Polyvalent vaccine approaches to combat HIV‐1 diversity

Abstract

SummaryA key unresolved challenge for developing an effective HIV‐1 vaccine is the discovery of strategies to elicit immune responses that are able to cross‐protect against a significant fraction of the diverse viruses that are circulating worldwide. Here, we summarize some of the immunological implications of HIV‐1 diversity, and outline the rationale behind several polyvalent vaccine design strategies that are currently under evaluation. Vaccine‐elicited T‐cell responses, which contribute to the control of HIV‐1 in natural infections, are currently being considered in both prevention and treatment settings. Approaches now in preclinical and human trials include full proteins in novel vectors, concatenated conserved protein regions, and polyvalent strategies that improve coverage of epitope diversity and enhance the cross‐reactivity of responses. While many barriers to vaccine induction of broadly neutralizing antibody (bNAb) responses remain, epitope diversification has emerged as both a challenge and an opportunity. Recent longitudinal studies have traced the emergence of bNAbs in HIV‐1 infection, inspiring novel approaches to recapitulate and accelerate the events that give rise to potent bNAb in vivo. In this review, we have selected two such lineage‐based design strategies to illustrate how such in‐depth analysis can offer conceptual improvements that may bring us closer to an effective vaccine.

Artificial Epitope-Based Immunogens in HIV-Vaccine Design

“…An alternative approach to solving this problem includes constructing completely artificial polyepitope anti-HIV-1 immunogens comprising a set of protective epitopes assembled in a single mosaic (polyepitope) construct. Unfortunately, the most bNAbs recognize conformational epitopes and considerably more rarely linear epitopes [37][38][39]. Furthermore, conformational B-cell epitopes are frequently formed in HIV by lipids and glycans or their combinations [37][38][39][40].…”

cGMP production and analysis of BG505 SOSIP.664, an extensively glycosylated, trimeric HIV‐1 envelope glycoprotein vaccine candidate

“…The quest for an effective vaccine to protect against human immunodeficiency virus type 1 (HIV‐1) infection continues. Various hypotheses about the nature of protective immunity are being explored using a variety of vaccine designs in animal models and human volunteers (Escolano et al, ; Haynes & Mascola, ; Korber, Hraber, Wagh, & Hahn, ; Safrit et al, ). One active area of research is to identify ways to induce broadly neutralizing antibodies (bNAbs) that target the envelope glycoprotein (Env) trimer on the surface of infectious HIV‐1 virions (Haynes & Mascola, ; Sanders & Moore, ; Stamatatos et al, ).…”

A versatile high throughput strategy for cloning the env gene of HIV-1

“…Conserved regions of the HIV-1 envelope were selected for primers design to clone the viral env gene, to accommodate for the high envelope sequence diversity, uneven base composition (on average 36% adenine, 22% thymine, 24% guanine and 18% cytosine) and high propensity of secondary structure in the AT-rich HIV-1 genome (42,43). Given that HIV-1 diverges overtime (1,2), we first updated our primer repository to ensure optimum amplification of the env gene (onwards called env/rev cassettes, as partial fragment for rev gene is part of the env gene). Two-step nested PCR reactions were used to amplify env/rev cassettes, where the forward primers (Fw1 and Fw2) bind to the tat region (upstream to the env gene), and the reverse primers (Rv1 and Rv2) bind to nef region (downstream to the env gene) ( Fig.…”

“…Rapid evolution of HIV-1 strains is increasing the global viral diversity. High baseline rates of mutation (nucleotide substitution rate) due to an error prone reverse transcriptase, rapid replication cycle, in combination with continuous immune-driven selection within the host generates a unique and complex viral quasispecies in each infected individual (1,2). In the context of HIV-1, the viral species in each infected individual accrues immunologically relevant mutations, generating a viral pool of highly complex and unique variants circulating within each host (3–5).…”