Viral phylodynamics

Viral phylodynamics is defined as the study of how epidemiological, immunological, and evolutionary processes act and potentially interact to shape viral phylogenies.Since the coining of the term in 2004, research on viral phylodynamics has focused on transmission dynamics in an effort to shed light on how these dynamics impact viral genetic variation. Transmission dynamics can be considered at the level of cells within an infected host, individual hosts within a population, or entire populations of hosts. Viral phylodynamics is defined as the study of how epidemiological, immunological, and evolutionary processes act and potentially interact to shape viral phylogenies.Since the coining of the term in 2004, research on viral phylodynamics has focused on transmission dynamics in an effort to shed light on how these dynamics impact viral genetic variation. Transmission dynamics can be considered at the level of cells within an infected host, individual hosts within a population, or entire populations of hosts. Many viruses, especially RNA viruses, rapidly accumulate genetic variation because of short generation times and high mutation rates.Patterns of viral genetic variation are therefore heavily influenced by how quickly transmission occurs and by which entities transmit to one another.Patterns of viral genetic variation will also be affected by selection acting on viral phenotypes.Although viruses can differ with respect to many phenotypes, phylodynamic studies have to date tended to focus on a limited number of viral phenotypes.These include virulence phenotypes, phenotypes associated with viral transmissibility, cell or tissue tropism phenotypes, and antigenic phenotypes that can facilitate escape from host immunity.Due to the impact that transmission dynamics and selection can have on viral genetic variation, viral phylogenies can therefore be used to investigate important epidemiological, immunological, and evolutionary processes, such as epidemic spread, spatio-temporal dynamics including metapopulation dynamics, zoonotic transmission, tissue tropism, and antigenic drift.The quantitative investigation of these processes through the consideration of viral phylogenies is the central aim of viral phylodynamics. In coining the term phylodynamics, Grenfell and coauthors postulated that viral phylogenies '... are determined by a combination of immune selection, changes in viral population size, and spatial dynamics'.Their study showcased three features of viral phylogenies, which may serve as rules of thumb for identifying important epidemiological, immunological, and evolutionary processes influencing patterns of viral genetic variation. Although these three phylogenetic features are useful rules of thumb to identify epidemiological, immunological, and evolutionary processes that might be impacting viral genetic variation, there is growing recognition that the mapping between process and phylogenetic pattern can be many-to-one. For instance, although ladder-like trees could reflect the presence of directional selection, ladder-like trees could also reflect sequential genetic bottlenecks that might occur with rapid spatial spread, as in the case of rabies virus. Because of this many-to-one mapping between process and phylogenetic pattern, research in the field of viral phylodynamics has sought to develop and apply quantitative methods to effectively infer process from reconstructed viral phylogenies (see Methods). The consideration of other data sources (e.g., incidence patterns) may aid in distinguishing between competing phylodynamic hypotheses. Combining disparate sources of data for phylodynamic analysis remains a major challenge in the field and is an active area of research. Phylodynamic models may aid in dating epidemic and pandemic origins.The rapid rate of evolution in viruses allows molecular clock models to be estimated from genetic sequences, thus providing a per-year rate of evolution of the virus.With the rate of evolution measured in real units of time, it is possible to infer the date of the most recent common ancestor (MRCA) for a set of viral sequences.The age of the MRCA of these isolates is a lower bound; the common ancestor of the entire virus population must have existed earlier than the MRCA of the virus sample.In April 2009, genetic analysis of 11 sequences of swine-origin H1N1 influenza suggested that the common ancestor existed at or before 12 January 2009.This finding aided in making an early estimate of the basic reproduction number R 0 {displaystyle R_{0}} of the pandemic. Similarly, genetic analysis of sequences isolated from within an individual can be used to determine the individual's infection time. Phylodynamic models may provide insight into epidemiological parameters that are difficult to assess through traditional surveillance means.For example, assessment of R 0 {displaystyle R_{0}} from surveillance data requires careful control of the variation of the reporting rate and the intensity of surveillance.Inferring the demographic history of the virus population from genetic data may help to avoid these difficulties and can provide a separate avenue for inference of R 0 {displaystyle R_{0}} .Such approaches have been used to estimate R 0 {displaystyle R_{0}} in hepatitis C virus and HIV.Additionally, differential transmission between groups, be they geographic-, age-, or risk-related, is very difficult to assess from surveillance data alone.Phylogeographic models have the possibility of more directly revealing these otherwise hidden transmission patterns.Phylodynamic approaches have mapped the geographic movement of the human influenza virus and quantified the epidemic spread of rabies virus in North American raccoons.However, nonrepresentative sampling may bias inferences of both R 0 {displaystyle R_{0}} and migration patterns.Phylodynamic approaches have also been used to better understand viral transmission dynamics and spread within infected hosts. For example, phylodynamic studies have been used to infer the rate of viral growth within infected hosts and to argue for the occurrence of viral compartmentalization in hepatitis C infection. Phylodynamic approaches can also be useful in ascertaining the effectiveness of viral control efforts, particularly for diseases with low reporting rates. For example, the genetic diversity of the DNA-based hepatitis B virus declined in the Netherlands in the late 1990s, following the initiation of a vaccination program. This correlation was used to argue that vaccination was effective at reducing the prevalence of infection, although alternative explanations are possible. Viral control efforts can also impact the rate at which virus populations evolve, thereby influencing phylogenetic patterns. Phylodynamic approaches that quantify how evolutionary rates change over time can therefore provide insight into the effectiveness of control strategies. For example, an application to HIV sequences within infected hosts showed that viral substitution rates dropped to effectively zero following the initiation of antiretroviral drug therapy. This decrease in substitution rates was interpreted as an effective cessation of viral replication following the commencement of treatment, and would be expected to lead to lower viral loads. This finding is especially encouraging because lower substitution rates are associated with slower progression to AIDS in treatment-naive patients. Antiviral treatment also creates selective pressure for the evolution of drug resistance in virus populations, and can thereby affect patterns of genetic diversity. Commonly, there is a fitness trade-off between faster replication of susceptible strains in the absence of antiviral treatment and faster replication of resistant strains in the presence of antivirals. Thus, ascertaining the level of antiviral pressure necessary to shift evolutionary outcomes is of public health importance. Phylodynamic approaches have been used to examine the spread of Oseltamivir resistance in influenza A/H1N1.