Foamy Virus Envelope Glycoprotein-Mediated Entry Involves a pH-Dependent Fusion Process

Abstract

In general, enveloped viruses use two different entry strategies and are classified accordingly into pHdependent and pH-independent viruses. Different members of the retrovirus family use one or the other strategy. Little is known about the uptake of foamy viruses (FV), a special group of retroviruses, into the target cells. In this study, we examined the pH dependence of FV entry by analyzing FV envelope glycoprotein (Env)-mediated infection of target cells with murine leukemia virus or FV vector pseudotypes in the presence of various lysosomotropic agents. Similar to vesicular stomatitis virus glycoprotein G (VSV-G)-mediated uptake, FV Env-mediated entry was inhibited by various lysosomotropic agents, suggesting a pH-dependent endocytic pathway. However, in contrast to its effect on VSV-G pseudotypes, chloroquine failed to reduce the infectivity of FV Env pseudotypes, implying that the pathway is different from that of VSV-G. Glycoproteins of various other FV species showed inhibition profiles similar to that of the prototype FV (PFV) Env. Analysis of the pH dependence of the FV Env-mediated fusion process in a cell-to-cell fusion assay revealed an induction of syncytium formation by a short exposure to acidic pH, peaking around pH 5.5. Interestingly, of all FV Env species analyzed, only the PFV Env had a significant fusion activity at neutral pH. Taken together, these data suggest a pH-dependent endocytic pathway for infection of target cells by FV.

Comparative analysis of the envelope glycoproteins of foamy viruses

“…The function of the FP is still unclear. But it has been proven that the FPs in almost all FVs need to be exposed to a low pH, in order to insert themselves into the target membranes (Picard-Maureau et al, 2003).…”

Molecular biology of foamy viruses

“…However, while the results with various lysomotropic reagents, such as concanamycin A, ammonium chloride, methylamine, and baWlomycin A1, were consistently pointing to a pH-dependent cellular uptake, the results obtained with chloroquine diverged and also indicated that there are as yet not understood diVerences to other glycoproteins that show pH dependency of their fusion activity [97].…”

“…Concerning the cellular uptake of FV virions, it was established that it likely follows a pathway known from some other enveloped viruses such as inXuenza virus or VSV [97] that is virus uptake relies on the acidiWcation of Env for the generation of a fusion-competent molecule [97]. However, while the results with various lysomotropic reagents, such as concanamycin A, ammonium chloride, methylamine, and baWlomycin A1, were consistently pointing to a pH-dependent cellular uptake, the results obtained with chloroquine diverged and also indicated that there are as yet not understood diVerences to other glycoproteins that show pH dependency of their fusion activity [97].…”

An Envelope-determined Endocytic Route of Viral Entry Allows HIV-1 to Escape from Secreted Phospholipase A2 Entry Blockade

“…33,35 Retroviral entry mediated by receptor priming and low-pH triggering of the envelope glycoprotein has, however, been reported in the case of the avian leucosis virus and the foamy virus. 50,51 To verify whether the envRBV-3 mediated fusion process can occur under acidic conditions, envRBV-3 expressing cells have been induced to undergo syncytium formation upon the artificial lowering of the extracellular pH. We have shown that envRBV-3 is able to induce membrane fusion both at neutral and low pH, with an optimal pH around 5.0.…”

“…The pH dependence of the fusion activity of envRBV-3 protein was analysed by using a cell-to-cell fusion assay as described 51 with minor modifications. The 293 cells (4x10 5 ) were transiently transfected with 2 μg of pEnvRBV-3, pAD-2 or pCMV-G and 2 μg of the Tat expression vector pCMVTat.…”