RESUMO
Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4(+) cells and inhibited HIV-1 replication by up to 5.79 log10. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8(+) T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro.
Assuntos
Vacinas contra a AIDS/imunologia , Epitopos de Linfócito T/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Linfócitos T/imunologia , Vacinas contra a AIDS/genética , Adolescente , Adulto , Sequência de Aminoácidos , Células Cultivadas , Sequência Conservada/imunologia , Mapeamento de Epitopos , Epitopos de Linfócito T/química , Feminino , Infecções por HIV/prevenção & controle , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Replicação Viral/imunologia , Adulto Jovem , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene pol do Vírus da Imunodeficiência Humana/imunologiaRESUMO
OBJECTIVES: Since May 2022, cases of human monkeypox virus (hMPXV) with human-to-human cross-transmission have significantly increased in nonendemic countries. Our aim was to characterize diagnostic features of patients with confirmed and possible monkeypox to guide future risk stratification and to describe a virtual care model. METHODS: We performed a retrospective case-control study of 140 patients assessed and screened for suspected monkeypox; on hMPXV polymerase chain reaction testing, 70 were confirmed positive, and 70 were negative. Data were compared to generate odds ratios of demographic and clinical features. RESULTS: Patients who tested positive were predominantly cis-male (99%) and self-identified as gay, bisexual, and other men who have sex with men (94%). Lymphadenopathy at presentation was associated with a higher likelihood of a positive result (odds ratio [OR] 7.69 [95% confidence interval (CI) 3.58, 16.51]). Patients who tested positive were more likely to have a rash affecting the genital (OR 5.38 [95% CI 2.57, 11.23]) or buttocks/perianal region (OR 3.79 [1.70, 8.45]) than negative controls. A total of 79% of patients were engaged with a virtual ward follow-up. CONCLUSION: These data can inform a risk-based approach to the management of suspected monkeypox in gay, bisexual, and other men who have sex with men populations. Lymphadenopathy at presentation and the location of the rash were more associated with a positive hMPXV result. Health authorities can consider a virtual ward approach in the hMPHXV outbreak.