Recent Progress in Preclinical HIV-1 Vaccine Research

Since isolation in humans in 1983 [1,2], HIV-1 has developed into a global pandemic. But an effective HIV-1 vaccine has not been succeeded despite multiple human vaccine trials performed [3,4]. Challenges to an effective vaccine arise from intrinsic virological and immunological features of HIV-1 [3-8]. For example, the envelope (Env) spike – composed of trimers of the receptor-binding subunit gp120 and the transmembrane subunit gp41, is the sole antigen available on the viral surface targeted by antibodies. However, the spike surface is shielded by an extensive glycan coat [7,9,10], which prevents most protein surface area from being recognized by antibody. The Env protein is also extremely unstable (e.g. frequent gp120/gp41 dissociation) [6,8,11] and evolves at an extremely fast rate [12,13], which frequently alters its immunogenicity to escape host immune surveillance [7]. Nonetheless, in the past 10 years, advanced technologies have been combined to reveal numerous aspects of HIV-1 interaction with the immune system, including but not limited to isolation of broadly neutralizing antibodies (bNabs) in natural infection coupled with structural characterization and/or neutralization profiling to identify sites of vulnerability [14-19], B cell repertoire sequencing of infected donors, and computational algorithms to characterize B cell response to HIV-1 and to identify determinants of affinity maturation of HIV-1 bNabs [20-27], de novo and grafted immunogen design and antigenicity enhancement [2838], and genetically engineered animal models to evaluate immunogen efficacy [39-41]. The knowledge gained from these studies has revolutionized HIV-1 vaccine research. Recent studies on passive administration of bNabs showed efficacy for HIV prevention (reviewed in [4,42], indicating that the elicitation of bNabs by vaccination could in principle provide a long-term solution for HIV prevention. However, many HIV-1 bNabs have unusual features (e.g. high somatic hypermutation or long complementarity determining region 3 (CDR3)), which may require years of affinity maturation, and could thus form roadblocks for elicitation [3,4,15]. To conquer these potential barriers, new vaccine strategies have been developed such as vaccines designed to elicit antibodies against a specific site of vulnerability (epitope-based vaccine design) and to mature a specific antibody class (antibody lineage-based design) (reviewed in [5]). Here, we review recent progress in preclinical HIV-1 vaccine research.