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XMRV and chronic fatigue syndrome

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XMRVA retrovirus that has been implicated in prostate cancer has now been found in the blood of patients with chronic fatigue syndrome. What is this virus and where did it come from?

Chronic fatigue syndrome (CFS) is a disease characterized by fatigue and chronic inflammation that can last years and may affect ~1% of the world’s population. The etiology of the disease is unknown, although several viruses have been suggested to be involved, including enteroviruses and herpesviruses.

The retrovirus XMRV (xenotropic Moloney murine leukemia virus-related virus) was recently identified in the tumor tissue of individuals with prostate cancer. XMRV nucleic acid was detected by polymerase chain reaction in the blood of 68 out of 101 samples (67%) from CFS patients. The virus was also found in 8 of 213 samples (3.7%) from healthy individuals. Antibodies to the virus were found in 19 of 30 CFS blood samples, but not in 16 healthy control specimens. Viral proteins were identified in both B and T lymphocytes, and infectious virus could be cultured from these cells.

Nucleotide sequence analysis of two XMRV genomes cloned from patient samples revealed that the virus is >99% identical to the virus identified in prostate cancers. Nevertheless, the two XMRV genomes are sufficiently different to suggest that the two CFS patients were independently infected.

These findings must be verified by more extensive analysis of CFS and healthy populations worldwide. But XMRV is real and its presence in people raises many questions.

Where did XMRV come from? The retroviruses identified in patients with CFS or prostate cancer are highly related (more than 90% DNA sequence identity) to a group of viruses of wild and laboratory mice called xenotropic murine leukemia virus. Xenotropic MLVs are endogenous retroviruses of mice – the viral DNA is integrated into the mouse genome. Mice produce low levels of the virus – a few infectious viruses per milliliter of blood – but the virus cannot reinfect mouse tissues (hence the name ‘xenotropic’, meaning a virus that can grow in species other than that of its origin). These viruses can infect many cells, including human cells. Therefore it is not unreasonable to hypothesize that XMRV is a xenotropic MLV that crossed from mice to humans. Remember the zoonotic pool?

Does XMRV cause CFS? While the presence of XMRV in 67% of CFS samples seems impressive, it could be misleading. For example, the samples could be from regions where XMRV infection is common. Alternatively, patients with CFS could be more susceptible to infection. This is why more extensive epidemiological studies must be done.

How would XMRV be transmitted? Since XMRV is in the blood, it could be transmitted via transfusion, intravenous drug use, or by any other blood-borne route. Whether or not other modes of transmission (respiratory, sexual) are involved depends on where else the virus is found in humans.

How would XMRV cause disease? One idea is that infection with XMRV, which is present in high titers in the blood, leads to a continuous, long-term immune response. Think about how you feel during the 5 days of an influenza virus infection. A vigorous immune response exhausts the body, especially when it is chronic.

Many CFS patients develop cancer. It will be interesting to determine if XMRV integration into human DNA activates oncogenes, leading to cell transformation.

What about the 3.7% of healthy people who have XMRV? If this number is representative of the general population, then many millions of individuals would harbor the virus. XMRV could be involved in other diseases of unknown origin.

It will take time to answer the many questions raised by the discovery of XMRV. The good news is that some of the anti-retroviral drugs licensed for treating AIDS can be immediately tested for their efficacy against CFS.

Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, & DeRisi JL (2006). Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS pathogens, 2 (3) PMID: 16609730

Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, & Mikovits JA (2009). Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science (New York, N.Y.) PMID: 19815723

Schlaberg R, Choe DJ, Brown KR, Thaker HM, & Singh IR (2009). XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proceedings of the National Academy of Sciences of the United States of America, 106 (38), 16351-6 PMID: 19805305

TWiV 50: XMRV

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twiv-200Hosts: Vincent Racaniello and Jason Rodriguez

On episode #50 of the podcast “This Week in Virology”, Vincent and Jason review influenza 2009 H1N1 vaccine trials and protection against the virus conferred by the 1976 swine flu vaccine, then move on to a virus called XMRV and its possible role in prostate cancer.

