Rhinoviruses (RVs)...a primer

Schematic of a human rhinovirus (RV) genome. (+)ssRNA genome.
Based on GenBank accession no. NC_001490 for HRV-C3 (f.QPM).
Use images freely but please cite www.newsmedicalnet.blogspot.com.au 
and Dr. Ian M Mackay as their source.
Click on image to enlarge

More than 100 serologically distinct types (serotypes), and another 50 or more genotypically defined and distinct types (genotypes) of human rhinovirus (RV; Greek rhin = nose) exist within the genus Enterovirus. Along with other members of the family Picornaviridae, the RVs are unenveloped viruses with a positive sense, single-stranded RNA genome that is preceded by a genome-linked protein (5' VPg) and terminated with a poly(A) tract (3').

Other genera within the family include Aphthovirus, Aquamavirus, Avihepatovirus, Cardiovirus, Cosavirus, Dicipivirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Megrivirus, Parechovirus, Salivirus, Sapelovirus, Senecavirus, Teschovirus and Tremovirus.

HRV discovery...

Click on image to enlarge.

The first rhinovirus to be isolated in cell culture was at the Common Cold Unit (Salisbury, UK).[4] By 1967, 55 serologically distinct (sero)types had been recognized. In 2006 the first report[3] defining a distinct genetic grouping of RV types not previously recognized by Mackay and colleagues contributed to the addition of 50 more distinct types assigned to a new species, RV-C. In 2014, a number of additional RV genomes, as well as known ones, were sequenced and published.[7,8,9]

HRV taxonomy: a tale of types and variants...

Predictive capsid model of a rhinovirus C virion (RV-C3, f.QPM).
3D rendering of predicted RV-C3 capsid providing imagery
similar to that obtained by cryo-electron microscopy
reconstruction at 10 � resolution.
doi:10.1371/journal.pone.0001847.g005 [10]       

RV genotypes and serotypes are most simply referred to as "types". Keep in mind that individual types are still written as �HRV-blahblah� whereas the species shorthand or conversationally written form has dropped the �H� to leave �RV�. The 2 best RV schemes for genetically defining an RV type versus a variant of an RV type (the same RV type, but detected in another patient - very little genetic distance separates one RV variant from another in any region of the genome), have been described by Prof Peter Simmonds and colleagues.[5,6] For the latest naming development check the Picornavirus Study Group�s websites.[1,2]

HRVs and pneumonia...

Pneumonia is a disease that of the young and the elderly in particular. It is responsible for millions of deaths each year and is associated with viral and/or bacterial infections. Pneumonia requires an X-Ray confirmation of inflammatory infiltration of the lung tissue. Community-acquired pneumonia (CAP) in children is frequent in developing countries. CAP can also make existing chronic medical conditions worse and takes advantage of the ageing immune system.

HRVs play some role in the development of bacterial pneumonia, but the extent is likely to be underestimated. Determining the cause of pneumonia is made difficult by the low frequency of sampling the lower respiratory tract, by studies that are  conducted over short periods of time and by the complexity of the viral and bacterial mix involved. Quick and  easy sampling of the upper airways is ideal for routine sampling of patients. This convenience and reduced risk  associated with some sampling methods (needle aspirates for example) sampling of the lower respiratory tract  means that often, detection of putative viral or bacterial pathogens in the upper airways is assumed to be related  to LRT disease, especially in children under the age of 5 years. Studies of pneumonia studies are also  complicated by the infrequent inclusion of a control patient group and by the fact that sputum is not produced  from the healthy lower airway. 

Before PCR methods, respiratory syncytial virus (RSV) and then RVs were described as the major viral  contributors to CAP (between 1 and 2 thirds of cases). In the golden PCR age, RVs are increasingly the major  viral group detected from both upper and lower respiratory tract (sputum) specimens from children with CAP.  These findings are supported even when studies span more than a 12-month period, which should encompass  change in the prevalence of seasonal viruses. 

Viruses, including RVs, are thought to pave the way for bacterial super-infection in some direct or indirect way.  There are data from laboratory research studies which support this as well as clinical data finding a high proportion of  RV and bacterial co-detections. Despite considerable comment in the literature, rhinoviruses are in fact less likely to be co-detected with another virus, than are many other viruses.[11]

Other rhinovirus posts at VDU...

