Data-driven models for replication kinetics of Orthohantavirus infections.

The Hantaviridae constitute a family of viruses harbored by mice, rats, shrews, voles, moles and bats. Intriguingly, only viruses harbored by mice and rats may cause disease in humans with up to 40% case fatality rate in the Americas. Transmission of virus from rodents to humans occurs via the respiratory route and results in replication of the virus in the microvascular endothelial cells of the lung or kidney. Understanding the replication kinetics of these viruses in various cell types and how replication is abrogated by the host is critical to the development of effective therapeutics for treatment for which there are none. We formulate several new ordinary differential equation (ODE) models to examine the replication kinetics of Prospect Hill orthohantavirus (PHV). The models are distinguished by the distribution of the viral replication delay. A new threshold, RGE, the genome equivalent replication number, is defined in terms of the model parameters. New final density relations are derived that associate RGE to the asymptotic number of virions in each model. All models are fit to real time (qRT)-PCR data of genomic RNA from PHV released from Vero E6 cells over 192 h. A sensitivity analysis of the parameters is performed and models are tested for best fit. Our findings provide a basis for future research into formulating more complex mathematical models for evaluation of the replication of hantaviruses in various cell types and sources.

The von Hippel-Lindau Cullin-RING E3 ubiquitin ligase regulates APOBEC3 cytidine deaminases.

The 7 members of the A3 family of cytidine deaminases (A3A to A3H) share a conserved catalytic activity that converts cytidines in single-stranded (ss) DNA into uridines, thereby inducing mutations. After their initial identification as cell-intrinsic defenses against HIV and other retroviruses, A3s were also found to impair many additional viruses. Moreover, some of the A3 proteins (A3A, A3B, and A3H haplotype I) are dysregulated in cancer cells, thereby causing chromosomal mutations that can be selected to fuel progression of malignancy. Viral mechanisms that increase transcription of A3 genes or induce proteasomal degradation of A3 proteins have been characterized. However, only a few underlying biological mechanisms regulating levels of A3s in uninfected cells have been described. Here, we characterize that the von Hippel-Lindau tumor suppressor (pVHL), via its CRLpVHL, induces degradation of all 7 A3 proteins. Two independent lines of evidence supported the conclusion that the multiprotein CRLpVHL complex is necessary for A3 degradation. CRLpVHL more effectively induced degradation of nuclear, procancer A3 (A3B) than the cytoplasmic, antiretroviral A3 (A3G). These results identify specific cellular factors that regulate A3s post-translationally.

Mixed Effects of Habitat Degradation and Resources on Hantaviruses in Sympatric Wild Rodent Reservoirs within a Neotropical Forest.

Understanding the ecology of rodent-borne hantaviruses is critical to assessing the risk of spillover to humans. Longitudinal surveys have suggested that hantaviral prevalence in a given host population is tightly linked to rodent ecology and correlates with changes in the species composition of a rodent community over time and/or habitat composition. We tested two hypotheses to identify whether resource addition and/or habitat composition may affect hantavirus prevalence among two sympatric reservoir hosts in a neotropical forest: (i) increased food resources will alter the rodent community and thus hantaviral prevalence; and (ii) host abundance and viral seroprevalence will be associated with habitat composition. We established a baseline of rodent-virus prevalence in three grid pairs of distinct habitat compositions and subjected one grid of each pair to resource augmentation. Increased rodent species diversity was observed on grids where food was added versus untreated control grids during the first post-treatment sampling session. Resource augmentation changed species community composition, yet it did not affect the prevalence of hantavirus in the host population over time, nor was there evidence of a dilution effect. Secondly, we show that the prevalence of the virus in the respective reservoir hosts was associated with habitat composition at two spatial levels, independent of resource addition, supporting previous findings that habitat composition is a primary driver of the prevalence of hantaviruses in the neotropics.

Habitat, species richness and hantaviruses of sigmodontine rodents within the Interior Atlantic Forest, Paraguay.

Four of the nine sigmodontine tribes have species that serve as reservoirs of rodent-borne hantaviruses (RBO-HV), few have been studied in any depth. Several viruses have been associated with human cases of hantavirus pulmonary syndrome often through peridomestic exposure. Jabora (JABV) and Juquitiba (JUQV), harbored by Akodon montensis and Oligoryzomys nigripes, respectively, are endemic and sympatric in the Reserva Natural de Bosque Mbaracayú (RNBM), Paraguay, a protected area of the Interior Atlantic Forest. Rodent communities were surveyed along a 30 km stretch of the RNBM in eight vegetation classifications (Low, High, Bamboo, Riparian and Liana Forests, Bamboo Understory, Cerrado, and Meadow/Grasslands). We collected 417 rodents from which 11 species were identified; Akodon montensis was the predominant species (72%; 95%CI: 64.7%-76.3%), followed by Hylaeamys megacephalus (15% (11.2%-18.2%)) and Oligoryzomys nigripes (9% (6.6%-12.4%)). We examined the statistical associations among habitat (vegetation class) type, rodent species diversity, population structure (age, sex, and weight), and prevalence of RBO-HV antibody and/or viral RNA (Ab/RNA) or characteristic Leishmania tail lesions. Ab/RNA positive rodents were not observed in Cerrado and Low Forest. A. montensis had an overall Ab/RNA prevalence of 7.7% (4.9%-11.3%) and O. nigripes had an overall prevalence of 8.6% (1.8%-23.1%). For A. montensis, the odds of being Ab/RNA positive in High Forest was 3.73 times of the other habitats combined. There was no significant difference among age classes in the proportion of Ab/RNA positive rodents overall (p = 0.66), however, all 11 RNA-positive individuals were adult. Sex and habitat had independent prognostic value for hantaviral Ab/RNA in the study population; age, presence of tail scar/lesion (19% of the rodents) and weight did not. Adjusting for habitat, female rodents had less risk of becoming infected. Importantly, these data suggest habitat preferences of two sympatric rodent reservoirs for two endemic hantaviruses and the importance of including habitat in models of species diversity and habitat fragmentation.