The R5 to X4 Coreceptor Switch: A Dead-End Path, or a Strategic Maneuver? Lessons from a Game Theoretic Analysis

In this paper, we show how a game theoretic analysis can provide a model to explain the interdependence of host produced APOBEC3G levels and virus encoded Vif levels. We then use the relationship between these two opposing proteins in order to predict the success of two different HIV-1 viral variants, R5 and X4. From our analysis, we show that when APOBEC3G strongly favors mutation from an R5 strain to an X4 strain, it can be optimal for HIV-1 to suppress transmission of the X4 variant, despite the loss of X4 fitness potential. This is particularly true when the X4 strain significantly interferes with the host adaptive immune response, when Vif production is limited, or when host APOBEC3G targets the X4 strain more severely than the R5 strain. Using the proposed game theoretic analysis, we show that transmitting only R5 viruses has two advantages so far as HIV-1 is concerned. First, it allows for an increased R5 viral load due to immune interference caused by the X4 strain, and second, it forces the host to down-regulate APOBEC3G production, which is automatically favorable to the virus. APOBEC3G down-regulation, which is predicted in our model for a wide range of parameter values, may offer an explanation for the observed low level of APOBEC3G transcription and translation in hosts infected with HIV-1.