[powerpress url=”http://traffic.libsyn.com/twiv/TWiV050.mp3″]

Click the arrow above to play, or right-click to download TWiV #50 (54 MB .mp3, 74 minutes)

Subscribe to TWiV in iTunes, by the RSS feed, or by email

Links for this episode:
One dose of influenza 2009 H1N1 vaccine without adjuvant is enough
Partially completed study on influenza 2009 H1N1 vaccine with MF59 adjuvant
1976 swine flu vaccine induces cross-reactive antibodies against influenza 2009 H1N1 strain
Explanation of hemagglutination-inhibition and microneutralization assays
FDA approves influenza 2009 H1N1 vaccine
XMRV is present in malignant prostatic epithelium and is associated with prostate cancer
Identification of a novel gammaretrovirus in prostate tumors
CDC page on Guillain-Barré syndrome

Weekly Science Picks
Jason Glass Microbiology
Vincent FluWeb Influenza Historical Resources Database

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv or leave voicemail at Skype: twivpodcast. You can also send articles that you would like us to discuss to delicious and tagging them with to:twivpodcast.

A retrovirus is invading the Koala genome

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friendly-male-koalaThere are 62 koalas in Japanese zoos, and 50 of them are infected with koala retrovirus (KoRV). Infection may lead to leukemia and lymphoma, which could negatively impact Koala populations. What is the origin of KoRV?

The koala is native to Australia where they are found in eastern and southern coastal areas. All koalas in the eastern state of Queensland are infected with KoRV, while there are still some uninfected animals in the south. In particular, the koalas on Kangaroo Island do not carry the virus. Koalas were imported to Kangaroo Island in the early 1900s, and apparently those animals were free of KoRV. The island is 8 miles offshore which may contribute to the absence so far of the virus. However, the koalas sent to Japanese zoos likely carried KoRV.

Curiously, 38 koalas have been born in Japanese zoos since the original importation, and 36 of these animals are infected with KoRV. This high rate of infection is a consequence of the fact that KoRV DNA integrates into DNA of koala germ cells. The viral genome is transmitted vertically, from mother to offspring.

The nucleic acid of retroviruses is RNA, but it is converted to a DNA copy during infection and integrates into host cell DNA. If the viral DNA integrates into the germ line, then it can remain in the organism for many generations. The genomes of most higher organisms contain remnants of retroviral genomes called endogenous retroviruses (ERVs). In primates these infections appear to have occurred millions of years ago; in humans, they comprise 6-8% of the genome, more than protein coding sequences (1-2%)! Most ERVs are defective but the koala ERVs are unique because they appear to produce viral particles.

No one has ever observed germ-line infection of a species with retroviruses – until infection of koalas with KoRV was discovered.  This process of ‘endogenization’ can now be studied in real time.

When did the KoRV begin invading the koala genome? It has been suggested that the initial infection occurred less than 100 years ago, but examination of preserved Koala DNA will be required to confirm this estimate.

The origin of most ERVs is unknown because the original infecting viruses disappeared long ago. But it might be feasible to identify the precursor of KoRV, which entered the genome relatively recently. KoRV appears to be closely related to an ERV of the Asian mouse Mus caroli. If this relationship is correct it will have to be determined how the virus was transmitted from mice in Southeast Asia to koalas in Australia.

Infection with KoRV in captive animals may lead to fatal lymphomas or immunosuppression and chlamydial infection. It is possible that infection of wild animals might lead to further decreases in this dwindling population. Should a KoRV vaccine developed to prevent extinction? Development and testing of a vaccine would require the use of koalas. It’s a difficult question, because the spread of KoRV among koalas is a natural part of evolutionary selection. Should we interfere?

