Rhesus macaque cytomegalovirus deploys viral Fcγ receptors to evade antibody-mediated cellular immunity

Abstract

Abstract Cytomegalovirus (CMV) is a top priority in vaccine development due to the high burden of disease in immunocompromised populations and congenitally infected infants. Evidence suggests that CMV-specific Fc-mediated antibody effector responses, such as antibody dependent cellular phagocytosis and cytotoxicity, are key for prevention of multiple CMV disease outcomes. However, human CMV expresses three Fcγ receptors that have been shown in vitro to synergistically interfere with anti-CMV IgG engagement of host Fcγ receptors (FcγRs). We recently identified three functionally homologous viral Fcγ receptors (vFcγRs) in rhesus macaque (RM) CMV (RhCMV), which allow us to validate the function of vFcγRs in vivo. Using a full-length (FL) RhCMV backbone (Taher, et al. 2020), we produced a mutant RhCMV lacking all identified vFcγRs (ΔvFcγR) and compared infection of CMV-seronegative male RMs with ΔvFcγR RhCMV (n=4) to FL RhCMV (n=3). RMs infected with ΔvFcγR and FL RhCMV experienced similar peak DNAemia levels 1 week post infection but ΔvFcγR RhCMV DNAemia was contained by week 3 while FL RhCMV remained detectable in plasma through week 9. The observed early control of infection is concurrent with the development of RhCMV-specific IgG responses which peak 3–4 weeks post infection in both groups. The kinetics of RhCMV-specific binding and neutralizing antibody responses were similar between the two groups of RMs, suggesting that anti-RhCMV Fc-mediated antibody effector responses may have been more effective against the RhCMV deleted of vFcγRs. Thus, vFcγRs are promising candidates for vaccine immunogens to improve Fc mediated effector responses and efficacy to reduce incidence of CMV-associated birth defects and transplant complications. Supported by grants from NIH P01-AI129859 and P01-AI129859_S1, NIH T32-CA009111, National CMV Foundation ECRA