingöz, O., Martinez, A., Kung, H.-J., Tepper, C.G., Hu, W.-S., Fivash, M.J., Jr., Coffin,
J.M., and Pathak, V.K. (2011) Recombinant origin of the retrovirus XMRV (PDF - 336 K). Science 333: 97-101.
Knox, K., Carrigan, D., Simmons, G., Teque, F., Zhou, Y., Hackett, J., Jr., Qiu, X., Luk, K.C., Schochetman, G., Knox, A., Kogelnik, A.M., and Levy, J.A. (2011) No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected (PDF - 644 K). Science 333: 94-97.
For a Q&A on XMRV, please go to http://www.cancer.gov/newscenter/qa/2011/xmrv_qa.
Vastag, B. (2011) Reports: Mouse virus doesn’t cause chronic fatigue syndrome. Washington Post, May 31.
Tuller, D. (2011) 2 studies examine syndrome of fatigue. New York Times, June 1.
Racaniello, V., Dove, A., Condit, R., and Goff, S. (2011) Exit XMRV. This Week in Virology podcast #136, June 5.
Smith, S.A. (2011) XMRV and chronic fatigue syndrome: So long, and thanks for all the lulz, Part II. ScienceBlogsTM June 1 ERV post.
Delviks-Frankenberry, K., Cingoz, O., Coffin, J.M., and Pathak, V.K. (2012) Recombinant origin, contamination, and de-discovery of XMRV. Curr. Opin. Virol. 2: 499-507.
Science Watch Fast Breaking Paper Commentary, 2012: NCI’s Vinay K. Pathak on the “De-Discovery” of a Retrovirus-Disease Link
Parrish, N. (2012) Science Watch names Pathak’s article
“fast breaking paper”. The Poster Dec 12: 4.
In a Class by Themselves: HIV-Positive Individuals with Exceptional Immune Control
Researchers in the HIV Drug Resistance Program and their collaborators are moving closer toward understanding why approximately 1 in 200 people who are infected with HIV-1 rarely develop AIDS. This “elite controllers” group is distinguished as having viral loads below the detectable limit of standard HIV-1 assays and having normal CD4+ T-cell counts for at least 7 years without undergoing antiviral therapy. From previous studies of these healthy patients, it was unclear whether HIV-1 is able to infect new cells or whether replication of the virus is absent or completely blocked. A recent study of elite controllers by Mens et al. is the first to document that two key gene regions of HIV-1 are evolving in these individuals, suggesting that the virus undergoes full cycles of replication. In contrast, the persistent low-grade viremia in patients on successful antiviral therapy likely stems from a reservoir of long-lived cells, not from infection of new cells, as viral replication is completely blocked in these individuals. The authors conclude that natural control of HIV infection is very different from the control obtained through the use of antiviral therapy. These results raise hope for the development of more effective drugs or vaccines that can delay disease progression and prevent transmission by reducing the viral load, even if such therapies do not completely block HIV replication.
Mens, H., Kearney,
M., Wiegand, A., Shao, W., Schřnning, K., Gerstoft, J., Obel, N., Maldarelli,
F., Mellors, J.W., Benfield, T., and Coffin,
J.M. (2010) HIV-1 continues to replicate and evolve in patients with natural control of HIV infection (PDF - 840 K). J. Virol. 84: 12971-12981. [Link to Microbe feature: Exceptional Immune Response Suppresses HIV-1]
Analysis of a Retroviral RNA Packaging Signal
All viruses must somehow specifically package their RNA or DNA genome into assembling virus particles. In the case of retroviruses, the genomic RNA is selectively packaged by virtue of a poorly defined "packaging signal," called Ψ, near the 5’ end of the RNA. Retroviral RNAs are present in the virus particles in dimeric form: two copies of the viral RNA are joined together by a limited number of base pairs. Detailed structural analysis, using both NMR and a chemical probing technique termed SHAPE, has previously shown that there are differences in the structure of monomeric and dimeric RNAs of Moloney murine leukemia virus (MLV), a prototypical gammaretrovirus. Specifically, two copies of the sequence UCUG-UR-UCUG (where R is G or A) are partially base-paired in monomeric RNA, but become unpaired when the RNA dimerizes. In collaboration with the laboratories of Kevin Weeks (University of North Carolina) and Robert Gorelick (SAIC-Frederick), we have extended these studies and shown that a) nucleocapsid protein, the principal RNA-binding viral protein, is bound to this sequence within MLV particles; b) recombinant Gag (the building block of retrovirus particles) and nucleocapsid proteins specifically bind this sequence in vitro; and c) replacement of the UCUG-UR-UCUG in viral RNA with UCUA-UR-UCUA completely prevents selective packaging of the RNA.
These results show that the G residues in this sequence motif are essential for selective RNA packaging and that Gag selects the viral RNA for packaging because Ψ is a high-affinity binding site for the protein. This study also explains why dimeric RNAs are selectively packaged, and has broader implications for RNA recognition involving simple sequence elements embedded in a large RNA structure.
