Hansen Scott G, Schell John B, Marshall Emily E, Ojha Sohita, Feltham Shana, Morrow David, Hughes Colette M, Gilbride Roxanne M, Ford Julia C, Cleveland-Rubeor Hilary C, McArdle Matthew R, Whitmer Travis, Barber-Axthelm Aaron, Bochart Rachelle, Smedley Jeremy, Oswald Kelli, Fast Randy, Shoemaker Rebecca, Kosmider Ewelina, Edlefsen Paul T, Lifson Jeffrey D, Malouli Daniel, Früh Klaus, Picker Louis J
Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, United States.
AIDS and Cancer Virus Program, SAIC Frederick, Inc., Frederick National Laboratory, Leidos Biomedical Research, Inc., Frederick, MD, United States.
J Immunol. 2025 Aug 1;214(8):1969-1981. doi: 10.1093/jimmun/vkaf104.
Strain 68-1 rhesus CMV (RhCMV) vectors induce immune responses that mediate early, complete replication arrest of SIV infection in ∼60% of vaccinated rhesus macaques (RMs). This unique efficacy depends on the ability of these vectors to elicit effector memory (EM)-biased CD8+ T cells recognizing SIV peptides presented by MHC-E, rather than MHC-Ia. These efficacious responses still occurred when spread of the 68-1 vector was impaired by deletion of the viral anti-host intrinsic immunity factor phosphoprotein 71 (pp71), but efficacy was lost with a more stringent attenuation strategy based on destabilization of Rh108, the ortholog of the essential human CMV (HCMV) transcription factor UL79 that is required for late viral gene expression. Although unable to produce infectious progeny (ie single-cycle infection), Rh108-deficient vectors elicited durable, high frequency, EM-biased, SIV-specific CD8+ T-cell responses in RMs, but these responses were MHC-Ia-restricted and therefore non-efficacious. Here, we tested a different single-cycle attenuation strategy based on deletion (Δ) of the glycoprotein L (gL) that is essential for viral entry but allows for late gene expression and viral assembly. ΔgL 68-1 RhCMV/SIV vectors, grown on gL-complementing fibroblasts, were robustly immunogenic at doses above 105 PFU, generating high frequency, EM-biased, SIV-specific CD8+ T-cell responses that were also unconventionally restricted, including the MHC-E restriction associated with efficacy. Indeed, these single-cycle vectors manifested replication arrest efficacy in 70% of vaccinated RMs, further linking MHC-E restriction with efficacy, and demonstrating that 68-1 RhCMV/SIV efficacy does not require vector dissemination within the host.
68 - 1株恒河猴巨细胞病毒（RhCMV）载体可诱导免疫反应，在约60%的接种恒河猴（RM）中介导对SIV感染的早期、完全复制阻滞。这种独特的功效取决于这些载体引发效应记忆（EM）偏向性CD8⁺T细胞的能力，这些细胞识别由MHC - E而非MHC - Ia呈递的SIV肽段。当通过缺失病毒抗宿主固有免疫因子磷蛋白71（pp71）来损害68 - 1载体的传播时，这些有效的反应仍然会发生，但基于对Rh108（人类巨细胞病毒（HCMV）必需转录因子UL79的直系同源物，晚期病毒基因表达所必需）的不稳定化的更严格减毒策略会导致功效丧失。尽管无法产生感染性后代（即单周期感染），但缺乏Rh108的载体在恒河猴中引发了持久、高频、EM偏向性、SIV特异性CD8⁺T细胞反应，但这些反应受MHC - Ia限制，因此无效。在此，我们测试了一种基于缺失对病毒进入至关重要但允许晚期基因表达和病毒组装的糖蛋白L（gL）的不同单周期减毒策略。在gL互补成纤维细胞上生长的ΔgL 68 - 1 RhCMV/SIV载体，在剂量高于10⁵ PFU时具有强大的免疫原性，产生高频、EM偏向性、SIV特异性CD8⁺T细胞反应，这些反应也是非常规限制的，包括与功效相关的MHC - E限制。实际上，这些单周期载体在70%的接种恒河猴中表现出复制阻滞功效，进一步将MHC - E限制与功效联系起来，并证明68 - 1 RhCMV/SIV的功效不需要载体在宿主体内传播。