• Happy Birthday rhinoviruses (RVs) - 60 years old today!

References... 

1. Nick Knowles, Chair of the Picornavirus Study Group's excellent Picornaviridae website 
2. The official Picornaviridae Study Group website 
3. KE Arden et al. Frequent detection of human rhinoviruses, paramyxoviruses, coronaviruses, and bocavirus during acute respiratory tract infections. J Med Virol.  2006. 78(9):1232-40 
4. IM Mackay, Human rhinoviruses: The cold wars resume. J Clin Virol. 2008. 42:297-320 
5. P Simmonds and colleagues. Proposals for the classification of human rhinovirus species C into genotypically assigned types. J Gen Virol. 2010. 91(Pt 10):2409- 19. 
6. CL McIntyre and colleagues. Proposals for the classification of human rhinovirus species A, B and C into genotypically assigned types. J Gen Virol. 2013  94(Pt8):1791-806. 
7. Liggett and colleagues. Genome sequences of rhinovirus C isolates from Wisconsin pediatric respiratory studies. Genome Announc. 2014 2(2) e00203-14. 
8. Liggett and colleagues. Genome sequences of rhinovirus B isolates from Wisconsin pediatric respiratory studies. Genome Announc. 2014 2(2) e00202-14. 
9. Liggett and colleagues. Genome sequences of rhinovirus A isolates from Wisconsin pediatric respiratory studies. Genome Announc. 2014 2(2) e00200-14. 
10. McErlean and colleagues. Distinguishing molecular features and clinical characteristics of a putative new rhinovirus species, human rhinovirus C (HRV C). PLoS  One. 2008 3(4):e1847
11. Greer and colleagues. Do rhinoviruses reduce the probability of viral co-detection during acute respiratory tract infections? J Clin Virol. 2009 45(1):10-5

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Wheezing after respiratory virus infection...

Takeyama and colleagues from Japan delved into the viruses present among young children (= 3-years of age) hospitalized with a clinically defined lower respiratory tract infection.

This exemplifies what many such studies do; sample from the upper respiratory tract to find signs of replicating virus in order to study a disease of the lower respiratory tract. 

It's a stretch but if you go along with it you are implying that an upper respiratory tract infection either triggers the symptoms from afar or that the virus travels into the lower respiratory tract to directly cause inflammation and/or cell destruction.

Viruses were detected by PCR-based methods.

Some key findings...

• Respiratory syncytial virus (RSV) was the virus detected most often (51/102 samples from 153 children) in children who were admitted with wheezing followed by rhinoviruses (RV; 21 or 14%), RSV+RV (12 or 8%) and then parainfluenza virus 3 (PIV3; 8 or 5%), influenza virus (IFV; 5 or 3%) or human metapneumovirus (hMPV; 5 or 3%)
• A similar pattern was observed in 259 children who were admitted without wheezing (RSV-25%; RV 9%; IFV 7%; RSV+RV-4%; PIV3-3%; hMPV-1%)
• 67% of children with wheezing were virus positive (POS)
• Children with an allergic predisposition (IgE antibody levels >30IU/mL at admission and a parental history of asthma) POS for RSV more often had wheezing later
• Children who were wheezing & RV POS when they were admitted were more likely to wheeze again than were those who were RV POS without wheeze at admission.

So [allergic predisposition + RSV] or [wheeze/clinical severity + RV] were 2 factors related to subsequent wheeze.

The authors also raised the spectre of RV positivity occurring in asymptomatic individuals in other studies. However, that can happen to some extent with all respiratory viruses. No other virus has 160 distinct type like the RVs...but that's another story.

Article...

1. http://www.ncbi.nlm.nih.gov/pubmed/24535712

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Little rhino...

To the tune of �I�m a little teapot�

I�m a little rhino,

Strain in doubt

Bind with my canyon

Bind without

When I�ve replicated

Just the right amount

You�ll need to get a tissue to blow me out

[alternate: exacerbate your wheezing and cough me out]

Thanks to Cassandra Faux for putting this one together back in 2007.

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Randall the red-nosed toddler...

