Abstract
The subgroup A through E avian sarcoma and leukosis viruses (ASLV(A) through ASLV(E)) are a group of highly related alpharetroviruses that have evolved their envelope glycoproteins to use different receptors to enable efficient virus entry due to host resistance and/or to expand host range. Previously, we demonstrated that ASLV(A) in the presence of a competitor to the subgroup A Tva receptor, SUA-rIgG immunoadhesin, evolved to use other receptor options. The selected mutant virus, RCASBP(A)Δ155–160, modestly expanded its use of the Tvb and Tvc receptors and possibly other cell surface proteins while maintaining the binding affinity to Tva. In this study, we further evolved the Δ155–160 virus with the genetic selection pressure of a soluble form of the Tva receptor that should force the loss of Tva binding affinity in the presence of the Δ155–160 mutation. Viable ASLVs were selected that acquired additional mutations in the Δ155–160 Env hypervariable regions that significantly broadened receptor usage to include Tvb and Tvc as well as retaining the use of Tva as a receptor determined by receptor interference assays. A similar deletion in the hr1 hypervariable region of the subgroup C ASLV glycoproteins evolved to broaden receptor usage when selected on Tvc-negative cells.
Highlights
All retroviruses initially synthesize their envelope glycoproteins as a precursor that is subsequently processed into two glycoproteins, the surface (SU) and transmembrane (TM) glycoproteins that form a trimer of SU:TM heterodimers [1]
Two different mutant virus pools were selected by the RCASBP(A)∆155–160 virus to escape the cksTva-mIgG immunadhesin entry inhibitor
The RCASBP(A)∆155–160 mutant virus evolved under the selective pressure of SUA-rIgG immunadhesin that reduced the expression of the Tva receptor on the cell surface, and if Tva was displayed, competed with the subgroup A envelope glycoproteins on the virion for binding the cell surface Tva receptor, forcing RCASBP(A) to alter its receptor usage to enter cells
Summary
All retroviruses initially synthesize their envelope glycoproteins as a precursor that is subsequently processed into two glycoproteins, the surface (SU) and transmembrane (TM) glycoproteins that form a trimer of SU:TM heterodimers [1]. The subgroup A through E avian sarcoma and leukosis viruses (ASLV(A) through ASLV(E)) are a group of highly related alpharetroviruses that have evolved their env genes encoding the viral envelope glycoproteins from a common ancestor to use members of very different host protein families as receptors to enable efficient virus entry [2,3,4]. A variety of studies have identified hr and hr as the principle binding domains between the viral glycoprotein trimer and the host protein receptor, with vr contributing to the specificity of the receptor interaction for initiating efficient infection (Figure 1) [8,9,10,11,12,13]
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