TY - JOUR
T1 - Enhancing safety of cytomegalovirus-based vaccine vectors by engaging host intrinsic immunity
AU - Marshall, Emily E.
AU - Malouli, Daniel
AU - Hansen, Scott G.
AU - Gilbride, Roxanne M.
AU - Hughes, Colette M.
AU - Ventura, Abigail B.
AU - Ainslie, Emily
AU - Selseth, Andrea N.
AU - Ford, Julia C.
AU - Burke, David
AU - Kreklywich, Craig N.
AU - Womack, Jennie
AU - Legasse, Alfred W.
AU - Axthelm, Michael K.
AU - Kahl, Christoph
AU - Streblow, Daniel
AU - Edlefsen, Paul T.
AU - Picker, Louis J.
AU - Früh, Klaus
N1 - Publisher Copyright:
© 2019 The Authors.
PY - 2019/7/17
Y1 - 2019/7/17
N2 - Rhesus cytomegalovirus (RhCMV)-based vaccines maintain effector memory T cell responses (TEM) that protect ∼50% of rhesus monkeys (RMs) challenged with simian immunodeficiency virus (SIV). Because human CMV (HCMV) causes disease in immunodeficient subjects, clinical translation will depend upon attenuation strategies that reduce pathogenic potential without sacrificing CMV's unique immunological properties. We demonstrate that "intrinsic" immunity can be used to attenuate strain 68-1 RhCMV vectors without impairment of immunogenicity. The tegument proteins pp71 and UL35 encoded by UL82 and UL35 of HCMV counteract cell-intrinsic restriction via degradation of host transcriptional repressors. When the corresponding RhCMV genes, Rh110 and Rh59, were deleted from 68-1 RhCMV (ΔRh110 and ΔRh59), we observed only a modest growth defect in vitro, but in vivo, these modified vectors manifested little to no amplification at the injection site and dissemination to distant sites, in contrast to parental 68-1 RhCMV. ΔRh110 was not shed at any time after infection and was not transmitted to naïve hosts either by close contact (mother to infant) or by leukocyte transfusion. In contrast, ΔRh59 was both shed and transmitted by leukocyte transfusion, indicating less effective attenuation than pp71 deletion. The T cell immunogenicity of ΔRh110 was essentially identical to 68-1 RhCMV with respect to magnitude, TEM phenotype, epitope targeting, and durability. Thus, pp71 deletion preserves CMV vector immunogenicity while stringently limiting vector spread, making pp71 deletion an attractive attenuation strategy for HCMV vectors.
AB - Rhesus cytomegalovirus (RhCMV)-based vaccines maintain effector memory T cell responses (TEM) that protect ∼50% of rhesus monkeys (RMs) challenged with simian immunodeficiency virus (SIV). Because human CMV (HCMV) causes disease in immunodeficient subjects, clinical translation will depend upon attenuation strategies that reduce pathogenic potential without sacrificing CMV's unique immunological properties. We demonstrate that "intrinsic" immunity can be used to attenuate strain 68-1 RhCMV vectors without impairment of immunogenicity. The tegument proteins pp71 and UL35 encoded by UL82 and UL35 of HCMV counteract cell-intrinsic restriction via degradation of host transcriptional repressors. When the corresponding RhCMV genes, Rh110 and Rh59, were deleted from 68-1 RhCMV (ΔRh110 and ΔRh59), we observed only a modest growth defect in vitro, but in vivo, these modified vectors manifested little to no amplification at the injection site and dissemination to distant sites, in contrast to parental 68-1 RhCMV. ΔRh110 was not shed at any time after infection and was not transmitted to naïve hosts either by close contact (mother to infant) or by leukocyte transfusion. In contrast, ΔRh59 was both shed and transmitted by leukocyte transfusion, indicating less effective attenuation than pp71 deletion. The T cell immunogenicity of ΔRh110 was essentially identical to 68-1 RhCMV with respect to magnitude, TEM phenotype, epitope targeting, and durability. Thus, pp71 deletion preserves CMV vector immunogenicity while stringently limiting vector spread, making pp71 deletion an attractive attenuation strategy for HCMV vectors.
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U2 - 10.1126/scitranslmed.aaw2603
DO - 10.1126/scitranslmed.aaw2603
M3 - Article
C2 - 31316006
AN - SCOPUS:85069925068
SN - 1946-6234
VL - 11
JO - Science translational medicine
JF - Science translational medicine
IS - 501
M1 - eaaw2603
ER -