ROLES FOR CHOLESTEROL IN HERPES SIMPLEX VIRUS ENTRY AND INFECTIVITY

George Ayuba Wudiri

ROLES FOR CHOLESTEROL IN HERPES SIMPLEX VIRUS ENTRY AND INFECTIVITY Abstract George Ayuba Wudiri, DVM, Ph.D. Washington State University November 2016 Chair: Anthony V. Nicola The herpes simplex viruses (HSVs) are prevalent pathogenic viruses of humans. The World Health Organization estimates 60-90% of adults are infected (1). Manifestations include oral, genital, neuronal and sometimes fatal neonatal infections (2). There is no known cure. There is a complex interaction between viral and host cell factors during HSV-1 entry into cells, which can proceed via different pathways (3-5). Following entry, HSV-1 replicates within the cell nucleus and produces progeny that spread to neighboring uninfected cells causing disease pathology. Identification and elucidation of HSV-1 entry factors helps in understanding the virus-host interactions and may lead to the development of effective, novel interventions. Cholesterol is an important sterol component of cell membranes and is critical for cellular homeostasis (6, 7). It is also a component of the HSV-1 envelope that is derived from an infected cell (8). Cholesterol in both the host cell and viral envelope is required for the HSV-1 entry process (9), but the precise step in entry and/or beyond entry is unknown. I hypothesized that cellular cholesterol is required for HSV-1 entry at the internalization and fusion steps and viral cholesterol is required at the fusion step of HSV-1 entry. I also hypothesized that host cell cholesterol plays additional role(s) in HSV-1 replicative cycle beyond initial entry. I employed both chemical depletion of cholesterol from cells or the virus, as well as the use of cells that were genetically defined to express another sterol, desmosterol in order to assess the specific contribution of cholesterol in entry and viral replication. I identified virus-mediated cell fusion as the target in entry for both cellular and viral envelope cholesterol. The requirement of viral cholesterol for fusion was not associated with the ability of viral gB to undergo a conformational change. The stability of HSV-1 was dependent on cholesterol levels. Cellular cholesterol facilitated HSV-1 replicative cycle after entry. Viral protein expression, the release and cell-to-cell spread of HSV-1 were all cholesterol-dependent. Desmosterol also supported HSV-1 entry and replication albeit at altered levels relative to cholesterol. Together, these investigations revealed multiple targets in the HSV-1 replicative cycle that involve cholesterol.

ROLES FOR CHOLESTEROL IN HERPES SIMPLEX VIRUS ENTRY AND INFECTIVITY

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