The prevailing model of retroviral biology explain the vast majority of empirical observations regarding these biomedically important pathogens. However, there are certain observations that lie beyond these paradigms. These include the host cell molecules present in retroviral particles, which do not match those of the plasma membrane, the highly focal nature of cell surface retroviral budding, the reports of ENV-independent infection by retrovirusers, and the fact that few if any animals are able to generate sterilizing immunity towards their cognate retroviruses. While these observations might be explained by mechanistically trivial phenomena, we recently developed a hypothesis that is capable of explaining both the main body of data on retroviruses and these (and other) outlying observations. This Trojan exosome hypothesis states that retroviruses (1) use the pre-existing, non-viral exosome biogenesis pathway for the formation of infectious particles, and (2) exploit the pre-existing, non-viral pathway of exosome uptake for a receptor-independent, Env-independent mode of infection. As discussed in a recent article, this hypothesis provides a mechanistic explanation for retroviurus budding at endosomal membrane, the nature of the host cell proteins and lipids that are present in retroviral virions, the requirement for Class E VPS proteins in retroviral budding, and the ability of Env-deleted viruses to bind efficiently to target cells, and in some cases even infect target cells. While there is considerable empirical and conceptual support for this hypothesis, some predictions of this hypothesis remain to be tested while others remain to be tested directly. The goal of this proposal is to accelerate the rejection or acceptance of the Trojan exosome hypothesis by testing a few of its critical yet incompletely evaluated predictions regarding the cell biology of retrovirus budding.
| Fang, Yi; Wu, Ning; Gan, Xin et al. (2007) Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol 5:e158 |
| Booth, Amy M; Fang, Yi; Fallon, Jonathan K et al. (2006) Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol 172:923-35 |
