Dengue Virus Evolution under a Host-Targeted Antiviral.

UNLABELLED: The host-targeted antiviral drug UV-4B reduces viral replication and promotes survival in a mouse model of experimental dengue virus (DENV) infection. UV-4B is an iminosugar that inhibits the α-glucosidase family of enzymes and subsequently the folding of glycosylated proteins, both viral and host. Here, we utilized next-generation sequencing to investigate evolution of a flavivirus under selective pressure by a host-targeted antiviral in vivo. In viral populations recovered from UV-4B-treated mice, there was a significant increase in the number of single-nucleotide polymorphisms (SNPs) and the ratio of nonsynonymous to synonymous SNPs compared to findings in viral populations from vehicle-treated mice. The strongest evidence of positive selection was in the glycosylated membrane protein, thereby providing in vivo validation of the mechanism of action of an iminosugar. In addition, mutations in glycosylated proteins were present only in drug-treated mice after a single passage. However, the bulk of the other mutations were present in both populations, indicating nonspecific selective pressure. Together with the continued control of viremia by UV-4B, these findings are consistent with the previously predicted high genetic barrier to escape mutations in host-targeted antivirals. IMPORTANCE: Although hundreds of millions of people are infected with DENV every year, there is currently no approved vaccine or antiviral therapy. UV-4B has demonstrated antiviral activity against DENV and is expected to enter clinical trials soon. Therefore, it is important to understand the mechanisms of DENV resistance to UV-4B. Host-targeted antivirals are thought to have a higher genetic barrier to escape mutants than directly acting antivirals, yet there are very few published studies of viral evolution under host-targeted antivirals. No study to date has described flavivirus evolution in vivo under selective pressure by a host-based antiviral drug. We present the first in vivo study of the sequential progression of viral evolution under selective pressure by a host-targeted antiviral compound. This study bolsters support for the clinical development of UV-4B as an antiviral drug against DENV, and it provides a framework to compare how treatment with other host-targeted antiflaviviral drugs in humans and different animal models influence viral genetic diversity.

Influence of antibodies and T cells on dengue disease outcome: insights from interferon receptor-deficient mouse models.

Dengue virus (DENV) is a globally important mosquito-borne virus that causes a spectrum of diseases ranging from dengue fever (DF) to dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), affecting 3.6 billion people in 128 countries [1,2(•)]. There is an urgent need for a drug or vaccine against DENV, yet none are presently available. In fact, results from recent Phase IIb and III trials of an attenuated tetrameric vaccine revealed that the vaccine provided limited protection against DENV serotype 2 in DENV-immune people, and no protection against any serotype in naïve individuals [3-5], highlighting the difficulties associated with dengue vaccine development. A challenge in the development of a DENV vaccine is that a vaccine must protect against all four DENV serotypes, which co-circulate in endemic areas. Further complicating DENV vaccine development is that the correlates of protection are not fully defined, mechanisms regulating the generation of protective antibody and T cell responses against all four DENV serotypes are as yet to be deciphered, and the adaptive immune response may actually contribute to severe disease. Recent studies using the only available animal model of DHF/DSS in mice lacking one or more components of the interferon (IFN) system have begun to provide crucial insights into the protective versus pathogenic nature of both antibody and T cell responses to DENV. Herein, we highlight key studies using the IFN receptor-deficient mouse models toward understanding the contribution of antibodies and T cells in impacting the outcome of DENV infection.