Journal of General Virology - Current Issue

Respiratory syncytial virus (RSV) is associated with considerable healthcare burden; as such, prevention and treatment of RSV have long been considered a priority. Historic failures in RSV vaccine development had slowed the research field. However, the discovery of the conformational change in the RSV fusion protein (F) has led to considerable advancements in the field. The RSV pharmaceutical landscape has drastically changed in recent years with successful trials of both vaccines and second-generation mAbs leading to licensing and roll-out of these agents in several countries. RSV preventative and therapeutic measures will likely have a significant impact on RSV-related morbidity and mortality. However, there are still gaps in the protection that these immunizations offer that should be addressed. Many unanswered questions about RSV infection dynamics and subsequent disease should be a focus of ongoing research. This review discusses the currently licensed RSV pharmaceuticals and others that have recently progressed to clinical trials.

Aminopeptidase N (APN) is a transmembrane protein that mediates the attachment of the spike protein of several clinically important coronaviruses (CoVs) responsible for respiratory and intestinal diseases in animals and humans. To assess the potential for APN-mediated viral tropism, we characterized APN receptor distribution in the respiratory and intestinal tissues of various artiodactyls (cervids, bovids, camelids and suids) and carnivores (canids, felids, mustelids and phocids) using immunohistochemistry. In the lungs, APN expression was limited to artiodactyls, with strong expression in the bronchiolar epithelium and weaker expression in pneumocytes. Nasal turbinate and tracheal samples, where available, showed stronger APN expression in artiodactyls over carnivores. APN was consistently detected on the microvilli of enterocytes in the small intestine across multiple taxa, while the presence in the colon was more variable. Of the animals examined, pig and alpaca consistently expressed the most abundant APN in the upper and lower respiratory tract. In silico evaluation of APN orthologue sequences from humans, artiodactyls and carnivores identified distinct evolutionary relationships. Further in silico binding predictions for alpaca alphacoronavirus and human coronavirus 229E with cognate and heterologous alpaca and human APN revealed substantial overlapping binding footprints with high conservation of amino acid residues, suggesting an evolutionary divergence and subsequent adaptation of a 229E-like or ancestral virus within a non-human animal host. This combined anatomical and in silico approach enhances understanding of host susceptibility, tissue tropism and viral transmission mechanisms in APN-dependent CoVs and has the potential to inform future strategies for disease modelling, surveillance and control.

Actin-associated proteins have been implicated in several stages of virus infection. However, the role of myosins, which are actin-dependent molecular motors, during virus infection and pathogenesis is poorly understood. Myosin IXB (Myo9b) is a member of the myosin family abundantly expressed in immune cells. Myo9b displays a RhoGTPase-activating protein domain capable of modulating actin dynamics by inhibiting RhoGTPase activity. To enquire upon Myo9b participation in virus infections, we have silenced Myo9b in U937 and Jurkat cells and infected them with vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped HIV-1. Myo9b-silenced U937 showed a remarkable increase of above ten times more HIV-VSV-G infection than control cells. We observed a similar pattern in Jurkat cell infection with both WT Env and VSV-G-pseudotyped HIV, albeit to a lesser extent. Myo9b-silenced U937 cells presented elevated levels of phosphorylated cofilin, but lower levels of polymerized actin. The use of a RhoA, B and C inhibitor, as well as a Rac1 inhibitor, reduced virus infection. Finally, we have also observed an increment in virus internalization and fusion in cells knockdown for Myo9b, which may explain the increase in virus infection. Taken together, our data suggests that Myo9b might hinder viral entry and infection by controlling the activity of RhoGTPases in immune cells.

Recombinant koala retrovirus (recKoRV) is a recently discovered variant of koala retrovirus (KoRV), which likely emerged due to recombination with another retrovirus (such as Phascolarctos endogenous retrovirus). KoRV spread and endogenization in Australia were thought to be ongoing in a north to south direction given the low prevalence of the virus in southern koala populations, based on molecular detection of the pol gene. However, recKoRV has highlighted that fragments of KoRV with the pol region missing are present within southern koalas. In this study, a new 5′-region-based KoRV PCR assay was developed, capable of detecting both intact KoRV and all known variants of recKoRV. Using this assay, 319 archived DNA samples from 287 Victorian koalas were retested to investigate KoRV endogenization. We found 98.3% (282/287) of these samples were positive for the KoRV-5′ fragment, the majority of which were KoRV-pol negative (222/287) on prior testing. Our findings demonstrate extensive KoRV integration into the Victorian koala populations, suggestive of a historic presence of KoRV in Victorian koalas. This finding makes biological sense relative to the translocation history of Victorian koalas, compared to the prior paradigm of low virus prevalence, and provides new epidemiological and practical management implications.