XMRV transmission via direct cell-cell contact is more efficient than diffusion through the extracellular milieu

The Journal of Virology, August 2011,p. 7672-7682, Vol. 85, No. 15
Viral Determinants of Polarized Assembly for the Murine Leukemia Virus

Jing Jin, Fei Li,, and Walther Mothes*:

Section of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Ave., New Haven, Connecticut 06536

Received 28 February 2011/ Accepted 10 May 2011

Retrovirus transmission via direct cell-cell contact is more efficient than diffusion through the extracellular milieu. This is believed to be due to the ability of viruses to efficiently coordinate several steps of the retroviral life cycle at cell-cell contact sites (D. C. Johnson et al., J. Virol. 76:1–8, 2002; D. M. Phillips, AIDS 8:719–731, 1994; Q. Sattenau, Nat. Rev. Microbiol. 6:815–826, 2008). Using the murine leukemia virus (MLV) as a model retrovirus, we have previously shown that interaction between viral envelope (Env) and receptor directs viral assembly to cell-cell contact sites to promote efficient viral spreading (J. Jin et al., PLoS Biol. 7:e1000163, 2009). In addressing the underlying mechanism, we observed that Env cytoplasmic tail directs this contact-induced polarized assembly. We present here the viral determinants in the Env cytoplasmic tail and Gag that are important in this process. A tyrosine residue within the cytoplasmic tail of Env was identified, which directs polarized assembly. MLV matrix-mediated membrane targeting is required for Gag recruitment to sites of cell-cell contact. Our results suggest that MLV polarized assembly is mediated by a direct or indirect interaction between both domains, thereby coupling Gag recruitment and virus assembly to Env accumulation at the cell-cell interface. In contrast, HIV Gag that assembles outside of cell-cell interfaces can subsequently be drawn into contact zones mediated by MLV Env and receptor, a finding that is consistent with the previously observed lateral movement of HIV into the virological synapse (W. Hubner et al., Science 323:1743–1747, 2009; D. Rudnicka et al., J. Virol. 83:6234–6246, 2009). As such, we observed two distinct modes of virus cell-to-cell transmission that involve either polarized or nonpolarized assembly, but both result in virus transmission.



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* Corresponding author. Mailing address: Microbial Pathogenesis, Yale School of Medicine, 295 Congress Ave., BCMM 335, New Haven, CT 06536. Phone: (203) 737-2203. Fax: (203) 737-2630. E-mail: walther.mothes@yale.edu.