To the tune of Rudolph the red-nosed reindeer

Randall the red-nosed toddler
Had a very runny nose 
Asthma exacerbation 
Fever adding to his woes 

All of the other toddlers 
Didn't have immunity 
They all came down with symptoms 
Differing in severity 

Then one group of researchers 
Virus-hunting was their game 
Swabbed, extracted, amplified
A rhino POS of course was spied 

Randall�s rhino was sequenced 
Turned out to be rhino C
Randall the red-nosed toddler
Just a 'common' cold indeed!

Randall the red-nosed toddler

Had a very runny nose 
Asthma exacerbation 
Fever adding to his woes 


Thanks to Katherine Arden and Cassandra Faux for helping me put these together back in 2008.

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Happy Birthday rhinoviruses (RVs) - 60 years old today!

Predicted capsid model of HRV-QPM (Q=Queensland;
PM-initials of the then PhD student who did all the work).
This distinct virus is now known as HRV-C3.
It was the first HRV-C type to be sequenced,
clinically, epidemiologically and virologically
characterised and modelled. It was the third HRV-C
polyprotein sequence to be placed on  GenBank.

On September 12th 1953, the Common Cold Unit (CCU, Salisbury, United Kingdom) reported isolating the agent of the common cold in laboratory cultures. The article was authored by Dr (later Sir)Christopher Andrewes and colleagues in The Lancet.

The isolate, called D.C. after Dr Donna M. Chaproniere's donated cold sample, was only able to be grown while the lung tissue from a particular embryo remained. Once stock was exhausted, the viral culture failed. The D.C. type was not able to be characterized until 1968, by which time another variant of that type had already be given a name; RV-9.

More reliable, repeatable RV culture were achieved in 1956 Price et al (the JH type) and 1957 by Pelon et al (the 2060 type). Back at the CCU, it was found that increasing the acidity, lowering temperatures and rotating the cultures increased the success of virus isolation. The use of increased acidity was discovered by accident when CCU's Dr David Tyrrell had to replace some medium that was killing his cultures. He borrowed (as we do) others' stocks to tide him over. During this process he noted a sign of viral replication  his cultures were being killed  He eventually deduced it was because of the acidity of the new medium compared to his previous work.

 21,915 days later there have been a number of interesting developments to come from the study of RVs:

• A type is the name for a distinct RV; that type found in another patient anywhere around the world is called a variant of the type. Specific criteria now exist to define types and variants, and to identify a new HRV type.
• Recently, HRVs became RVs - the host bit was dropped but their individual names remain "HRV" and they now have the species name included e.g. HRV-A1
• There are >150 distinct RV types
• As many as 70 RV types can circulate at a single site at one study period
• The early RVs were initially classified as echoviruses (ECHO-28; later RV-1) and have also been called ERC viruses, muriviruses, Salisbury strains, coryzaviruses and enterovirus-like viruses
• RV-Cs do not grow using any routinely used cell culture lines, but can be grown in primary tissues and differentiated multilayer cell cultures at the air-liquid interface
• RVs are the most frequent virus to be detected in children and adults with acute upper respiratory tract infections including the "common cold"
• RV infection of adult chronic obstructive pulmonary disease ( COPD) patients may precipate outgrowth of Haemophilus influenzae, not seen among healthy RV infectees
• RVs are also associated with fever and influenza-like illness (ILI), where and they can be near impossible to discriminate from some ILIs without laboratory testing
• RVs are the viruses most frequently detected in wheezing exacerbations ("attacks") in those with asthma where they, more than any other virus, seem to take advantage of antiviral immune deficiencies. While RV-Cs appear to be more exacerbatory, I personally believe this is just an artefact of small, short studies
• RVs are found more often than other viruses in people without overt signs of respiratory disease; but as a proportion of all viruses, RVs are less often found in well people compared to most other respiratory viruses. 
• RVs do not persist (a given RV type is not detected beyond 2-4 weeks) except in those with serious immune deficiency such as those undergoing lung transplant
• There used to be a genus Rhinovirus, but that was abolished and now the three RV species (A, B, C) sit under the genus Enterovirus
• There is no vaccine or broadly available antiviral for HRVs although both are being actively researched now.
• Prior to the use of PCR to detect RVs in 1988/1989, epidemiology studies looking at the impact of a specific respiratory could not account for 50+ HRV-Cs (and perhaps some fastidious HRV-As and Bs)
• RV-Bs are considered "wimps" by those in the know and they are always under-represented when found i.e they appear to circulate in smaller numbers than chance would dictate they should

So, many happy returns little guys. Long may you educate our immune systems with your constant challenges, long may you interfere with the seasons of other viruses and long may you make me write silly titles for reviews when under your mind-altering influence (that's my excuse anyway). 

