INFLUENZA VIRUS AND CHOLESTEROL: TOUCH POINTS

Abstract---This review considers the observations concerning the interactions of influenza virus with cholesterol and consequences of these interactions for both the virus and a host cell. There are at least two crucial “touch points”, when IFV deals with cholesterol: first, cholesterol is required for influenza virus entry into the cell. Second, during budding, when new viral particles form their envelopes from plasma membrane of the infected cell, selectively acquiring “raft lipids”, cholesterol and sphingolipids. One possible mechanism ensuring selective accumulation of cholesterol in the viral envelope is the presence of cholesterol-binding motifs (CRAC motifs) in protein M1 and possibly other viral proteins involved in this process. These motifs could be responsible for binding of cell membrane´s cholesterol by the viral protein. The important role of cholesterol in the influenza virus life cycle raises the possibility that lowering cholesterol levels in host cells (e.g., with statins) can be useful in reducing influenza virus infectivity and productivity. However, lowering cholesterol in cell membranes below an optimal level may not be compatible with normal cell function. There is experimental evidence that CRAC-containing peptide derived from influenza virus protein M1 is indeed cytotoxic, and that extraction of membrane cholesterol with mbCD lowers the concentration of the peptide´s cytotoxic effect by an order of magnitude. In the conditions of reduced cholesterol, any infection with enveloped virus sequestering cholesterol from cell membranes may be detrimental, as further lowering cholesterol level in cell membrane during virus budding may lead to cell damage or death. Perhaps to minimize the virus infectivity and the consequences of the massive virus budding, advantageous can be alternative approaches, such as a search for and design of agents that would selectively interfere with cholesterol-dependent virus–cell interactions and inhibit them. Understanding the mechanisms and consequences of these interactions should be useful in the developing of new antiviral drugs.