---
title: "Notes"
author: "Duncan Golicher"
output:
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    collapsed: yes
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link-citations: yes
bibliography: mendeley.bib
---

```{r setup, include=FALSE}
knitr::opts_chunk$set(echo = TRUE)
```

# Virology 1.01

## Field's virology 

Over 2000 pages. 

![](figs/fields.png)
![](figs/chapter1.png)

## Chapter 1

- Viruses not recognised until 1880s
- Adolf Meyer working on tobacco at Wageningen identified TMV
- Infectious, but could not fulfill Koch's postulates .. as only cultivable in living cells
- Koch's postulate issue continues to muddy debates to this day
- Beijerinck called the agent a "contagium vivum luidum"" or a contagious living liquid. 
- d’Herelle developed the plaque assay in 1917 
- First electron micrographs were taken of tobacco mosaic virus (TMV) in 1939.

## Bacteriophages and animal viruses

- Lytic (pathogneic) and lysogenic (non pathogenic) infections identified
- Experiments with viruses resulted in the discovery of mRNA and the role of DNA
- Experiments on viruses of animals used immortalised human cell lines and monkey kidney cells
- Polioovirus early focus
- Virology allowed key insights into oncology and cancer
- Key in the understanding of evolutionary processes .. viruses are now known to evolve at high rates following basic Darwinian principles, but in a time frame shorter than that of any other organism. 
 - RNA virus populations exist as a quasispecies or a swarm of individual viral genomes where every member is unique. Species concept cannot be applied. 



## Quasispecies

We show that experimental approaches using in vitro and in vivo laboratory models are largely focused on short-term intrahost evolutionary mechanisms, and may not always be relevant to natural systems. In contrast, the comparative approach relies on the phylogenetic analysis of natural virus populations, usually considering data collected over multiple cycles of virus–host transmission, but is divorced from the causative evolutionary processes. [@Geoghegan2018]

![@Geoghegan2018](figs/evol.png)

In simple terms, the quasispecies is a form of mutation–selection balance in which a distribution of variant viral genomes is ordered around the fittest, or “master,” sequence. Central to quasispecies theory is that mutation rates in RNA viruses are so high that the frequency of any variant is not only a function of its own replication rate (fitness), but also the probability that it is produced by mutation from other variants in the population that are linked to it in sequence space. This “mutational coupling” leads to a distribution of evolutionarily interlinked viral genomes, which in turn means that the entire mutant distribution behaves as a single unit, with natural selection acting on the mutant distribution as a whole rather than on individual variants. The quasispecies as a whole therefore evolves to maximize its average fitness. 

![@Geoghegan2018](figs/evol2.png)
![@Geoghegan2018](figs/evol3.png)

# Detection of corona viruses

Before SARS in 2003, there were only 19 known coronaviruses, including 2 human, 13 mammalian, and 4 avian coronaviruses. By 2010 more than 20 additional novel coronaviruses have been described with complete genome sequences. These include 3 human coronaviruses, 15 mammalian coronaviruses, and 4 avian coronaviruses [@Lau2011]

# Emergence


# Virulence

## OC43

![@Corman2018](figs/corman2018.png)

Other related coronaviruses can also cause severe disease in the elderly, while usually going undetectected. In the summer of 2003 in Canada 95 care home residents and 5 experienced symptoms of respiratory infection. Eight residents died, six with pneumonia. Initially PCR suggested SARS-CoV at a national reference laboratory were suspected to represent false positives, but this was confounded by concurrent identification of antibody to N protein on serology. Subsequent testing by reverse transcriptase-polymerase chain reaction confirmed HCoV-OC43 infection. Convalescent serology ruled out SARS. Notably, sera demonstrated cross-reactivity against nucleocapsid peptide sequences common to HCoV-OC43 and SARS-CoV [@Patrick2006]

Phylogenetic analysis showed at least three distinct clusters of HCoV-OC43, although 10 unusual strains displayed incongruent phylogenetic positions between RdRp and spike genes. This suggested the presence of four HCoV-OC43 genotypes (A to D), with genotype D most likely arising from recombination. This genotype appears more virulent in the elderly.
[@Lau2011]


![@Forni2017](figs/oc43a.png)

[@Forni2017]

![@Perlman2017](figs/oc43b.png)

## Receptor

For SARS-CoV, the angiotensin 1-converting enzyme 2 (ACE2) molecule has been shown to serve as a receptor [@Liu2007], CD209L has been implicated as a coreceptor in entry [@Jeffers2004]
Receptor usage, as well as binding of other molecules, varies by group and even by strain among the coronaviruses [@Graham2010]

## Zoonosis

Coronavirus (CoV) phylogeny and biology, as demonstrated during the severe acute respiratory syndrome (SARS) epidemic in 2002-2003, are likely characterized by frequent hostshifting events, whether they be animal-to-human (zoonosis), human-to-animal (reverse zoonosis), or animal-to-animal [@Graham2010]


![@Jo2020](figs/zoonotic.png)

### Bats

For CoV, our study indicates clearly that virus amplification takes place in maternity colonies, confirming our earlier statistical implications from studies in a different region and on a different species [@Drexler2011]. Although an origin of SARS-related CoV in bats is confirmed SARS-CoV precursors have existed in carnivores some time before the SARS epidemic and have been transmitted from carnivores to humans again at least one additional time after the end of the epidemic 
[@Graham2010]

![@Wu2016](figs/bat_viral_diversity.png)

![@Wu2016](figs/bat_covid_tree.png)


# Mutations

## Recombinations

Coronaviruses are unique in having a high frequency of homologous RNA recombination which is a result of random template switching during RNA replication that is thought to be mediated by a copy-choice mechanism. Their tendency for recombination and high mutation rates may allow them to adapt to new hosts and ecological niches. 

Early studies in SARS1 suggested that phylogenetic patterns cited as evidence for recombination are more probably caused by a variation in substitution rate among lineages and that recombination is unlikely to explain the appearance of SARS in humans.[@Holmes2004]

A novel genotype of OC43 has been attributed to natural recombination [@Lau2011]

## Quasi-species

Quasispecies [@Eigen1996] are known in RNA viruses such as hepatitis C virus and human immunodeficiency virus.1 Owing to poor fidelity of RNA polymerases, RNA-virus populations typically contain genetic variants that form a heterogeneous virus pool. In SARS-1 sequences of the S gene from different samples collected at different times from the same patient showed similar, but not identical, variation profiles. We speculate that the higher frequency of variations in the S gene than in previous reports might be due to a broader sample collection over a longer period of time. [@Xu2004]

# T cells

![@Nikolich-Zugich2008](figs/tcells.png)

[@Nikolich-Zugich2008]

# Super spreaders

![@Perlman2017](figs/suerspreader.png)


# References
