Vaccine-elicited Human T Cells Recognizing Conserved Protein Regions Inhibit HIV-1

Abstract

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.

Transient IL-10 receptor blockade can enhance CD8+T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen

“…HIVconsv, which was recently shown to be immunogenic in a phase I clinical trial. 5 We report that IL-10R blockade significantly enhanced both the frequency and function of CD8 C T cell responses to ChAdV63.HIVconsv.…”

“…14 ChAdV63.HIVconsv was produced at the Clinical Biomanufacturing Facility (CBF), University of Oxford, UK, as described previously. 5 Experimental animals and immunizations Six-week-old female BALB/c mice were purchased from Harlan. All procedures were conducted in accordance with the UK Animals (Scientific Procedures) Act under Project License PPL 30/2833 and Personal License PIL 40/1027 and approved by the University of Oxford Animal Care and Ethical Review Committee.…”

“…3 The field has now turned to rare human adenoviruses (HAdVs 26 and 35) and simian adenovirus ChAdV63 for which seroprevalence in humans is low. 5 However, such vectors may be less potent than HAdV5, 6 though capable of eliciting strong immune responses when included in heterologous primeboost regimens. 5 A potential approach to increasing the immunogenicity of adenovirus vectors is to modulate inhibitory signals, such as interleukin-10 (IL-10), that are induced alongside pro-inflammatory cytokines and chemokines as a compensatory anti-inflammatory response.…”

“…5 However, such vectors may be less potent than HAdV5, 6 though capable of eliciting strong immune responses when included in heterologous primeboost regimens. 5 A potential approach to increasing the immunogenicity of adenovirus vectors is to modulate inhibitory signals, such as interleukin-10 (IL-10), that are induced alongside pro-inflammatory cytokines and chemokines as a compensatory anti-inflammatory response. 7 IL-10 inhibits the activation and migration of na€ ıve T cells by downregulating MHC class II and CD86 on antigen-presenting cells 8,9 and inhibiting the production of cytokines and chemokines such as IL-1a, MCP-1, IP-10 and TNFa.…”

Comment on Clinical Development of Candidate HIV Vaccines: Different Problems for Different Vaccines

“…10 Some vaccines tested in Phase I trials have generated T cells that can suppress virus 11 but not yet as well as CD8 T cells from infected patients who control HIV-1 well. Yang et al 10 have shown that this immune parameter, when measured in early infection, is inversely correlated with viral load set point and can predict the rate of CD4 T cell decline; if that result can be confirmed on a larger scale it would be a very useful measure to test potential vaccine effectiveness.…”