virology blog

About viruses and viral disease

AIDS

Ten cool facts about viruses

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facts1. Some parasitic wasps lay eggs in caterpillars, where they mature into adult wasps. The wasp eggs contain a virus, encoded in the wasp genome, which prevents the caterpillar from rejecting the eggs.

2. There are a million virus particles per milliliter of seawater – for a global total of 1030 virions! Lined up end to end, they would stretch 200 million light years into space.

3. The genetic information of viruses can be DNA or RNA; single or double stranded; one molecule or in pieces.

4. The name virus was coined from the Latin word meaning slimy liquid or poison.

5. Walter Reed discovered the first human virus, yellow fever virus, in 1901.

6. Viruses are not alive – they are inanimate complex organic matter. They lack any form of energy, carbon metabolism, and cannot replicate or evolve. Viruses are reproduced and evolve only within cells.

7. Over 1016 human immunodeficiency virus genomes are produced daily on the entire planet. As a consequence, thousands of viral mutants arise by chance every day that are resistant to every combination of antiviral compounds in use or in development.

8. The first human influenza virus was isolated in 1933. In 2005, the 1918 pandemic influenza virus strain was constructed from nucleic acid sequence obtained from victims of the disease.

9. The biggest known viruses are mimiviruses, which are 400 nanometers (0.0004 millimeters) in diameter. The viral genome is 1,200,000 nucleotides in length and codes for over 900 proteins.

10. The smallest known viruses are circoviruses, which are 20 nanometers (0.00002 millimeters) in diameter. The viral genome is 1,700 nucleotides in length and codes for two proteins.

Bonus fact: The HIV-1 genome, which is about 10,000 nucleotides long, can exist as 106020 different sequences. To put this number in perspective, there are 1011 stars in the Milky Way galaxy and 1080 protons in the universe.

I made up this list a few weeks ago in response to a request from a journalist. The final version, shortened and re-ordered by an editor, was published online at ColumbiaNews.

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 52: Scott Hammer, MD on AIDS vaccines

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twiv-200Hosts: Vincent Racaniello and Scott Hammer, MD

On episode #52 of the podcast “This Week in Virology”, Vincent and Dr. Scott Hammer talk about different types of AIDS vaccines and how they are tested in clinical trials.

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TWiV 51: ALVAC-HIV and AIDSVAX B/E

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twiv-200Hosts: Vincent Racaniello, Dick Despommier, and Alan Dove

On episode #52 of the podcast “This Week in Virology”, Vincent, Dick, and Alan (with a cameo appearance by Rich Condit) review the world’s largest Phase III study of a complex HIV vaccine candidate in Thailand, immunization of salmon against infectious salmon anemia virus, and an outbreak of blueberry shock virus in Michigan.

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Click the arrow above to play, or right-click to download TWiV #51 (60 MB .mp3, 84 minutes)

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

Links for this episode:
HIV vaccine shows promise for the first time – description of the program, FDA background document (pdf), NEJM review on why AIDS vaccine is difficult (pdf), and arguments for the trial
Chile immunizes salmon (USGS article on the virus, pdf)
Blueberry virus strikes Michigan research center (information on the disease and the virus)
Rotavirus seasonality (thanks Didier!)
Viruses and the tree of life at virology blog
Big brains have evolved twice (thanks Arsen!)

Weekly Science Picks
Alan Bat Rabies and Other Lyssavirus Infections
Dick Boosting Vaccines: The Power of Adjuvants (Scientific American; subscription required)
Vincent The Ig Nobel Prizes by Marc Abrahams

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.

Polyomavirus JC, multiple sclerosis, Tysabri, and an anti-malaria drug

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mefloquineBiogen has announced that an anti-malaria compound may be useful for treating a brain infection, progressive multifocal leukoencephalopathy (PML), that is an adverse effect of the company’s multiple sclerosis/Crohn’s disease drug Tysabri. How does JC virus fit into this story?

