Challenges in the Design of a T Cell Vaccine in the Context of HIV-1 Diversity

Abstract

The extraordinary variability of HIV-1 poses a major obstacle to vaccine development. The effectiveness of a vaccine is likely to vary dramatically in different populations infected with different HIV-1 subtypes, unless innovative vaccine immunogens are developed to protect against the range of HIV-1 diversity. Immunogen design for stimulating neutralizing antibody responses focuses on “breadth” – the targeting of a handful of highly conserved neutralizing determinants on the HIV-1 Envelope protein that can recognize the majority of viruses across all HIV-1 subtypes. An effective vaccine will likely require the generation of both broadly cross-neutralizing antibodies and non-neutralizing antibodies, as well as broadly cross-reactive T cells. Several approaches have been taken to design such broadly-reactive and cross-protective T cell immunogens. Artificial sequences have been designed that reduce the genetic distance between a vaccine strain and contemporary circulating viruses; “mosaic” immunogens extend this concept to contain multiple potential T cell epitope (PTE) variants; and further efforts attempt to focus T cell immunity on highly conserved regions of the HIV-1 genome. Thus far, a number of pre-clinical and early clinical studies have been performed assessing these new immunogens. In this review, the potential use of these new immunogens is explored.

Increased frequencies of CD8+CD57+ T cells are associated with antibody neutralization breadth against HIV in viraemic controllers

“…Vaccination strategies targeted towards eliciting bNAbs include delivery of such antibodies via VIP [13,23], sequential immunization to mimic the antigenic evolution needed to drive generation of bNAbs [1,6] and “mosaic” immunogen design based on the structure of bNAbs and their ligands [24]. The anticipated success of such vaccination approaches in inducing HIV-specific bNAbs is supported by the fact that there is no evidence for genetic predisposition to produce bNAbs [25] and that production of bNAbs seems to be linked to the initial Env sequence encountered by the immune system during early infection [26–28].…”

Approaches to preventative and therapeutic HIV vaccines

“…Pathogenesis studies revealed that the magnitude and breadth of the early CD8+ T-cells markedly influenced early viral control, so cytotoxic T-cell (CTL)-based vaccines were designed primarily to control post-infection viremia, but there were also hopes they could prevent HIV acquisition. The strategy to induce CTL responses to HIV proteins was to insert HIV genes into recombinant viral vectors and shuttle these genes into the Class I antigen-presenting pathway [6]. …”

“…A leading second-generation vector under development is replication-incompetent Ad26 in combination with modified vaccinia Ankara (MVA) and recombinant protein. The vectors contain novel mosaic inserts designed to elicit cross-clade immunity [6]. Non-human primate studies using Ad26/MVA/trimeric gp140/ASO1B adjuvant demonstrated protection from mucosal challenge.…”

Immunotherapeutic strategies for sexually transmitted viral infections: HIV, HSV and HPV

“…Early viral control is markedly influenced by breadth and magnitude of early CD8+ T-cells therefore, CTLbased vaccines or cytotoxic T lymphocyte vaccines were developed primarily to target post-infection viremia, and prevention of HIV acquisition was anticipated. Cytotoxic T lymphocyte responses against HIV proteins are induced by inserting HIV genes into recombinant viral vectors and shuttling these genes into Class I antigen-presenting pathway [73].…”