Selected Grantee Publications
Modulation of MHC-E Transport by Viral Decoy Ligands Is Required for RhCMV/SIV Vaccine Efficacy
Verweij et al., Science. 2021.
https://doi.org/10.1126/science.abe9233
Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (SIV) vaccines elicit strong CD8+ T cell responses that can clear SIV infections. Peptides targeted by these T cells are presented on major histocompatibility complex (MHC) II and MHC-E rather than MHC-Ia. Researchers showed that VL9 drives intracellular transport of MHC-E and recognition of RhCMV-infected targets by MHC-E-restricted CD8+ T cells. Specific-pathogen-free (SPF) rhesus macaques vaccinated with a mutant 68-1 RhCMV lacking VL9 showed no priming of MHC-E-restricted CD8+ T cells and no protection against SIV, suggesting that future effective CMV-based HIV vaccines will require MHC-E-restricted CD8+ T cell priming. Supported by ORIP (U42OD023038, P51OD011092), NIAID, and NCI.
Functional Convergence of a Germline-Encoded Neutralizing Antibody Response in Rhesus Macaques Immunized with HCV Envelope Glycoproteins
Chen et al., Immunity. 2021.
https://doi.org/10.1016/j.immuni.2021.02.013
Immunoglobulin heavy chain variable gene IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection in humans. An IGHV1-69 ortholog, VH1.36, is preferentially used for bnAbs isolated from rhesus macaques immunized against HCV Env. Researchers investigated the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by HCV Env vaccination of macaques and compared their findings to IGHV1-69-encoded bnAbs from HCV patients. The investigators found that macaque VH1.36- and human IGHV1-69-encoded bnAbs share many common features, which provides an excellent framework for rational HCV vaccine design and testing. Supported by ORIP (P51OD011133, U42OD010442), NIAID, NCI, and NIGMS.
New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention, and Cure
Li et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.00071-21
Researchers knew that substitution of HIV-1 Env residue 375-serine by aromatic residues enhances binding to rhesus CD4 enabling primary HIV-1 Envs to support replication as simian-human immunodeficiency virus (SHIV) chimeras in rhesus monkeys. The investigators constructed SHIVs containing 10 primary Envs corresponding to HIV-1 subtypes A, B, C, AE, and AG. Only one with histidine at Env375 replicated efficiently in rhesus cells. Replacement of wild-type Env375 residues by tryptophan, tyrosine, phenylalanine, or histidine in the other 9 SHIVs led to efficient replication. These new SHIVs transmit via mucosal routes like HIV-1 and have use for vaccine testing in nonhuman primates. Supported by ORIP (U42OD021458, P40OD012217), NIAID, and NCI.
Modified Adenovirus Prime–Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge
Malherbe et al., Frontiers in Immunology. 2021.
https://doi.org/10.3389/fimmu.2020.626464
Researchers conducted a comparative vaccine challenge study in rhesus macaques. One group of monkeys was vaccinated using co-immunization with DNA Gag and Env expression plasmids and trimeric Env gp140 glycoprotein. The other group was primed with two replicating simian adenovirus-vectored vaccines expressing Gag and boosted with trimeric Env gp140. Both strategies elicited antigen-specific humoral and cellular immune responses, but neither approach provided significant protection from viral acquisition upon repeated mucosal challenges with a heterologous Tier 2 SHIV. Nevertheless, both regimens significantly lowered cell-associated viral DNA in multiple tissues, thus potentially dampening the infection and providing clues for further vaccine development. Supported by ORIP (U42OD023038, P51OD011092) and NIAID.
Responses to Acute Infection with SARS-CoV-2 in the Lungs of Rhesus Macaques, Baboons and Marmosets
Singh et al., Nature Microbiology. 2020.
https://www.nature.com/articles/s41564-020-00841-4
Investigators compared acute SARS-CoV-2 infection in young and old rhesus macaques and baboons. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies; both age groups recovered within 2 weeks. Baboons had prolonged viral RNA shedding and more lung inflammation compared with macaques; inflammation in bronchoalveolar lavage was increased in old versus young baboons. Macaques developed T-cell memory responses and bystander cytokine production. Old macaques had lower titers of SARS-CoV-2-specific IgG antibody levels compared with young macaques. The results indicate macaques and baboons experience acute respiratory distress that recapitulates the progression of COVID-19 in humans. Supported by ORIP (P51OD111033 and U42OD010442) and NIAID.