Ecology, evolution and immune responses of hantaviruses. The reserach in the lab seeks
to further the understanding of the epidemiology and evolution of hantaviruses within
populations in their natural rodent reservoir that are endemic in the Interior Atlantic
Forest of Paraguay. These studies build upon our efforts (with Robert Owen) and the
research of others, that suggest that host-virus relationships may not be exclusive,
and that host-switching and adaptation to new hosts may account for much of the observed
geographic diversity of hantaviruses. Our current funding presents a valuable opportunity
for understanding standing genetic diversity and plasticity of RNA viruses in wildlife
in rapidly changing environments and genetic determinants driving its epidemiology.
We have endeavored to mathematically model these relationships in collaboration with
Dr. Linda Allen (Texas Tech University). The modeling revealed many aspects in the
ecology of the rodent-virus relationship that are not presently understood and led
us to develop a theoretical biological model of these relationships based on the immune
response of the rodent (reservoir versus nonreservoir). Our recent efforts with Dr.
Allen and funded by NSF seek to model immune regulatory mechanisms in reservoir, nonreservoir
and humans which is important to interpretation of systemic and localized immune responses
in human disease.
Antiviral Discovery. The research in our lab has been focused on the discovery of
antivirals for many years. The currentCenter of Excellence for Encephalitic Alphavirus
Therapeutics program proposes to advance the development of potent small molecule
leads targeting Venezuelan equine encephalitis virus (VEEV), Eastern equine encephalitis
virus (EEEV) and Western equine encephalitis virus (WEEV) or V/E/WEEV herein. The
collaborations among the scientists at University of Louisville (UofL; Chung), University
of Wisconsin-Madison (UW; Golden, Elder), University of Tennessee Health Science Center
(UTHSC; Jonsson, Meibohm, Fitzpatrick) and University of Texas Medical Branch at Galveston
(UTMB; Rossi, Weaver) provides multidisciplinary expertise in virology with relevant
expertise in ABSL-3/select agents, small and large animal models, medicinal chemistry,
pharmacokinetics, and assessment of antiviral compounds in vitro with mechanism of
action capabilities. Moreover, the network has an experienced team led by UTHSC (Bares)
to organize the commercial plan for development of the broad-spectrum antiviral (Encephlavir)
for treatment against V/E/WEEV. The broad, long-range objectives of the Center are
to; (1) Optimize the lead quinazolinone series to identify those with favorable profiles
for nonGLP studies with WEEV and EEEV that have broad-spectrum activity for V/E/WEEV;
(2) Define scale-up synthesis of the lead drug substance suitable for later cGMP manufacturing;
(3) Conduct nonclinical virology studies that will aid in the evaluation of the safety
and efficacy, the mechanism of action, target specificity and drug resistance monitoring
plan.
