The Evans Lab studies how hosts and viruses interact, with a focus on how this interface affects both viral tropism and the capacity of hosts to clear infections. Our research is focused on the hepatitis C virus (HCV), which only efficiently infects human liver cells, and Flaviviruses such as dengue and Zika viruses, which infect a wide range of species and tissues. Furthermore, HCV exhibits an interesting mechanism of persistence. The majority of HCV infections last for the life of the host, even though this virus does elicit host immune responses and does not have a stable replication intermediate or latent phase. HCV is also an important human pathogen, as it is responsible for more than half of liver cancers in the Western Hemisphere. While therapies to treat HCV are improving dramatically, these drugs may not be available to all patients. Thus, further study of this virus is warranted for both therapeutic and vaccine design.

One aim of the Evans Lab is to understand how viruses enters host cells. Unlike many other viruses that require a single receptor on a host cell for infection, numerous host cell factors are used by HCV in a sequential manner during viral host cell entry. Tissue specific expression profiles of some of these entry factor influence that preference for HCV to infect hepatocytes. Furthermore, differences between the sequence of some of these proteins between species impacts why humans and chimpanzee are more able to support HCV infection. Using a novel HCV permissive polarized cell system, we found that tight junction proteins that we previously identified as critical to HCV cell entry are used late in this process. We are currently exploring how virion translocation to tight junctions occurs and endocytic signals within tight junction proteins are responsible for virion internalization.

The restricted tropism of HCV is also influenced after the host cell entry stage. We also study how a liver specific microRNA, miR-122, influences HCV replication and tropism. By modulating miR-122 expression, we created a new cell system that exhibits authentic innate immune responses to HCV infection. We also showed the HCV genetics influences response to miR-122 inhibitors that are currently in clinical development. Another aim of the Evans Lab is to determine how host differences impact the tight HCV species tropism. By defining the blocks to HCV infection in nonhumans, and devising strategies to overcome these blocks, we hope to establish an immunocompent HCV animal model that will be essential for HCV pathogenesis and vaccine studies.

In vivo, over 80% of HCV infections last for the life of the individual. Thus, this persistence depends of the ability of this virus to suppress or evade host immune responses. HCV infection occurs in foci in only a subset of hepatocytes in the liver. We hypothesize that these foci represent a balance between viral spread and immune suppression. We will use novel cell culture and in vivo systems to test the theory that infections are maintained primarily by direct cell to cell spread which is suppressed by innate immune responses. We are also using these systems to study how the adaptive immune response fails to effectively clear HCV infections, and develop vaccine candidates that would prevent persistent infections.

Our Flavivirus studies also focus on how virus and host genetics impact viral tropism. We intend to dissect the cell entry pathways for dengue and Zika viruses, and examine their mechanisms for counteracting host immune responses. We have recently developed a system to genetically manipulate Zika virus, which will allow use to define how viral proteins mediate these processes.