Exploitation of Unconventional CD8 T-Cell Responses Induced by Engineered Cytomegaloviruses for the Development of an HIV-1 Vaccine
After four decades of intensive research, traditional vaccination strategies for HIV-1 remain ineffective due to HIV-1′s extraordinary genetic diversity and complex immune evasion mechanisms. Cytomegaloviruses (CMV) have emerged as a novel type of vaccine vector with unique advantages due to CMV per...
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2025-01-01
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| author | Joseph Bruton Tomáš Hanke |
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| description | After four decades of intensive research, traditional vaccination strategies for HIV-1 remain ineffective due to HIV-1′s extraordinary genetic diversity and complex immune evasion mechanisms. Cytomegaloviruses (CMV) have emerged as a novel type of vaccine vector with unique advantages due to CMV persistence and immunogenicity. Rhesus macaques vaccinated with molecular clone 68-1 of RhCMV (RhCMV68-1) engineered to express simian immunodeficiency virus (SIV) immunogens elicited an unconventional major histocompatibility complex class Ib allele E (MHC-E)-restricted CD8<sup>+</sup> T-cell response, which consistently protected over half of the animals against a highly pathogenic SIV challenge. The RhCMV68-1.SIV-induced responses mediated a post-infection replication arrest of the challenge virus and eventually cleared it from the body. These observations in rhesus macaques opened a possibility that MHC-E-restricted CD8<sup>+</sup> T-cells could achieve similar control of HIV-1 in humans. The potentially game-changing advantage of the human CMV (HCMV)-based vaccines is that they would induce protective CD8<sup>+</sup> T-cells persisting at the sites of entry that would be insensitive to HIV-1 evasion. In the RhCMV68-1-protected rhesus macaques, MHC-E molecules and their peptide cargo utilise complex regulatory mechanisms and unique transport patterns, and researchers study these to guide human vaccine development. However, CMVs are highly species-adapted viruses and it is yet to be shown whether the success of RhCMV68-1 can be translated into an HCMV ortholog for humans. Despite some safety concerns regarding using HCMV as a vaccine vector in humans, there is a vision of immune programming of HCMV to induce pathogen-tailored CD8<sup>+</sup> T-cells effective against HIV-1 and other life-threatening diseases. |
| format | Article |
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| institution | Kabale University |
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| spelling | doaj-art-e6e214c14e384dd98f5947238c72bdf62025-01-24T13:51:51ZengMDPI AGVaccines2076-393X2025-01-011317210.3390/vaccines13010072Exploitation of Unconventional CD8 T-Cell Responses Induced by Engineered Cytomegaloviruses for the Development of an HIV-1 VaccineJoseph Bruton0Tomáš Hanke1Hertford College, University of Oxford, Oxford OX1 3BW, UKThe Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UKAfter four decades of intensive research, traditional vaccination strategies for HIV-1 remain ineffective due to HIV-1′s extraordinary genetic diversity and complex immune evasion mechanisms. Cytomegaloviruses (CMV) have emerged as a novel type of vaccine vector with unique advantages due to CMV persistence and immunogenicity. Rhesus macaques vaccinated with molecular clone 68-1 of RhCMV (RhCMV68-1) engineered to express simian immunodeficiency virus (SIV) immunogens elicited an unconventional major histocompatibility complex class Ib allele E (MHC-E)-restricted CD8<sup>+</sup> T-cell response, which consistently protected over half of the animals against a highly pathogenic SIV challenge. The RhCMV68-1.SIV-induced responses mediated a post-infection replication arrest of the challenge virus and eventually cleared it from the body. These observations in rhesus macaques opened a possibility that MHC-E-restricted CD8<sup>+</sup> T-cells could achieve similar control of HIV-1 in humans. The potentially game-changing advantage of the human CMV (HCMV)-based vaccines is that they would induce protective CD8<sup>+</sup> T-cells persisting at the sites of entry that would be insensitive to HIV-1 evasion. In the RhCMV68-1-protected rhesus macaques, MHC-E molecules and their peptide cargo utilise complex regulatory mechanisms and unique transport patterns, and researchers study these to guide human vaccine development. However, CMVs are highly species-adapted viruses and it is yet to be shown whether the success of RhCMV68-1 can be translated into an HCMV ortholog for humans. Despite some safety concerns regarding using HCMV as a vaccine vector in humans, there is a vision of immune programming of HCMV to induce pathogen-tailored CD8<sup>+</sup> T-cells effective against HIV-1 and other life-threatening diseases.https://www.mdpi.com/2076-393X/13/1/72cytomegalovirusHCMVRhCMV68-1HLA-ECD8 T-cellsHIV-1 vaccines |
| spellingShingle | Joseph Bruton Tomáš Hanke Exploitation of Unconventional CD8 T-Cell Responses Induced by Engineered Cytomegaloviruses for the Development of an HIV-1 Vaccine Vaccines cytomegalovirus HCMV RhCMV68-1 HLA-E CD8 T-cells HIV-1 vaccines |
| title | Exploitation of Unconventional CD8 T-Cell Responses Induced by Engineered Cytomegaloviruses for the Development of an HIV-1 Vaccine |
| title_full | Exploitation of Unconventional CD8 T-Cell Responses Induced by Engineered Cytomegaloviruses for the Development of an HIV-1 Vaccine |
| title_fullStr | Exploitation of Unconventional CD8 T-Cell Responses Induced by Engineered Cytomegaloviruses for the Development of an HIV-1 Vaccine |
| title_full_unstemmed | Exploitation of Unconventional CD8 T-Cell Responses Induced by Engineered Cytomegaloviruses for the Development of an HIV-1 Vaccine |
| title_short | Exploitation of Unconventional CD8 T-Cell Responses Induced by Engineered Cytomegaloviruses for the Development of an HIV-1 Vaccine |
| title_sort | exploitation of unconventional cd8 t cell responses induced by engineered cytomegaloviruses for the development of an hiv 1 vaccine |
| topic | cytomegalovirus HCMV RhCMV68-1 HLA-E CD8 T-cells HIV-1 vaccines |
| url | https://www.mdpi.com/2076-393X/13/1/72 |
| work_keys_str_mv | AT josephbruton exploitationofunconventionalcd8tcellresponsesinducedbyengineeredcytomegalovirusesforthedevelopmentofanhiv1vaccine AT tomashanke exploitationofunconventionalcd8tcellresponsesinducedbyengineeredcytomegalovirusesforthedevelopmentofanhiv1vaccine |