Gherghe, C., Lombo, T., Leonard, C.W., Datta, S.A.K., Bess, J.W., Jr., Gorelick, R.J., Rein, A., and Weeks, K.M. (2010) Definition of a high-affinity Gag recognition structure mediating packaging of a
retroviral RNA genome. Proc. Natl. Acad. Sci. USA 107: 19248-19253.
[Link to PNAS Online version of article - 640 K]
Getting off to a Good Start: Conformational Dynamics of the HIV Initiation Complex
Human immunodeficiency virus (HIV) initiates reverse transcription from a cellular tRNALys,3 hybridized to a specific region near the 5’ terminus of its (+) viral RNA (vRNA) genome, designated the primer binding site or PBS. This process has been characterized biochemically by a slow initiation phase with specific pauses, followed by a fast elongation phase. However, the mechanisms underlying the slow initiation and the transition to the elongation phase have not been fully elucidated. In this publication Liu et al. report a single-molecule study that monitors the dynamics of individual initiation complexes, comprised of the vRNA template, tRNA primer and HIV-1 reverse transcriptase (RT). RT dynamically transitions (“flips”) between two opposite binding orientations on tRNA:vRNA complexes, and the prominent pausing events are caused by enzyme binding in an orientation opposite to the polymerase-competent configuration. A stem-loop structure ahead of the PBS is responsible for maintaining the enzyme predominantly in this flipped orientation. Disrupting the stem-loop structure, through site-directed mutagenesis or inclusion of the HIV-1 nucleocapsid protein, triggers the transition to the elongation phase. These results highlight the important role played by the structural dynamics of the initiation complex in directing transitions between early reverse transcription phases.
Liu, S., Harada, B.T., Miller, J.T., Le Grice, S.F.J., and Zhuang, X. (2010) Initiation complex dynamics direct the transitions between distinct phases of early HIV reverse transcription (PDF – 793 K). Nat. Struct. Mol. Biol. 17: 1453-1460.
Anti-HIV Drugs and Host APOBEC3 Proteins Inhibit XMRV
A newly discovered retrovirus, XMRV, isolated from prostate cancer tissues for the first time in 2006, has recently also been reported to be isolated from patients with chronic fatigue syndrome (CFS). However, five subsequent studies could not validate these reports. Since XMRV was isolated from the T and B cells of CFS patients, Vinay Pathak and his colleagues in the HIV Drug Resistance Program sought to determine how XMRV was countering intracellular defense mechanisms that inhibit retroviral replication in human cells.
Studies of interactions between HIV-1 and human host proteins have revealed intracellular defense mechanisms that inhibit the replication of a variety of viruses. For example, the proteins APOBEC3G (A3G) and APOBEC3F (A3F) are members of a family of cytidine deaminases that potently inhibit the replication of HIV-1 in the absence of the virally encoded Vif protein, in part by inducing massive amounts of G-to-A mutations in the viral genome. A3G and A3F also inhibit murine leukemia virus, a virus closely related to XMRV, and these proteins are expressed in human peripheral mononuclear cells such as CD4+ T and B cells. The Pathak team showed that XMRV is also highly sensitive to inhibition by A3G and A3F, and therefore, this virus most likely does not efficiently replicate in the CD4+ T and B cells that express these inhibitory proteins. Their study suggests that the virus may replicate in cells that do not express these proteins, and has important implications for the in vivo cells targeted by XMRV for infection.
XMRV is a member of the gammaretroviruses genus of viruses, which infect a wide range of mammalian species and are associated with a variety of cancers and neurological or immunological disorders. So far, it has not been established that XMRV infection contributes to the pathogenesis of prostate cancer or CFS. However, in view of the potential of gammaretroviruses to cause disease, Pathak and his colleagues sought to identify drugs that could inhibit XMRV replication in humans. They developed a cell culture assay to test the ability of anti-HIV-1 drugs to inhibit XMRV replication and found that three of the eight drugs tested — AZT, tenofovir, and raltegravir — inhibited XMRV replication at concentrations similar to those that inhibit HIV-1 replication. In fact, XMRV was about 2.5-fold more sensitive to raltegravir than HIV-1. Although inhibition of XMRV by AZT had been previously reported, the Pathak group showed for the first time that XMRV replication could be inhibited potently by tenofovir and raltegravir. Their results suggest that if XMRV is indeed found to contribute to human disease, the anti-HIV-1 drugs AZT, tenofovir, and raltegravir may be useful for treatment of XMRV infection. Importantly, it may be possible to devise combination antiviral therapy for treatment of XMRV infection by using these inhibitors. Combination therapies with three or more drugs have been an effective tool for controlling HIV-1 replication and suppressing the emergence of drug-resistant HIV-1 in patients; therefore, a similar strategy may prove efficacious against XMRV replication. [Excerpted from the CCR In the Journals article "Retrovirus XMRV Is Inhibited by Host Proteins and Anti-HIV Drugs AZT, Tenofovir, and Raltegravir." To read more, click
Paprotka, T., Venkatachari, N.J., Chaipan, C., Burdick, R., Delviks-Frankenberry, K.A., Hu, W.-S., and Pathak, V.K. (2010) Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs (PDF – 1710 K). J. Virol. 84: 5719-5729.
HIV DRP Publications (February–May 2013)
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