Feeling tired? Blame it on a virus.

Chronic fatigue syndrome (CFS), as the name suggests, leads to extreme tiredness in people over many years, and unlike the fatigue most of us feel after hard work or an acute illness, is not relieved by rest. Think of it like you feel during a cold, except that it lasts years.

There are estimates that CFS may affect about 1% of the world population. Though viral etiologies have been suggested, including the involvement of enteroviruses and herpesviruses, the cause of CFS has remained unknown. A new report in the magazine Science, shows the association of a retrovirus, called XMRV (xenotropic murine leukemia virus-related virus), to CFS. This virus was earlier implicated in prostate cancer, one of the most common cancers in men.

Is there anything common between prostrate cancer and CFS? Its too early to say, but lets look at the science and the evidence.

A report in 2006 in the journal PLoS Pathogens first showed the presence of XMRV in prostate cancer patients. Hereditary prostate cancer (HPC), which accounts for 43% of early onset cases and about 9% of all cases, is due to germline mutations in HPC genes. Robert Silverman and colleagues at the Cleveland Clinic Foundation found the HPC1 gene to code for RNase L, a protein involved in antiviral immunity. This suggested the possibility that chronic viral infections might predispose men to prostate cancer.  Together with Joseph DeRisi and Don Ganem at the University of California San Francisco, Silverman discovered XMRV in tumor-bearing prostate tissues (picture below). Interestingly, XMRV was present in prostate tissues of men who have a variant HPC1 gene (which makes a reduced activity variant of RNase L), but rarely in men with the wild type gene making normal RNase L.

The recent Science paper by Judy Mikovits' group from the Whittemore Pederson Institute in Reno (Nevada, USA) and collaborators at the National Cancer Institute in Frederick (Maryland, USA) shows that 67% of CFS patients, but only 3.7% of healthy persons, had XMRV in their blood. In cell culture experiments, these workers also demonstrated that XMRV obtained from CFS patients is infectious and can be transmitted from an infected cell to a healthy cell.

Is XMRV the cause of CFS? This is not proven yet. We only have an association. XMRV was detected in the blood of 68 of 101 CFS patients. What about the other 33? They may have levels of XMRV too low to detect by molecular methods (though I doubt this very much), or there may be other etiologies for CFS. It is also possible that XMRV is a passenger virus whose replication is activated (and it is therefore detectable) more often in CFS patients than in healthy people. What could be the reason(s) for such activation? It could be weakened innate immunity due to the low activity variant of RNAse L. CFS patients, just like those prone to prostrate cancer, carry this gene variant more often than healthy people.

The Science study also reports XMRV in the blood of 8 of 213 healthy persons. This 3.7% positivity also raises various issues Are these people able to control XMRV more effectively? What about the RNAse L variant in these persons? This also shows that XMRV is far more prevalent than previously believed.

Where did XMRV come from? The DNA of XMRV from prostrate cancer patients shows >90% identity to xenotropic murine leukemia virus, a virus found in strains of wild and laboratory mice. Mice produce low levels of this virus, which does not reinfect mouse tissues, hence called xenotropic - a virus that can grow in a species other than its origin. It is possible that XMRV jumped from mice to humans, and unlike in mice, where the virus is in equilibrium with its host, it is still evolving in humans, and is therefore associated with some clinical syndromes.

XMRV is found in the blood of CFS patients. It can potentially be transmitted through transfusion, intravenous drug use and other routes involving blood/blood cells. Whether it can transmit by other routes will depend upon where else it is found in humans. But transmission studies have not yet been done.

Is there an association between CFS and prostrate cancer? These studies are suggestive, but more direct studies are required.

These studies raise interesting questions, which will keep the field busy for many years to come.

References:
Urisman A, et al (2006). Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathogens, 2 (3) PMID: 16609730
Lombardi V, et al (2009). Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science DOI: 10.1126/science.1179052

Discussing viruses in Napoleon's backyard

I just returned from Ajaccio (pronounced Ajak-cio) on the western coast of the island of Corsica, a French territory in the Mediterranean Sea, which is actually closer to Italy than it is to France. Besides being an extremely beautiful locale, its claim to fame is being the birthplace of Napoleon Bonaparte.

The purpose of this trip was to attend a meeting of the International Consortium on Antivirals (http://www.icav-citav.ca/), "a not-for-profit drug development organization dedicated to the discovery and development of anti-viral therapies for neglected and emerging diseases." This was a small "by invitation" conference with scientists from various parts of the world who discussed emerging viruses, neglected diseases and strategies to fight them over 3 days.

