Bivalent mRNA COVID vaccines elicit predominantly cross-reactive CD4+ T cell clonotypes.

Bivalent COVID vaccines containing mRNA for ancestral and Omicron BA.5 spike proteins do not induce stronger T cell responses to Omicron BA.5 spike proteins than monovalent vaccines that contain only ancestral spike mRNA. The reasons for this finding have not been elucidated. Here, we show that healthy donors (HDs) and people living with HIV (PLWH) on antiretroviral therapy mostly target T cell epitopes that are not affected by BA.5 mutations. We use the functional expansion of specific T cells (FEST) assay to determine the percentage of CD4+ T cells that cross-recognize both spike proteins and those that are monoreactive for each protein. We show a predominance of cross-reactive CD4+ T cells; less than 10% percent of spike-specific CD4+ T cell receptors were BA.5 monoreactive in most HDs and PLWH. Our data suggest that the current bivalent vaccines do not induce robust BA.5-monoreactive T cell responses.

Orthopoxvirus-Specific T-Cell Responses in Convalescent Mpox Patients.

Orthopoxvirus-specific T-cell responses were analyzed in 10 patients who had recovered from Mpox including 7 people with human immunodeficiency virus (PWH). Eight participants had detectable virus-specific T-cell responses, including a PWH who was not on antiretroviral therapy and a PWH on immunosuppressive therapy. These 2 participants had robust polyfunctional CD4+ T-cell responses to peptides from the 121L vaccinia virus (VACV) protein. T-cells from 4 of 5 HLA-A2-positive participants targeted at least 1 previously described HLA-A2-restricted VACV epitope, including an epitope targeted in 2 participants. These results advance our understanding of immunity in convalescent Mpox patients.

Proviral location affects cognate peptide-induced virus production and immune recognition of HIV-1-infected T cell clones.

BACKGROUNDHIV-1-infected CD4+ T cells contribute to latent reservoir persistence by proliferating while avoiding immune recognition. Integration features of intact proviruses in elite controllers (ECs) and people on long-term therapy suggest that proviruses in specific chromosomal locations can evade immune surveillance. However, direct evidence of this mechanism is missing.METHODSIn this case report, we characterized integration sites and full genome sequences of expanded T cell clones in an EC before and after chemoradiation. We identified the cognate peptide of infected clones to investigate cell proliferation and virus production induced by T cell activation, and susceptibility to autologous CD8+ T cells.RESULTSThe proviral landscape was dominated by 2 large clones with replication-competent proviruses integrated into zinc finger (ZNF) genes (ZNF470 and ZNF721) in locations previously associated with deeper latency. A third nearly intact provirus, with a stop codon in Pol, was integrated into an intergenic site. Upon stimulation with cognate Gag peptides, infected clones proliferated extensively and produced virus, but the provirus in ZNF721 was 200-fold less inducible. While autologous CD8+ T cells decreased the proliferation of cells carrying the intergenic provirus, they had no effect on cells with the provirus in the ZNF721 gene.CONCLUSIONSWe provide direct evidence that upon activation of infected clones by cognate antigen, the lower inducibility of intact proviruses in ZNF genes can result in immune evasion and persistence.FUNDINGOffice of the NIH Director and National Institute of Dental & Craniofacial Research; NIAID, NIH; Johns Hopkins University Center for AIDS Research.