Sunday, 23 June 2013

Agricultural Shows; a virus' dream?

This week saw the annual event when farmers descend from all parts of Scotland to compare their animals: The Royal Highland Show. I went along and, after a while wandering around the tractors, had a look around the livestock. Looking at the plethora of pampered sheep and cattle, a few things occurred to me. 
First was a half-hearted feeling of 'missed opportunity'. Sheep in particular, but also cattle, had come from across Scotland (and beyond). Imagine if a blood sample of every animal had been taken. Schmallenberg virus (SBV) is known to have reached, and circulated, in Scotland, but nobody knows to what extent. Perhaps testing these animals may have given a cross-section of SBV distribution across Scotland. Maybe even an idea of variation in breed susceptibility; although there's nothing really suggesting that such differences exist.

Show time: a Jacob sheep gets a final trim in the sheep yard prior to showing at the Royal Highland Show.
Second was considering the potential for transmission and dissemination of pathogens across wide geographical areas. In 2001 in the UK the dispersal of Foot and Mouth Disease Virus to various regions was due, at least in part, to the mixing and distribution of sheep from Hexham Market. Agricultural shows represent a similar type of mixing event, and last for days rather than hours. In the case of Foot and Mouth, the clinical signs are mild in sheep, thus allowing infected animals to go unnoticed.

Bringing animals to the show with clinical signs of disease is unlikely to happen as the idea is obviously to show the best animals. That restricts the possibility of infectious animals to those in a pre-clinical incubation stage. However, shows lasting for several days gives sufficient time in which to develop a viraemia and allow transmission, either via direct contact, fomites or vectors. Unsurprisingly there are already studies on the role of agricultural shows. One regarding UK shows (Webb, 2006) revealed competitors at shows to form a large network, with some competitors travelling to shows up to 600 km apart. Clearly there is potential, but thus far nothing seems to have been nailed down showing an outbreak resulting from mixing at agricultural shows.

Fig. 4
The impact of time-between shows: the number of days between shows affects the network, no time limit results in a mass network (a) whereas time limits of 14 days (b), 10 days (c) or 7 days (d) reduce the number of nodes, effectively separating shows and breaking links. From Webb 2006.

Third was the zoonotic potential.
It is well established that  cross-species transmission of zoonotic pathogens occurs at the interface between the animal source and humans. These shows represent perfect scenarios for such interactions. Largely absent from the Royal Highland Show were pigs, which have previously been shown to be a source of influenza A infection. Pigs may therefore represent more of a risk due to their ability to sustain various zoonotic agents. Likewise shows where chickens and ducks are present, offering the possibility for the transmission of avian influenza.  

Odd choice: A sheep decides a coat is preferable to hay.

The idea of catching bugs from farm animals at these kind of events, as well as at petting farms for kids etc., is not new. And it is true, infections do happen. The knee-jerk response of a modern nanny state society, at least in the UK, would therefore dictate the banning of such scenarios, including all agricultural shows without question. But this is another case of putting risk into perspective; of all the millions of animals, and the millions of contacts with humans that have happened at these shows over the years, how many infections have occurred, or at least been serious enough to cause alarm? The simple answer: not many. For now though, the relative importance that agricultural shows play in the transmission, evolution and species transfer of viruses remains largely unknown.

Webb, C.R. (2006) Investigating the potential spread of infectious diseases of sheep via agricultural shows in Great Britain. Epidemiol Infect. 134(1)31-40. doi: 10.1017/S095026880500467X

Sunday, 9 June 2013

Françoise Barré-Sinoussi visits the Centre for Virus Research
Few stories in virology can have been more frequently or comprehensively covered as the early days of the HIV/AIDS epidemic. Randy Shilts' 'And the Band Played On' is surely one of the most detailed accounts and, whilst massive, provides insights into what went on in the first few years of the epidemic. If you don't fancy reading the book, there's always the resulting film to watch, although it concentrates much more on the heroics of the epidemiologist Don Francis. 

And The Band Played On: Don Francis fights HIV in the face of politics and business.
There are so many aspects discussed both in the book/film and in general about the discovery of HIV as the cause of AIDS, but for me it is the politics which strikes the hardest. The political scene was set for the emergence of a disease like AIDS; a disease emerging largely in sections of society which a conservative government would rather not acknowledge. The original CDC Morbidity and Mortality Weekly Report  MMWR) is rather poignant, now that we know what it represented - I've pasted it at the end (copied from the CDC Website). 

Scientifically, politics became an issue too. A rather bitter rivalry built up between two particular virology groups as everyone raced to figure out the ultimate cause of AIDS. Now it seems obvious that it was a virus attacking T lymphocytes, but at the time things were much more unknown. As an example, one red herring in the early days was poppers/alkyl nitrates as a result of their association with homosexual bathhouses. Ultimately the rivalry ended in dispute as to who had discovered the viral cause of AIDS - something that, in theory, should have taken second place over concentrating on doing something about it. In the end, the French group lead by Luc Montagnier, (as opposed to the US group lead by Robert Gallo) are generally regarded as being the discovers of HIV - the cause of AIDS - and Montagnier won the Nobel Prize in Physiology or Medicine in 2008. Together in receiving the prize was Françoise Barré-Sinoussi. In 1983 Barré-Sinoussi published a paper in Science reporting the isolation of a retrovirus from a suspected patient - effectively reporting the viral cause of AIDS.