Stoye, J. (2006). Koala retrovirus: a genome invasion in real time Genome Biology, 7 (11) DOI: 10.1186/gb-2006-7-11-241

Tarlinton, R., Meers, J., & Young, P. (2006). Retroviral invasion of the koala genome Nature, 442 (7098), 79-81 DOI: 10.1038/nature04841

TWiV #28: SARS

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twiv_aa_2001On episode #28 of the podcast “This Week in Virology”, Vincent, Dick, Alan, and Eric F. Donaldson discuss a new test for influenza H5N1, poliovirus in Minnesota, Koala retrovirus, batteries made from viruses, and SARS.

Click the arrow above to play, or right-click to download TWiV #28 or subscribe in iTunes or by email.

Integration of arenavirus DNA into the cell genome

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retrotransposonIs that title correct? Arenaviruses have an RNA genome which is not known to be copied into DNA at any stage of the replication cycle. How could a DNA copy of this virus be produced and be inserted into the host genome?

The RNA genome of retroviruses is converted to a DNA form during viral replication by the viral enzyme reverse transcriptase. The viral DNA then integrates into the host’s genome, becoming a permanent part of the cell. These events have no counterparts during replication of arenaviruses. The RNA genomes of these viruses are copied via an RNA intermediate, entirely in the cytoplasm of the cell. Nevertheless, the authors of a recent study found a DNA copy of the RNA genome of lymphocytic choriomeningitis virus (LCMV), a commonly studied arenavirus, integrated into host cell DNA.

This unusual story began in 1979 with the report that DNA complementary to the RNA genome of LCMV can be detected in about 1 in 103 to 104 infected cells. The authors speculated that retroviruses were involved but did not provide mechanistic evidence. Eighteen years later, the authors subcloned these cells to produce cell lines containing LCMV DNA. They then used polymerase chain reaction to isolate LCMV DNA from the cloned cells, including the cellular sequence flanking the viral genome. Nucleotide sequence analysis revealed that both cell lines contain a copy of the viral glycoprotein (GP) gene joined to cellular sequences encoding an IAP (intracisternal A type) retrotransposon. The authors identified LCMV integration both in cultured cells and infected mice.

Retrotransposons are sequences related to retroviruses that are found in the genome of many organisms. The gene content and arrangement are similar to retroviruses, but they lack an extracellular phase: they do not encode an env gene. Retrotransposons may be retroviral progenitors, or degenerate forms of these viruses. They are amazingly abundant: 42% of the human genome is made up of retrotransposons.

Based on their experimental results, the authors proposed that the following events occurred in a cell infected with LCVM. During copying of the retrotransposon RNA into a cDNA copy by reverse transcriptase, the enzyme switched templates and began copying the LCMV GP RNA. This hybrid DNA – retrotransposon linked to LCVM sequences -  then integrated into the host genome.

The results reported in this paper have enormous implications for evolution and for human gene therapy. Because retrotransposons transpose most efficiently in the thymus and testicles, the recombination events described could lead to transmission of RNA virus genes in the germline. Therefore the contribution of non-retroviral RNA viruses to evolution of the mammalian genome might be greater than previously believed. In addition, it is possible that RNA virus vectors used for gene therapy could integrate into the human genome via the mechanism described in this study. Such integration could lead to undesired mutation such as activation of oncogenes. Therefore the ability of specific RNA virus vectors to integrate into the human genome should be carefully tested before the vectors are approved for use in humans.

Rolf M. Zinkernagel, Paul Klenerman, Hans Hengartner (1997). A non-retroviral RNA virus persists in DNA form Nature, 390 (6657), 298-301 DOI: 10.1038/36876

M. B. Geuking, J. Weber, M. Dewannieux, E. Gorelik, T. Heidmann, H. Hengartner, R. M. Zinkernagel, L. Hangartner (2009). Recombination of Retrotransposon and Exogenous RNA Virus Results in Nonretroviral cDNA Integration Science, 323 (5912), 393-396 DOI: 10.1126/science.1167375