Retroviruses evolved to infect animal hosts at least 450 million years ago. Over the course of evolution, retroviruses have infected cells of the germ line, allowing the genome of the virus to be passed down from parent to offspring. In humans, these endogenous retroviruses (HERVs) make up about 8% of the genome, but in most cases, multiple mutations have made them inactive. One of the most recently incorporated (HERV-K), however, has been implicated in the development of amyotrophic lateral sclerosis (ALS). Like HIV, HERV-K utilizes an aspartic acid protease to process the viral polyprotein into its active components. HIV protease inhibitors were tested in an in vitro HERV-K infection model and demonstrated a moderate protective effect, though they were less effective than against HIV infection. To further investigate HERV-K inhibition, a detailed comparison of the HIV and HERV-K proteases was conducted. Since there is no crystal structure of the HERV-K protease available, comparative modeling was performed using the sequence alignment with HIV protease. A homology model was generated and refined using the Prime program in the Schrodinger Suites Software package. Overall, the model of the HERV-K protease produced a similar structure to that of HIV protease; however, the differences caused by a few amino acids in the active site could explain the reduction in antiviral activity. To experimentally correlate the level of antiviral activity to protease inhibition, a functional assay measuring the activity of HERV-K protease is currently being established. The first stage of assay development involved the optimization of HERV-K protease expression in Escherichia coli. Progress towards the identification of appropriate assay conditions employing a cleavable fluorescent peptide substrate will be discussed.

Examining the activity of HIV protease inhibitors against human endogenous retrovirus-K: A potential treatment for amyotrophic lateral sclerosis

254th National Meeting (2017)

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