As arboviruses, alphaviruses infect insect and vertebrate hosts. Since alphaviruses need to infect cells which provide widely divergent biochemical and genetic environments, it is likely that they either use a ubiquitous receptor, or are able to use multiple proteins as a receptor. The receptor/s has not been identified. Many proteins and polysaccharides have been implicated as being part of the receptor complex. The list includes, heparin sulfate, the major histocompatability complex (MHC), the major laminin receptor, DC sign, L sign, heat shock 70 protein, an unidentified 110 kDa nerve cell protein, and a 63 kDa protein in chicken cells. The length of the list of possible receptors strongly suggests that there are multiple proteins that alphaviruses can use, and that the specific receptor is both cell and virus specific. If, however, there is one widely used receptor it would have to be a fundamental piece of genetic and biochemical machinery that has been conserved throughout evolution. The alphaviruses have evolved to use highly conserved proteins that span the large breath of species that serve as hosts and/or multiple proteins as a receptors.
The concept that the receptor is, at least in part, proteinaceous comes from a study which showed that protease treatment of cells prior to adsorption decreased the number of infected cells. Phospholipase and neuraminidase treatment did not have an effect on infection. Using chemical cross-linking, the first candidate as a receptor was identified by Maassen and Terhorst as a 90 kDa protein. Following this report there were a number of additional studies that employed various techniques to determine the receptor. One such study used soluble glycoproteins from Semliki Forest Virus (SFV) and showed that the MHC bound the glycoproteins and that detergent soluble MHC protein was able to inhibit SFV infection of HeLa cells. Since then, a number of questions about the validity of this argument have arisen since cells that lack the MHC complex are not resistant to SFV infectio. Additionally, mosquito cells, which fundamentally lack a human immune system and thus do not express MHC, are also readily infected by alphaviruses.
The use of anti-idiotypic antibodies as receptor locators has been used as well to determine the receptor for alphaviruses. This approach is responsible for the discovery of the 63 kDa chicken protein and eventually led to the implication of the high-affinity laminin receptor. While this is considered a major receptor for alphaviruses, reexamination of the original experiment that identified the 63 kDa chicken protein revealed that this protein was not the chicken laminin receptor. Additionally antibody against the chicken laminin receptor did not inhibit infection significantly (< 10%). This suggests that although the laminin receptor is conserved across many species, it is not the only virus receptor. It is entirely likely that there are multi-protein complexes that are not required for, but enhance infection. Other investigations of the laminin receptor used anti-idiotype antibodies to examine the laminin receptor as a possible virus receptor in mosquito cells. In these studies a 32 kDa protein was discovered in mosquito cells to which Venezuelan Equine Encephalitis Virus (VEE) bound as did laminin and SINV. Antibodies were also used to investigate virus binding with a strain of SINV which was selected to be a rapid penetrating virus. Upon binding to the cell at neutral pH assumingly to its receptor, SFV was shown to go through conformational changes as new antibody epitopes were exposed on the surface of the virus. This is presumably related to the conformational change that is seen in reconstructed virus particles which were exposed to low pH.