HIV-Host Interactions: Implications for Vaccine Design

Abstract

Development of an effective AIDS vaccine is a global priority. However, the extreme diversity of HIV type 1 (HIV-1), which is a consequence of its propensity to mutate to escape immune responses, along with host factors that prevent the elicitation of protective immune responses, continue to hinder vaccine development. Breakthroughs in understanding of the biology of the transmitted virus, the structure and nature of its envelope trimer, vaccine-induced CD8 T cell control in primates, and host control of broadly neutralizing antibody elicitation have given rise to new vaccine strategies. Despite this promise, emerging data from preclinical trials reinforce the need for additional insight into virus-host biology in order to facilitate the development of a successful vaccine.

Figure 1. Model of the HIV-1 transmission bottleneck

Mucosal transmission reduces the genetic and phenotypic diversity of the donor HIV-1 quasi-species to only one or very few variants that seed infection in the recipient. Viruses that traverse the mucosa, but are defective or fail to initiate a productive infection (i.e., have a basic reproductive ratio R_o of lower than 1), will be extinguished. In contrast, the mucosal bottleneck selects for viruses with a high transmission fitness. Although the biological properties that comprise this phenotype remain to be fully elucidated, a high replicative capacity, increased infectivity, enhanced dendritic cell interaction, and greater resistance to the antiviral effects of type 1 interferons (IFNs) are likely to contribute (Parrish et al., 2013).

Figure 2

Co-evolution of HIV transmitted-founder virus and evolving neutralizing antibodies. The initial transmission event of sexually transmitted HIV-1 is mediated by one transmitted founder (TF) virus. The TF virus induces an initial antibody response, called the autologous neutralizing antibody, that is specific for the TF virus. The autologous neutralizing antibody neutralizes the TF but rapidly selects virus escape mutants, which in turn induces new antibody specifities. This process is repeated throughout virus evolution such that after years of infection, a spectrum of cross-reactive neutralizing antibodies are induced, with ~20% of chronically infected individuals making high levels of very broadly reactive neutralizing antibodies.

Figure 3

HIV-1 trimer and Broadly Neutralizing Antibody Binding Sites. Co-crystal structure of the HIV-1 trimer (Pancera et al. 2014) with gp120 in blue and gp41 in grey. The five areas targeted by broadly neutralizing antibodies are the CD4 binding site (orange), V1V2 glycans (red), V3 glycans (green), gp120-gp41 bridging site (purple) and the membrane proximal external region (dark red). The area of insertion of the envelope trimer into the membrane is noted by the transmembrane domain and the gp160 cytoplasmic domain is noted.

Figure 4

Cooperation of` B cell lineages in induction of HIV-1 broadly neutralizing antibodies. The transmitted founder (TF) virus induces both a broadly neutralizing antibody (bnAb) lineage (CH103 lineage in red) as well as a second lineage (the CH235 cooperating lineage in blue). The TF directly drives the bnAb lineage while the cooperating antibody lineage selects virus escape mutants that bind to and are neutralized by the bnAb lineage. Thus, in this case, the bnAb lineage is driven both by escape mutants from other cooperating lineages.

Figure 5

Degrees of HIV-1 control by vaccines that elicit CD8 T cell responses: Each vaccine was designed to elicit only or primarily, T cell responses. These were the STEP Adenovirus-5-Gag-Pol-Nef vaccine (McElrath et al., 2008), DNA-Adenovirus-5 SIV Gag (Casimiro et al., 2005), DNA-Adenovirus-5-mosaic Gag (Roederer et al., 2014), Adenovirus-26 gag + Adenovirus 5 gag (Liu et al., 2009), RhCMV68-1 – SIV (Hansen et al., 2011), and ChAd63-HIVconsv – MVA-HIVconsv (Borthwick et al., 2014) vaccines. The peak responses after vaccination are shown. On the y axis is the magnitude as virus specific T cells per million PBMC (either directly from Elispot values or converted from % CD8 T cells in flow cytometry assays). On the x axis is shown the number of epitopes reported (breadth) corrected for the degree of matching between vaccine and challenge/infecting virus. For perfect matches between the vaccine and challenge the correction value is 1.0, for the STEP vaccine it is estimated to be 0.7. The left hand plot shows values for the STEP trial compared to similar vaccines in the SIV model. In the right panel these are compared to the values for the RhCMV-68.1-SIV vaccine. Also shown here are the values for the HIVconsv conserved region vaccine in a phase I trial in humans where there was no HIV-1 exposure. Where known, the outcomes of SIV challenge of HIV-1 exposure are shown.