Advances in HIV-1 Vaccine Development

Abstract

An efficacious HIV-1 vaccine is regarded as the best way to halt the ongoing HIV-1 epidemic. However, despite significant efforts to develop a safe and effective vaccine, the modestly protective RV144 trial remains the only efficacy trial to provide some level of protection against HIV-1 acquisition. This review will outline the history of HIV vaccine development, novel technologies being applied to HIV vaccinology and immunogen design, as well as the studies that are ongoing to advance our understanding of vaccine-induced immune correlates of protection.

Keywords: HIV-1; antibodies; immunogen; neutralization; vaccine.

Figure 1

The HIV-1 mucosal transmission bottle neck and developing antibody response. Early after exposure, transmitted founder (T/F) viruses cross from the external mucosal lumen into the mucosal stroma and establish a foci of infection. Within a period of hours to days, the virus then migrates to local draining lymph nodes as either free virus or is carried there by migrating dendritic cells. Within the lymph node, there is an abundance of CD4 target cells to propagate infection, resulting in exponential viral amplification and systemic spread. During these initial few days and weeks, the infecting virus is clonal in nature with little genetic diversification. The early humoral immune response is characterized by the initial development of anti-gp41 antibodies before anti-gp120 are detectable. Over the next few weeks and months, the virus enters into an evolutionary arms race with the developing B cell response, resulting in genetic diversification of the transmitted founder into a viral quasi-species. These viral escape mutants help drive the anti-HIV B cell response and ultimately give rise to autologous neutralizing antibody responses and then to broadly neutralizing antibody responses within a subset of these infected individuals.

Figure 2

Structural models of the BG505.SOSIP.664 HIV Env protein. The HIV-1 BG505.SOSIP.664 protein PDB data file (PDB file 4ZMJ: Crystal Structure of Ligand-Free BG505 SOSIP.664 HIV-1 Env Trimer [91,92]) was imported to UCSF Chimera program [93] to visualize the molecular structure. The hydrophobicity model on the left (looking at the protein from the top) shows the typical propeller-shape of the BG505.SOSIP.664 HIV Env trimeric molecule, while the ribbon diagram on the right gives detail of the positions of the beta-pleated sheets, alpha-helices and loops that make the structure. The BG505.SOSIP.664 HIV Env exhibits a mature and pre-fusion closed trimer, a conformation recognised by bnAbs that would be expected to target the native trimer presented on infectious HIV. Further design modifications of the BG505 molecule and other Envs have increasingly succeeded in creating stabilised and more native-like trimer structures that are likely to be the next generation vaccine candidates to generate bnAbs.