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Truncating the Gp41 Cytoplasmic Tail of SIV Decreases Sensitivity to Neutralizing Antibodies without Increasing Envelope Content of Virions.

Truncating the Gp41 Cytoplasmic Tail of SIV Decreases Sensitivity to Neutralizing Antibodies without Increasing Envelope Content of Virions.
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White E, Wu F, Chertova E, Bess J, Roser JD, Lifson JD, Hirsch VM,


White E, Wu F, Chertova E, Bess J, Roser JD, Lifson JD, Hirsch VM, (click to view)

White E, Wu F, Chertova E, Bess J, Roser JD, Lifson JD, Hirsch VM,

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Journal of virology 2017 11 15() pii 10.1128/JVI.01688-17

Abstract

An incomplete understanding of native HIV and SIV envelope glycoprotein (Env) impedes the development of structural models of Env and vaccine design. This shortcoming is due in part to the low number of Env trimers on virus particles. For SIV, this low expression can be counteracted by truncating the cytoplasmic tail (CT) of Env. CT truncation has been shown to increase Env incorporation into the virion and is commonly used in vaccine and imaging studies, but its effects on viral antigenicity have not been fully elucidated. To study the effects of CT truncation of Env in viruses with similar genetic contexts, we introduced stop codons into the CT of a SIVsmE660 molecular clone and two neutralizing antibody (NAb) escape variants. These viruses shared 98% sequence identity in Env but were characterized as either Tier-1 (sensitive to neutralization), Tier-2 (moderately resistant), or Tier-3 (resistant). However, introduction of premature stop codons in Env at position Q741/Q742 converted all three transfection-derived viruses to a Tier-3-like phenotype that were uniformly resistant to neutralization by sera from infected macaques and monoclonal antibodies (mAbs). These changes in neutralization sensitivity were not accompanied by an increase in either virion Env content of infection-derived viruses or infectivity of transfection-derived viruses in human cells, suggesting that CT mutations may result in global changes to Env conformation. Our results demonstrate that some CT truncations can affect viral antigenicity, and as such may not be suitable surrogate models of the native HIV/SIV Env.IMPORTANCEModifications to the SIV envelope protein (Env) are commonly used in structural and vaccine studies to stabilize and increase the expression of Env, often without consideration for effects on antigenicity. One such widespread modification is truncation of the Env C-terminal tail. Here, we studied the effects of a particular cytoplasmic tail truncation in three SIVsm strains that have highly similar Env sequence but exhibit different sensitivities to neutralizing antibodies. After truncation of the Env CT, these viruses were all very resistant to neutralization by sera from infected macaques and monoclonal antibodies. The viruses with truncated Env CT also did not exhibit the desired and typical increase in Env expression. These results underscore the importance of carefully evaluating the use of truncated Env as a model in HIV/SIV vaccine and imaging studies, and of the continued need to find better models of native Env that contain fewer modifications.

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