Mutations in the feline immunodeficiency virus envelope glycoprotein confer resistance to a dominant-negative fragment of Tsg101 by enhancing infectivity and cell-to-cell virus transmission

Benjamin G Luttge; Prashant Panchal; Vinita Puri; Mary Ann Checkley; Eric O Freed

doi:10.1016/j.bbamem.2013.08.020

Mutations in the feline immunodeficiency virus envelope glycoprotein confer resistance to a dominant-negative fragment of Tsg101 by enhancing infectivity and cell-to-cell virus transmission

Biochim Biophys Acta. 2014 Apr;1838(4):1143-52. doi: 10.1016/j.bbamem.2013.08.020. Epub 2013 Sep 10.

Authors

Benjamin G Luttge¹, Prashant Panchal¹, Vinita Puri¹, Mary Ann Checkley¹, Eric O Freed²

Affiliations

¹ Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
² Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA. Electronic address: efreed@nih.gov.

Abstract

The Pro-Ser-Ala-Pro (PSAP) motif in the p2 domain of feline immunodeficiency virus (FIV) Gag is required for efficient virus release, virus replication, and Gag binding to the ubiquitin-E2-variant (UEV) domain of Tsg101. As a result of this direct interaction, expression of an N-terminal fragment of Tsg101 containing the UEV domain (referred to as TSG-5') inhibits FIV release. In these respects, the FIV p2(Gag) PSAP motif is analogous to the PTAP motif of HIV-1 p6(Gag). To evaluate the feasibility of a late domain-targeted inhibition of virus replication, we created an enriched Crandell-Rees feline kidney (CRFK) cell line (T5'(hi)) that stably expresses high levels of TSG-5'. Here we show that mutations in either the V3 loop or the second heptad repeat (HR2) domain of the FIV envelope glycoprotein (Env) rescue FIV replication in T5'(hi) cells without increasing FIV release efficiency. TSG-5'-resistance mutations in Env enhance virion infectivity and the cell-cell spread of FIV when diffusion is limited using a semi-solid growth medium. These findings show that mutations in functional domains of Env confer TSG-5'-resistance, which we propose enhances specific infectivity and the cell-cell transmission of virus to counteract inefficient virus release. This article is part of a Special Issue entitled: Viral Membrane Proteins-Channels for Cellular Networking.

Keywords: AIDS; Cell-to-cell virus transmission; ESCRT; FIV; HIV-1; Late domain; TSG-5' resistance; Tsg101.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Animals
Cats
Cells, Cultured
DNA-Binding Proteins / physiology*
Endosomal Sorting Complexes Required for Transport / physiology*
Immunodeficiency Virus, Feline / pathogenicity*
Mutagenesis, Site-Directed
Mutation*
Peptide Fragments / physiology*
Transcription Factors / physiology*
Viral Envelope Proteins / physiology*

Substances

DNA-Binding Proteins
Endosomal Sorting Complexes Required for Transport
Peptide Fragments
Transcription Factors
Tsg101 protein
Viral Envelope Proteins

Grants and funding

ZIA BC010776-03/Intramural NIH HHS/United States