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The study of animal virus entry is a very difficult endeavor with many obscurities; thus the field of virology finds itself with vast chasms of disagreement on this topic. To further complicate this difficulty, characteristics specific to each virus system combine to make experimental interpretation difficult. For example, a virus species may be programmed to enter through differing pathways depending on the cell type and host species of cell that it infects. Further, viruses can characteristically have high particle-to-plaque-forming unit (PFU) ratios that make observations by direct means difficult to interpret. These problems have plagued the field of virology for many years and will likely persist into the foreseeable future until methods and technologies advance to allow for increased resolution of these scientific impasses. This review will attempt to highlight the history, methodologies, and new developments within the field of alphavirus biology in the context of both receptor-mediated endocytosis and direct penetration hypotheses of virus penetration. Additionally, comparisons will be made between the proposed entry mechanisms of Alphaviruses
, and other enveloped viruses that may not follow orthodox pathways, to demonstrate the technical problems encountered by these studies.