Cell Entry by Enveloped Viruses: Redox Considerations for HIV and SARS-Coronavirus

Abstract

For enveloped viruses, genome entry into the target cell involves two major steps: virion binding to the cell-surface receptor and fusion of the virion and cell membranes. Virus-cell membrane fusion is mediated by the virus envelope complex, and its fusogenicity is the result of an active virus-cell interaction process that induces conformation changes within the envelope. For some viruses, such as influenza, exposure to an acidic milieu within the cell during the early steps of infection triggers the necessary structural changes. However, for other pathogens which are not exposed to such environmental stress, activation of fusogenicity can result from precise thiol/disulfide rearrangements mediated by either an endogenous redox autocatalytic isomerase or a cell-associated oxidoreductase. Study of the activation of HIV envelope fusogenicity has revealed new knowledge about how redox changes within a viral envelope trigger fusion. We discuss these findings and their implication for anti-HIV therapy. In addition, to compare and contrast the situation outlined for HIV with an enveloped virus that can fuse with the cell plasma membrane independent of the redox status of its envelope protein, we review parallel data obtained on SARS coronavirus entry.

Contribution of Redox Status to Hepatitis C Virus E2 Envelope Protein Function and Antigenicity

“…7) and is intriguing because the many viruses displaying a strong dependence on redox state for function of their envelopes and the very few that are poorly sensitive appear to fuse virus cell membranes by similar mechanisms. Severe acute respiratory syndrome coronavirus is an example of a virus whose envelope function is poorly sensitive to reduction (33).…”

“…However, several exofacial proteins exhibit plasticity in their disulfide-bonding post-biosynthesis, and their function may be triggered by redox changes at the cell surface (6,7). For instance, viral envelopes, which exhibit receptor-mediated conformational change to activate their fusogenicity, are, in some cases, subject to a redox reaction controlled by cell surface or autocatalytic oxidoreductase activities that trigger such structural changes (7).…”

“…For instance, viral envelopes, which exhibit receptor-mediated conformational change to activate their fusogenicity, are, in some cases, subject to a redox reaction controlled by cell surface or autocatalytic oxidoreductase activities that trigger such structural changes (7).…”

Prm1 Functions as a Disulfide-linked Complex in Yeast Mating

“…The Cys 120 disulfide bond might have to be reduced to facilitate exposure of the hydrophobic domain. Reduction of disulfide bonds is required to facilitate conformational shifts in several viral fusion proteins and is also essential for mammalian fertilization (37,38). The proposed interaction between hydrophobic regions of Prm1 in one cell and membrane lipids in the opposing plasma membrane can explain why Prm1 only needs to be expressed on one cell of a mating pair to promote fusion (3).…”

Hepatitis C virus entry into the hepatocyte

“…It is likely that disulfide rearrangements are required to prime HCV fusion process. Critical reshuffling of disulfide bonds has already been shown to occur for other viruses such as Sindbis virus and HIV [81,82]. For HIV, it has been proposed that protein disulfide isomerase (PDI) can act at a post-binding step to reduce two disulfide bonds in gp120 which consequently induces fusion competence.…”