The first step was isolating the virus. Cells from a lymph node biopsy from the patient were cultured in growth medium. Samples were taken over several days, and tested for reverse transcriptase (RT) activity (a hallmark of retroviruses). After 15 days they detected RT activity, suggesting a retrovirus was present. When some of the 'infected' cells were mixed with healthy cells, RT activity was again detected, but only after 15 days, therefore suggesting that transmission had occurred. Media without the cells could also infect umbilical cord lymphocytes, and when these were looked at using electron microscopy, viruses could be seen budding from the cells.

HIV budding from the cell membrane

Importantly, Barré-Sinoussi showed that, in addition to isolating a virus with a predilection for human T cells, it was different to the known human T cell leukaemia viruses (HTLV) discovered to that date (largely based upon serum cross-reactivity, but also the fact that this new virus killed the T cells, as opposed to causing cancer in the case of HTLV-I and -II), backing up data that the genetic sequence was distinct from HTLV-I and -II . Altogether the data pointed towards a retrovirus as being behind AIDS. 

Françoise Barré-Sinoussi receives the Nobel Prize for Physiology or Medicine in  2008.

Gallo was at times vilified, some might argue rightly so, but equally his work on T cells and viruses was fundamental towards the ability to isolate the virus in the first place. Thankfully things have placated somewhat and, when he visited the CVR, he gave an interesting talk about his views on what it is going to take to make a good HIV vaccine. My expectation is that Françoise Barré-Sinoussi's story will be equally enthralling.

The following MMRW essentially represents the first report of HIV:

Pneumocystis Pneumonia -- Los Angeles

MMWR 1981;30:250-2 (June 5, 1981)
In the period October 1980-May 1981, 5 young men, all active homosexuals, were treated for biopsy-confirmed Pneumocystis carinii pneumonia at 3 different hospitals in Los Angeles, California. Two of the patients died. All 5 patients had laboratory-confirmed previous or current cytomegalovirus (CMV) infection and candidal mucosal infection. Case reports of these patients follow.

Patient 1: A previously healthy 33-year-old man developed P. carinii pneumonia and oral mucosal candidiasis in March 1981 after a 2-month history of fever associated with elevated liver enzymes, leukopenia, and CMV viruria. The serum complement-fixation CMV titer in October 1980 was 256; in May 1981 it was 32.* The patient's condition deteriorated despite courses of treatment with trimethoprim-sulfamethoxazole (TMP/SMX), pentamidine, and acyclovir. He died May 3, and postmortem examination showed residual P. carinii and CMV pneumonia, but no evidence of neoplasia.

Patient 2: A previously healthy 30-year-old man developed P. carinii pneumonia in April 1981 after 5-month history of fever each day and of elevated liver-function tests, CMV viruria, and documented seroconversion to CMV, i.e., an acute-phase titer of 16 and a convalescent-phase titer of 28* in anticomplement immunofluorescence tests. Other features of his illness included leukopenia and mucosal candidiasis. His pneumonia responded to a course of intravenous TMP/SMX, but, as of the latest reports, he continues to have a fever each day.

Patient 3: A 30-year-old man was well until January 1981 when he developed esophageal and oral candidiasis that responded to Amphotericin B treatment. He was hospitalized in February 1981 for P. carinii pneumonia that responded to oral TMP/SMX. His esophageal candidiasis recurred after the pneumonia was diagnosed, and he was again given Amphotericin B. The CMV complement-fixation titer in March 1981 was 8. Material from an esophageal biopsy was positive for CMV.

Patient 4: A 29-year-old man developed P. carinii pneumonia in February 1981. He had had Hodgkins disease 3 years earlier, but had been successfully treated with radiation therapy alone. He did not improve after being given intravenous TMP/SMX and corticosteroids and died in March. Postmortem examination showed no evidence of Hodgkins disease, but P. carinii and CMV were found in lung tissue.

Patient 5: A previously healthy 36-year-old man with a clinically diagnosed CMV infection in September 1980 was seen in April 1981 because of a 4-month history of fever, dyspnea, and cough. On admission he was found to have P. carinii pneumonia, oral candidiasis, and CMV retinitis. A complement-fixation CMV titer in April 1981 was 128. The patient has been treated with 2 short courses of TMP/SMX that have been limited because of a sulfa-induced neutropenia. He is being treated for candidiasis with topical nystatin.
The diagnosis of Pneumocystis pneumonia was confirmed for all 5 patients ante-mortem by closed or open lung biopsy. The patients did not know each other and had no known common contacts or knowledge of sexual partners who had had similar illnesses. The 5 did not have comparable histories of sexually transmitted disease. Four had serologic evidence of past hepatitis B infection but had no evidence of current hepatitis B surface antigen. Two of the 5 reported having frequent homosexual contacts with various partners. All 5 reported using inhalant drugs, and 1 reported parenteral drug abuse. Three patients had profoundly depressed in vitro proliferative responses to mitogens and antigens. Lymphocyte studies were not performed on the other 2 patients.

Reported by MS Gottlieb, MD, HM Schanker, MD, PT Fan, MD, A Saxon, MD, JD Weisman, DO, Div of Clinical Immunology-Allergy, Dept of Medicine, UCLA School of Medicine; I Pozalski, MD, Cedars-Mt. Sinai Hospital, Los Angeles; Field Services Div, Epidemiology Program Office, CDC.

Barre-Sinoussi, F., Chermann, J., Rey, F., Nugeyre, M., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vezinet-Brun, F., Rouzioux, C., Rozenbaum, W., & Montagnier, L. (1983). Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS) Science, 220 (4599), 868-871 DOI: 10.1126/science.6189183