Most of the group traveled from Marseille to Ajaccio (map on left), an overnight journey on the ship Napoleon Bonaparte. I flew from Delhi to Paris, on to Ajaccio to land at the (you guessed it right) Napoleon Bonaparte airport. Ajaccio, the capital city of Corsica is at the northern end of Ajaccio Bay (map on right). The conference was in Ajaccio, but we stayed at a resort called Coralia Club across the Bay at Porticcio (map on right), about 20 km by road or a 15 minute ferry ride across the Bay.

Ajaccio Bay is beautiful with hills lining it all along. It makes for a perfect setting to watch the sunset, and if you can get up early enough in the morning when the moon is full, it offers a spectacular sight. The pictures below show various moods across Ajaccio Bay, from Ajaccio and Porticcio.

Corsica is the fourth largest island in the Mediterranean Sea, with a coastline of over 1000 km and a population of only around 250,000. Large parts of the island are Nature Reserves, which includes rare breeding sites for sea eagles and protection for other endangered species. Corsica has been inhabited continuously since the Mesolithic Age and over time acquired an indigenous population that has influenced Mediterranean history. It became part of the Roman Empire, and was claimed by the Repulics of Pisa and Genoa. The Genoese took possession in 1347 and governed till 1729, briefly being taken by the French in 1553. The Corsican Independence Movement began in 1729 and 26 years later, in 1755 an independent Corsican Republic was formed under the leadership of Pasquale Paoli, which remained sovereign till 1768. In 1764, Corsica was secretly purchased by the French from the Republic of Genoa. Following a  brief civil war in 1768-69, Corsica was incorporated into France in 1770.

Napoleon Bonaparte (Nabulione Buonaparte) was born in 1769 in the house of Charles-Marie Buonaparte, an attorney and secretary to Pasquale Paoli. The modest 4-storey home is now a museum in the heart of Ajaccio, not far from the central piazza, the cathedral and the Town Hall.

The central piazza has a statue of Napoleon on horseback surrounded by his four brothers. Napoleon's presence is all over this town in the form of statues, streets and lanes.

Travel to the northern point of Ajaccio Bay and you come across some interesting sights. At lands end the coast is rocky and the Sanguinaires archipelago is visible with its Genoese tower, which was used to sight pirates and warn the inland population by lighting fires. Similar towers can also be found inland to relay the message through smoke and drums.

Another very interesting and unique sight towards the northern end of Ajaccio Bay is the Cemetery. It is unique because unlike other cemeteries with graves, this one has small chapels, each for an individual or many times even for a family.

While strolling through the Cemetery, I captured an interesting view with the chapels in the foreground and modern apartments in the background. I call this "Apartments for the Dead and Living".

The beauty of this place is awesome. I forget I was actually here to discuss viruses, viral diseases and research on drugs against them. So, back to the science.

The Conference was held at the Palais des Congres, which overlooks the Ajaccio Port. The first session presented an innovative model for funding drug development research. This included adding a small tax on international travel, which has so far raised over $500 million to finance access to medicines in developing countries.

The session "HIV - Present and Future Challenges" discussed various aspects of HIV vaccines, including recent success of the ALVAC-AIDSVAX prime-boost vaccine combination (which I covered in an earlier blog; Sept 24), and the failed Merck vaccine trial last year. Discussions also  focused on the host response to HIV infection and ways to modulate the host to contain infection.

The session "Dengue - An integrated model for arthropod-borne viral disease control" was dominated by an elegant and comprehensive talk by Eva Harris from UC-Berkeley. Eva's efforts from the bench to bedside in dengue research, her reach in impoverished and under-developed scientific communities, and her efforts to make them part of the solution are truly inspiring. Various other lectures and discussions focused on new drug targets in dengue and other flavi viruses. The community seems to be coming together for drug design and testing that requires coordination between virologists, structural biologists, bioinformatics experts, organic chemists, industry and clinical trials experts.

The sessions on "Emerging Viruses" started with  an entertaining but highly informative talk by Ernst Gould from Oxford University. Ernie's appearance and mannerisms reminded me of one of the comedians on the very funny TV show "Whose Line Is It Anyway". Various other speakers dealt with drug design efforts against hepatitis C virus, influenza virus, and more generic approaches to broadly active drugs against positive- or negtive-stranded RNA viruses. Predictably, pandemic flu viruses dominated the discussions.