Tysabri is the trade name for Natalizumab, a monoclonal antibody against the cellular protein alpha-4 integrin. The antibody was approved by the US Food and Drug Administration for the treatment of multiple sclerosis and Crohn’s disease. Both are autoimmune diseases in which the immune system damages host tissues. In multiple sclerosis, the immune system attacks the central nervous system, causing loss of the myelin sheath that surrounds neurons – also known as demyelination. As a consequence, nerve function is impaired, leading to physical and cognitive deterioration. In Crohn’s disease, immune cells damage the gastrointestinal tract, which causes severe pain, diarrhea, vomiting, and weight loss. The membrane protein alpha-4 integrin is important in the movement of immune cells from the bloodstream into surrounding tissues. Treatment with an antibody to this protein is believed to inhibit such cell movement, thereby decreasing the immune attack in multiple sclerosis and Crohn’s disease.

Tysabri is an immunosuppressive drug, and the problem with treating any illness with such a compound is that opportunistic infections may occur. Indeed, shortly after Tysabri was approved, several cases of progressive multifocal leukoencephalopathy occurred in recipients of the drug. This is a rare and usually fatal neurological disease caused by the polyomavirus JC. The virus multiplies in and destroy oligodendrocytes, which are cells of the brain that produce the myelin sheath surrounding neurons. JCV was identified in 1971 by inoculation of brain material from a PML patient into cultured human fetal glial cells. In the same year, another polyomavirus, BK, was isolated from the urine of a human renal transplant patient.

Both JCV and BKV are widespread in humans: it has been estimated that up to 90% of the global population is infected with these viruses. Most infections are asymptomatic, making it difficult to determine how the virus is transmitted. They are probably shed intermittently throughout life and spread to others by respiratory or oral routes. Why these viruses can persist for long periods in humans without causing disease is a mystery.

When patients are immunosuppressed – for organ transplantation, as a consequence of AIDS, or by treatment with Tysabri or other monoclonal antibodies that dampen the host immune response – JCV  may multiply unchecked and cause PML. These observations tell us that the immune system is important in regulating the asymptomatic nature of  human polyomavirus infections.

MS is a relatively common disease (incidence 2-150 per 100,000 population) and therefore treatments such as Tysabri are extremely useful. Clearly it was important for Biogen to determine how to limit the incidence of PML in patients receiving this antibody. Screening a chemical library of 2000 FDA-approved drugs identified mefloquine as an inhibitor of JCV. This compound is now being tested in humans for treatment of PML.

Other human polyomaviruses, including Li, WU, and Merkel cell virus, have been identified in human samples. As immunosuppressive therapy becomes more commonly used to treat a variety of human illnesses, these and other yet undiscovered viruses are likely to emerge as new pathogenic agents. We do not know how many different viruses colonize humans without causing disease. But it is safe to conclude that the zoonotic pool is not the only source of new virus infections for us to worry about.

Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, & Dessel BH. (1971). Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet, 19, 1257-1260 PMID: 4104715

Gardner SD, Field AM, Coleman DV, & Hulme B. (1971). New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet, 19, 1253-1257 PMID: 4104714

Brickelmaier, M., Lugovskoy, A., Kartikeyan, R., Reviriego-Mendoza, M., Allaire, N., Simon, K., Frisque, R., & Gorelik, L. (2009). IDENTIFICATION AND CHARACTERIZATION OF MEFLOQUINE EFFICACY AGAINST JC VIRUS IN VITRO Antimicrobial Agents and Chemotherapy DOI: 10.1128/AAC.01614-08

TWiV #22: Viral Bioinformatics

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twiv-200In episode #22 of This Week in Virology, Vincent and Chris Upton converse about hepatitis B in India, AIDS gene therapy with a ribozyme, antibodies that neutralize many influenza virus strains, killing tumors with vaccinia virus, myxoma virus of rabbits, and the Viral Bioinformatics Resource Center.

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