Human parvovirus 4, ‘PARV4’, is a tiny, robust DNA virus. In the decade since it was first reported – the result of a trawling expedition by a North American virology group who went hunting for this unknown trophy  – we have uncovered enough to make certain robust statements, but also plenty to perplex and confound us. What we don’t know about it still seems far greater than what we do.
Two principal challenges have emerged around PARV4  – the first, obvious question that all of us ask when confronted with evidence of a new virus: what disease does it cause? The medical and scientific literature describes pathology ranging from a transient illness including flu-like symptoms, diarrhoea and rash, to potentially more serious lung and brain infections, and even foetal death. But is PARV4 really causing these effects, or is it just a minor contributor to some other disease process – or indeed an innocent bystander? Among the large numbers of individuals now identified to have evidence of PARV4 infection, there is no clear disease syndrome that has consistently arisen from the infection. However, dissecting out the true influence of the virus is very difficult, and no study to date has been able to address this issue systematically.
The second question arises from the observation that patterns of PARV4 infection in different human populations are strikingly and consistently different. The conundrum is this: in the Western world, evidence of PARV4 infection occurs only in the context of HIV and hepatitis B and C viruses, a history of injecting drug use, or multiple blood transfusions. In contrast, in southern Africa, between a third and a half of all adults and children have been infected – irrespective of any other co-infection or obvious risk factors. In Africa, the distribution suggests that PARV4 is simply acquired cumulatively over time – making it much more likely that it is simply transmitted by droplets (coughs and sneezes) or the faeco-oral route (dirty hands, or contaminated food and water).
Why should the same virus behave so differently in these two settings? Broadly speaking, two explanations are possible. It is plausible that slight differences in the genetic code of the predominant virus in Europe versus Africa accounts for an alteration in transmissibility or route of infection, but this would be unusual and is not recognized for other viruses. Perhaps then it is a host factor at play – any one, or a combination, of genetics, behaviour, co-infections and environment. With such a broad palate of potential influences, dissecting out the truly relevant factors is a complicated challenge that may need huge cohorts followed up over long periods of time.
So we are now at a cross-roads – to what extent do we pursue further investigation of these questions, versus diverting our time and resources to questions with a more immediate and tangible benefit? The human spirit of curiosity and enquiry plants in us all a desire to investigate: furthering knowledge and tackling the unknown can be a passion and motivation that needs no further justification.
However, there are also several more objective reasons for proceeding in pursuit of PARV4. The first of these is that, having established that this virus has infected around a third of the entire population of the African continent, should we not feel a strong ethical obligation to pursue further investigation? Furthermore, within the past few years, the global community has twice been hit by viruses that have emerged from obscurity to wreak devastating consequences. Both of these viruses had been observed and described decades before: Zika was reported from forests of rural Uganda in the 1950’s, and Ebola in 1976 from the surrounds of the eponymous central African river. But lack of imperative, insight, initiative or interest meant that they remained neglected until their re-emergence. History suggests that it can be unwise not to pursue investigation of any agent of human infection, even if it initially appears benign, insignificant or esoteric.
There is an increasing sense that viruses play important roles in human biology that may thus far have been neglected. Many ancient retroviruses are permanently integrated into the human genome, an indelible part of our genetic ancestry, while infections acquired early in childhood are likely to influence the development of the immature immune system. Viruses can also be exploited to our advantage, exemplified by the virus-mediated delivery of DNA as part of a vaccination strategy. In order to do this reliably and safely, meticulous and robust insights into the interaction between virus and host are essential.
For these reasons, although I will continue to apply myself primarily to other questions with a firmer, faster, clearer route to the advancement of human health, my view is that our difficult pursuit of PARV4 should nevertheless continue. In the same way as physicists continue to search for the smallest particles of the universe, and mathematicians seek solutions to abstract challenges, clinicians and biologists should be compelled not only to chase this enigmatic virus, but to look out for the next one as well.
 Jones MS, Kapoor A, Lukashov VV, Simmonds P, Hecht F, Delwart E. New DNA viruses identified in patients with acute viral infection syndrome. J Virol 2005;79:8230-8236.
 Matthews PC, Malik A, Simmons R, Sharp C, Simmonds P, Klenerman P. PARV4: an emerging tetraparvovirus. PLoS pathogens 2014;10:e1004036.