Much may have been written about other respiratory viruses over the years, but the HRVs are always with us, always challenging us and always causing problems for us. To study RVs is to study all respiratory viruses and diseases of the upper and lower respiratory tract. To exclude them from study or test is to fail to understand these diseases.

Some literature...

1. Hilding,A. The Common Cold. Arch Otolaryngol. Head Neck Surg. 12, 133-150 (1930). 
2. Tyrrell,D.A.J. & Fielder,M. Cold wars: The fight against the common cold (Oxford University Press, New York, 2002).
3. Propagation of common-cold virus in tissue cultures.
4. Outgrowth of the Bacterial Airway Microbiome following Rhinovirus Exacerbation of Chronic Obstructive Pulmonary Disease
5. Newly identified respiratory viruses in children with asthma exacerbation not requiring admission to hospital.
6. Newly identified human rhinoviruses: molecular methods heat up the cold viruses.
7. Human rhinoviruses: coming in from the cold.
8. Do rhinoviruses reduce the probability of viral co-detection during acute respiratory tract infections?
9. Molecular characterization and distinguishing features of a novel human rhinovirus (HRV) C, HRVC-QCE, detected in children with fever, cough and wheeze during 2003.
10. Prior evidence of putative novel rhinovirus species, Australia.
11. Human rhinoviruses: the cold wars resume.
12. Distinguishing molecular features and clinical characteristics of a putative new rhinovirus species, human rhinovirus C (HRV C).
13. Frequent detection of human rhinoviruses, paramyxoviruses, coronaviruses, and bocavirus during acute respiratory tract infections.

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A drug to stop rhinovirus (HRV) infections in patients with chronic obstructive pulmonary disease (COPD)?

For those who don't know, the HRVs are the most frequent infecting agents (that we know of) of the human upper (and perhaps lower but that work is not done) respiratory tract (URT).The first HRV was isolated in 1953 in the UK and the viruses were soon burdened by the label "common cold viruses". This was largely because early studies were conducted in adults who generally have milder outcomes.
There are about 77 genetically distinct HRV-As, 60 HRV-Cs and 30 HRV-Bs - that's nearly 170 distinct viruses (includes serotypes and genotypes)! Imagine 170 distinct coronaviruses.

In the past they were classified by the type of cell they infected/receptor they used into major (most of them used ICAM-I as the receptor) and minor (the rest; use VLDL-R as the receptor) groups. Sequencing is the preferred method to classify them today.

The receptor for the HRV-Cs remains unknown and they do not grow in routine cell lines instead needing more advanced culture methods. Because of this, studies predating 1988 (the first published PCR primers) generally don't account for the HRV-Cs, even though they were there and causing infections.

A.Prof Eva Kathryn Miller and I recently reviewed the HRV-Cs in some detail. Around 70 distinct HRV genotypes can circulate at a single place over a year...depending on the population being studied. I and others have found that to be the case in both the community and in hospital-based populations.

A recent article from Yamaya and colleagues suggests that a mucolytic drug (stimulates surfactant production and release to help the airways clear themselves of gunk) might be of use in treating HRV infections in COPD patients at least.

Exacerbations, which are mostly due to viruses, are the main contributor to disease burden in patients suffering from COPD, as they are in those with asthma.

The drug, ambroxol hydrochloride is already thought to reduce the frequency of URT disease and may reduce ICAM-I expression. The authors tested this using a major group HRV, HRV-B14 and found reduced release of virus, ICAM-I levels and reduced viral RNA levels.

Prophylactic use may inhibit HRV-B14 infection and modulate the inflammatory response to infection. Many of the differences were moderate (mostly arithmetic rather than logarithmic), albeit statistically significant.

It would be interesting to see what effect the drug has on other major group HRVs, minor group HRVs and on the hard to culture HRV-Cs.

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Editor's Note #6.

I've finally started to rebuild the rhinovirus (HRV) page. For someone whose main interest is these little dudes...well, it was in a pretty woeful state. How embarrassment. Expect to see it take shape over the coming weeks.

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