Determinants in gammaretroviral Env dictate the production of neutralizing antibodies

Protective immune responses are shaped by the nature of the infectious pathogen. Some viral infections are self-limiting and stimulate lasting immunity, while others activate poor responses that fail to control the infection or prevent development of disease. Little is known concerning the specific viral determinants that control whether a given viral infection will result in protective immunity. Here, we demonstrate that strains of the gammaretrovirus, murine leukemia virus, differ in their ability to stimulate neutralizing antibody production via a noncanonical pathway. Additionally, we show that virus-specific production of neutralizing immune responses is unique to infection, suggesting that the activation of alternative antibody responses is triggered by the infectious process rather than the unique nature of specific viral antigens. Viral chimeras indicate that activation of neutralizing antiviral antibody production is determined by the receptor-binding domain, and that the surface subunit controls binding to and infection of various cell types. The ability of specific viral factors to determine the outcome of infection and the induction of distinctive immune responses between closely related retroviral strains provides an ideal model for the dissection of both host and viral determinants underlying the control of viral infection and the production of neutralizing antibodies.