Screening for viral dependency factors

Millions of people worldwide are at risk for infection by dengue, a mosquito-borne virus. There is no commercial vaccine that protects against dengue virus infection.  One of the problems for vaccine development is that there are four viral serotypes, and infection by two different serotypes is associated with a severe form of dengue disease, called dengue hemorrhagic fever (DHF).

Approaches to find drugs that slow or block dengue replication could focus on either the host or the pathogen. Small molecules that inhibit the function(s) of either host or pathogen nucleic acids/proteins could, in theory, block the virus. A potential drawback of targeting the viral genome is that viral RNA replication is prone to making copying mistakes that can allow the virus to quickly acquire resistance or escape mutations.  Targeting host genes is less likely to result in resistance or escape mutations.

High throughput screening is a powerful approach for testing the effects of a drug candidate or gene knockout on host or viral functioning. Although a number of labs are doing genome-wide high throughput screening, that’s not the way we’re looking at the problem.  Our approach, designed by Dr. Irene Bosch, is to focus on a set of about 100 genes that is differentially regulated in primary cells following dengue virus infection.  Within this set  of up- and down- regulated genes are many antiviral response genes.  As expected, this gene set includes many interferon response genes that characterize an antiviral response.  We hypothesize, however, that the set also includes a set of host genes that the virus needs in order to replicate efficiently.  If one could block or minimize the role of these genes, which can be called dependency factors, it could represent an attractive approach for controlling virus replication. An even more exciting outcome would be to find that the same or related genes control replication of more than one virus, meaning that treatments for multiple viruses with a single therapeutic might be feasible.