Arbovirus evolution in vivo is constrained by host alternation

Abstract

The intrinsic plasticity of RNA viruses can facilitate host range changes that lead to epidemics. However, evolutionary processes promoting cross-species transfers are poorly defined, especially for arthropodborne viruses (arboviruses). In theory, cross species transfers by arboviruses may be constrained by their alternating infection of disparate hosts, where optimal replication in one host involves a fitness tradeoff for the other. Accordingly, freeing arboviruses from alternate replication via specialization in a single host should accelerate adaptation. This hypothesis has been tested by using cell culture model systems with inconclusive results. Therefore, we tested it using an in vivo system with Venezuelan equine encephalitis virus (VEEV), an emerging alphavirus of the Americas. VEEV serially passaged in mosquitoes exhibited increased mosquito infectivity and vertebratespecialized strains produced higher viremias. Conversely, alternately passaged VEEV experienced no detectable fitness gains in either host. These results suggest that arbovirus adaptation and evolution is limited by obligate host alternation and predict that arboviral emergence via host range changes may be less frequent than that of single host animal RNA viruses. adaptation ͉ RNA virus emergence ͉ venezuelan equine encephalitis virus T he emergence of pathogenic RNA viruses is often associated with their genomic plasticity and alterations in the environment that lead to novel host contacts. Nearly 50 new human pathogens, mostly RNA viruses, have been identified in the last quarter century, many as a result of introductions into human populations (1). Cross-species transfers often mediate pathogen emergence via the stochastic generation of virus variants able to replicate in a new host in the appropriate ecological setting. Several RNA viruses, including HIV (2), SARS coronavirus (3, 4), and the arbovirus dengue virus (DENV) (5) have caused recent epidemics by changing their host ranges to increase infections of humans.Evolutionary processes that mediate changes in host range are poorly understood. For most RNA viruses, it is unclear whether the expansion of host range involves adaptation to novel host(s) or preexisting infectivity. For example, phylogenetic analyses indicate that DENV emerged via a transfer from nonhuman primate to human hosts (5, 6). Given the similar selection pressures and evolutionary rates shared by other RNA arboviruses (7), evidence from DENV studies suggests that emergence of other arboviral pathogens via adaptation for urban transmission is also possible.

Current Strategic Thinking for the Development of a Trivalent Alphavirus Vaccine for Human Use

“…Passage history is another key concern for these viruses. Studies with VEEV have shown that removal of selective pressures associated with a two-host lifecycle results in accumulation of single nucleotide polymorphisms (SNPs), 46,47 and cell culture passages often result in adaptation for heparin sulfate binding, which can result in artificial attenuation. 48 Isolates with low numbers of passages and well-characterized passage histories would be a substantial benefit to the animal models.…”

Noncapped Alphavirus Genomic RNAs and Their Role during Infection

“…The maintenance of this cyclical transmission is vital to viral fitness, as prolonged serial passage within a single host results in attenuation in the alternate host (1)(2)(3)(4). Moreover, the ultimate outcome of alphaviral infection differs between vertebrate and invertebrate hosts, as infection of a vertebrate host results in acute cytolytic infection whereas infection of invertebrate hosts often results in persistent infection with minimal cell death (5)(6)(7)(8)(9)(10)(11).…”

Chikungunya Virus Host Range E2 Transmembrane Deletion Mutants Induce Protective Immunity against Challenge in C57BL/6J Mice

“…Severe joint pain and rheumatoid arthritis (RA)-like symptoms, which begin at the onset of infection, can persist for months or even years after virus clearance and are the most notable markers of ChikV disease (65,66). One hypothesis for pathogenic symptoms during RA is the interaction of IgG with mast cells and cytokines (26,67). Furthermore, increased IgG titers have been shown to correlate with disease severity and persistence in ChikV infection (68).…”

“…The virus particles themselves are hybrid structures composed of membrane and glycosylation components derived from the host, but all protein and RNA is encoded by the virus (28). Viruses derived from insect or mammalian cells have been found to exhibit functional (7,26,29) and structural (30,31) differences that emphasize their hybrid nature. It is hypothesized that these agents have developed a consensus genome capable of expression in divergent biochemical environments by interacting specifically with each of these distinct hosts through sequence elements necessary for viral replication in one host but not necessarily the other (32)(33)(34)(35).…”

“…Arboviruses are vectored in nature by blood-sucking insects in a complex life cycle in which an intermediate mammalian host is infected and transfers the virus during another insect's blood meal (10). These viruses have adapted over millions of years to replicate efficiently in two very different genetic and biochemical environments as natural chimeric genomes (26). The environments of the hosts differ biochemically and function optimally at different temperatures (27).…”