Structural Mimicry Drives HIV-1 Rev-Mediated HERV-K Expression.

Expression of the Human Endogenous Retrovirus Type K (HERV-K), the youngest and most active HERV, has been associated with various cancers and neurodegenerative diseases. As in all retroviruses, a fraction of HERV-K transcripts is exported from the nucleus in unspliced or incompletely spliced forms to serve as templates for translation of viral proteins. In a fraction of HERV-K loci (Type 2 proviruses), nuclear export of the unspliced HERV-K mRNA appears to be mediated by a cis-acting signal on the mRNA, the RcRE, and the protein Rec-these are analogous to the RRE-Rev system in HIV-1. Interestingly, the HIV-1 Rev protein is able to mediate the nuclear export of the HERV-K RcRE, contributing to elevated HERV-K expression in HIV-infected patients. We aimed to understand the structural basis for HIV Rev-HERV-K RcRE recognition. We examined the conformation of the RcRE RNA in solution using small-angle X-ray scattering (SAXS) and atomic force microscopy (AFM). We found that the 433-nt long RcRE can assume folded or extended conformations as observed by AFM. SAXS analysis of a truncated RcRE variant revealed an "A"-shaped topological structure similar to the one previously reported for the HIV-1 RRE. The effect of the overall topology was examined using several deletion variants. SAXS and biochemical analyses demonstrated that the "A" shape is necessary for efficient Rev-RcRE complex formation in vitro and nuclear export activity in cell culture. The findings provide insight into the mechanism of HERV-K expression and a structural explanation for HIV-1 Rev-mediated expression of HERV-K in HIV-infected patients. IMPORTANCE: Expression of the human endogenous retrovirus type K (HERV-K) has been associated with various cancers and autoimmune diseases. Nuclear export of both HIV-1 and HERV-K mRNAs is dependent on the interaction between a small viral protein (Rev in HIV-1 and Rec in HERV-K) and a region on the mRNA (RRE in HIV-1 and RcRE in HERV-K). HIV-1 Rev is able to mediate the nuclear export of RcRE-containing HERV-K mRNAs, which contributes to elevated production of HERV-K proteins in HIV-infected patients. We report the solution conformation of the RcRE RNA-the first three-dimensional topological structure for a HERV molecule-and find that the RcRE resembles the HIV-1 nuclear export signal, RRE. The finding reveals the structural basis for the increased HERV-K expression observed in HIV-infected patients. Elevated HERV expression, mediated by HIV infection or other stressors, can have various HERV-related biological consequences. The findings provide structural insight for regulation of HERV-K expression.

Neurological symptoms associated with oil spill response exposures: Results from the Deepwater Horizon Oil Spill Coast Guard Cohort Study.

INTRODUCTION: The Deepwater Horizon (DWH) oil spill was the largest marine oil spill in U.S. history, involving the response of tens of thousands clean-up workers. Over 8500 United States Coast Guard personnel were deployed in response to the spill. Little is understood about the acute neurological effects of oil spill clean-up-related exposures. Given the large number of people involved in large oil spill clean-ups, study of these effects is warranted. METHODS: We utilized exposure, health, and lifestyle data from a post-deployment survey administered to Coast Guard responders to the DWH oil spill. Crude oil exposure was assessed via self-reported inhalation and skin contact metrics, categorized by frequency of self-reported exposure to crude oil during deployment (never, rarely, sometimes, most/all of the time). Combined exposure to crude oil and oil dispersant was also evaluated. Adjusted log binomial regressions were used to calculate prevalence ratios (PRs) and 95% confidence intervals (CI), investigating the associations between oil spill exposures and neurological symptoms during deployment. Stratified analyses investigated potential effect modification by sex, exhaust fume exposure, personal protective equipment (PPE) use, and deployment duration and timing. RESULTS: Increasing frequency of crude oil exposure via inhalation was associated with increased likelihood of headaches (PRmost/all vs. never = 1.80), lightheadedness (PRmost/all vs. never = 3.36), difficulty concentrating (PRmost/all vs. never = 1.72), numbness/tingling sensation (PRmost/all vs. never = 3.32), blurred vision (PRmost/all vs. never = 2.87), and memory loss/confusion (PRmost/all vs. never = 2.03), with significant tests for trend. Similar results were found for crude oil exposure via skin contact. Exposure to both oil and oil dispersants yielded associations that were appreciably greater in magnitude than for oil alone for all neurological symptoms. Sensitivity analyses excluding responders in the highest environmental heat categories and responders with relevant pre-existing conditions indicated robustness of these results. Stratified analyses indicated possible effect modification by sex, PPE use, and heat exposure. CONCLUSIONS: This study provides evidence of a cross sectional association between crude oil exposures and acute neurological symptoms in a sample of U.S. Coast Guard responders. Additionally, it suggests that exposure to both crude oil and oil dispersant may result in stronger associations and that heat may interact synergistically with oil exposures resulting in more acute neurological symptoms. Future investigations are needed to confirm these findings.