Escape by Shifting: Viral Entry Tropism Shift as an Evolutionary Mechanism of Immune Evasion

PROJECT SUMMARY Viral entry tropism, largely governed by receptor specificity, is a major determinant for virus cellular and tissue tropism, pathogenesis, and host range. Alteration in receptor specificity could be closely related with viral pathogenesis, such as the process of “coreceptor switch” in HIV infection that is associated with faster progression to AIDS, and may contribute to host-jumping, as exemplified by coronavirus and influenza virus. However, the molecular mechanism underlying viral receptor usage alteration during natural infection is a fundamental gap in knowledge. Recent studies of our group for the first time elucidated the evolutionary process of coreceptor switch in natural HIV infection. The findings demonstrate that “driver mutations” responsible for coreceptor switch can confer complete escape to V3 broadly neutralizing antibodies. These novel observations, together with the fact that the receptor binding regions of many viruses overlap with antigenic epitopes, prompted us to propose a potentially paradigm-shifting concept termed “escape by shifting”. The central hypothesis is that for viruses with entry pathway flexibility, entry tropism alteration represents an evolutionary mechanism of immune evasion in vivo. We coin the term “receptor utilization space” to describe the repertoire of receptors that can be used by a particular virus. Under the immune pressure, a virus explores its “receptor tropism space” while exploring the sequence space and fitness landscape. Immune escape mutations and compensatory mutations could both confer novel receptor usage, which functions as a mechanism to maintain viral entry capacity while evading host immune recognition. We aim to test this novel concept by elucidating the biological mechanisms of HIV coreceptor switch. To this end, we will leverage a highly unique opportunity of the RV217 cohort which has longitudinal samples available from participants identified very early in acute HIV infection. The “escape by shifting” concept will be tested through three specific aims: 1) Determine the moment of coreceptor switch in vivo by identifying the driver mutations. 2) Characterize the function of driver mutations in evading autologous neutralizing antibodies. 3) Elucidate the impact of coreceptor switch on CD4 hemostasis and reservoir landscape. The proposed work is significant for several reasons. First, it is expected to answer a long-standing question in the HIV field which has direct implications for HIV pathogenesis, therapeutics, and functional cure. Second, the knowledge obtained is expected to provide important information to better inform HIV treatment, preventative, and cure strategies. Third, while we use HIV as a model, the central hypothesis of the “escape by shifting” concept is generalizable to viruses with entry pathway flexibility. Our long-term goal is to understand the molecular mechanisms of viral entry pathway evolution under the immune pressure, which has direct relevance to viral pathogenesis, transmissibility, as well as therapeutic and vaccine design. If successful, the proposed work will fundamentally advance our understanding of the immunopathogenesis of HIV beyond current boundaries and has the potential to open a new paradigm in the understanding of viral entry pathway evolution.