This is definitely one of the best meetings that I have attended in a long time. Besides the beautiful surroundings, the science was good, discussions were intense but friendly and informal, the organization was superb, and there were just enough people to make it scientifically interesting yet personal.

One advantage of meeting in a small place is that even scientists get noticed. The Mayor of Ajaccio organized a reception for us in the Town Hall. We passed through a ceremonial Guard of Honour and were welcomed and addressed by the Mayor himself in the richly decorated Napoleon Bonaparte room.

The ICAV recognizes the state of scientific research and the pharmaceutical industry in India, and expressed interest in starting an India Consortium. A few MOUs were signed between ICAV and Indian institutions. We return energized from this conference and hope to get more Indian colleagues involved in this unique effort. We also hope to organize the 2011 ICAV Annual Conference somewhere in India.

I would like to personally thank  the organizers for inviting me and a few other colleagues from India. Jeremy and Michel are the brains behind ICAV; Rajan and Christine did all the logistics. Thank you everyone for a wonderful and stimulating meeting.

I hope to see you all in Montreal next year.

Agra - a Photo Essay

Agra is the architectural garden of the Moghuls. The Moghul rule was most powerful and prosperous during the reigns of Akbar, Jahangir and Shahjahan, all having governed from Agra till Shahjahan built a new capital in Delhi (Shahjahanabad). This power and prosperity shows in the architecture of Agra.

The Agra Fort is one of the largest in India and was the seat of this power. The entrance is over a moat and through a long incline with fortified walls to repel any enemy force trying to gain access.

The Fort shows a progression of styles from  the rugged power of its ramparts and outer walls to the ornate carvings on its columns. Its 16 different palaces span three rulers and a variety of designs - from Akbar's heavy reliance of Rajput building style to Shahjehan's finesse in marble and motifs. The Diwan-e-Khas (Hall of Private Audience) is small and ornate, while the Diwan-e-Aam (Hall of Public Audience) is large, columnar and symmetrical.

Agra is home to some important Mughal tombs and I will present these on a progressing time scale.

Akbar's tomb is at Sikandra, about 10 km from Agra on the road to Delhi. When I last visited it over 10 years ago, it was still a small sleepy village. Today, there are traffic jams on the road right in front of Akbar's magnificent tomb. He built is during his reign and it shows in the richness of design, the jalis (screens) and the motifs. The gate to enter the tomb is impressive. The tomb itself shows the influence of Hindu/Rajput architecture on early Mughal tombs in India, mixed with a typical Mughal layout with the tomb in the middle of a square garden.

Not far from Akbar's tomb is the tomb of his wife Mariam Zamani, the Rajput princess Jodha. Unlike the Emperor's tomb, it is hard to find and you will miss it unless you really look for it. It is about 1 km upstream (towards Delhi), on the opposite side of the road. It is plain and uses an earlier 'baradari' to house the tomb. Makes sense as it was built not by a loving husband, but by a son who was by then the king, and much under the influence of his own wife - the powerful Nur Jehan.

Nur Jehan, wife of Jehangir, the fourth Mughal emperor is associated with one of the most beautiful tombs in Agra - the Itamadud-daulah Tomb, locally known as "Baby Taj". This is the tomb of her father, a Persian nobleman and minister in Jehangir's court. The tomb is small, set in the middle of a garden, with three gates and one pavilion by the river Yamuna.  

The inlay work, the motifs and the jalis (screens) on this tomb are just exquisite. Most tourists in a rush miss this tomb, on the other bank of Yamuna from the Fort and the Taj Mahal.

Further down from Itamadud-daulah's Tomb on the same bank of Yamuna is the delightful Mehtab Bagh, a garden developed recently, but one used by Shahjahan and the later Mughals to view the Taj Mahal on a moonlit night. At sundown, Mehtab Bagh offers a view of the Taj Mahal different from that seen by most tourists, and you dont have to jostle with the crowds.

The Taj Mahal, the ultimate expression of love, was built by the fifth Mughal emporer Shahjahan for his wife, Mumtaz Mahal. The beauty, symmetry and presentation of this most famous Mughal tomb can only be experienced; it cannot be described. It is different from other Mughal tombs in that it is not in the centre of a garden, but at one end of it. The Taj Mahal is from an era in which Mughal power reached its pinnacle of power and prosperity, and this shows in its finesse. No more descriptions, just enjoy.