Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Abstract

Advancement in immunogen selection and vaccine design that will rapidly elicit a protective Ab response is considered critical for HIV vaccine protective efficacy. Vaccine-elicited Ab responses must therefore have the capacity to prevent infection by neutralization-resistant phenotypes of transmitted/founder (T/F) viruses that establish infection in humans. Most vaccine candidates to date have been ineffective at generating Abs that neutralize T/F or early variants. In this study, we report that coimmunizing rhesus macaques with HIV-1 gp160 DNA and gp140 trimeric protein selected from native envelope gene sequences (envs) induced neutralizing Abs against Tier 2 autologous viruses expressing cognate envelope (Env). The Env immunogens were selected from envs emerging during the earliest stages of neutralization breadth developing within the first 2 years of infection in two clade B–infected human subjects. Moreover, the IgG responses in macaques emulated the targeting to specific regions of Env known to be associated with autologous and heterologous neutralizing Abs developed within the human subjects. Furthermore, we measured increasing affinity of macaque polyclonal IgG responses over the course of the immunization regimen that correlated with Tier 1 neutralization. In addition, we report firm correlations between Tier 2 autologous neutralization and Tier 1 heterologous neutralization, as well as overall TZM-bl breadth scores. Additionally, the activation of Env-specific follicular helper CD4 T cells in lymphocytes isolated from inguinal lymph nodes of vaccinated macaques correlated with Tier 2 autologous neutralization. These results demonstrate the potential for native Env derived from subjects at the time of neutralization broadening as effective HIV vaccine elements.

A Cytokine-Independent Approach To Identify Antigen-Specific Human Germinal Center T Follicular Helper Cells and Rare Antigen-Specific CD4+ T Cells in Blood

“…1A); and the IL-21 MFI was close to the limit of detection, which was insufficient to allow for confident identification of Strep-specific GC Tfh cells. This is similar to other studies in which antigen-specific GC Tfh responses have been difficult to identify via IL-21 production (15, 27). Strep-specific TCR stimulation did not increase IL-4 production (data not shown).…”

“…Detection of IL-21 protein from antigen-specific human GC Tfh cells within lymphoid tissue has been difficult, with perhaps only one reported success (15). In macaque studies, there have been little to no detection by ICS of IL-21 protein induction in antigen-specific GC Tfh cells (27, 64). IL-21 RNA can be detected in stimulated human GC Tfh cells, and an IL-21 fluorescent reporter mouse detects shifts in fluorescent reporter protein expression after antigen-stimulation in vivo (55), consistent with Il21 mRNA induction.…”

Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models

“…While gp140C proteins are not mimics of the native trimer (Ringe et al, 2013; Sanders et al, 2013), they have induced tier 2 autologous virus nAbs in macaques (Bradley et al, 2016; Hessell et al, 2016). To determine if a similar Env design using sequences from an individual that developed bnAbs could induce tier 2 heterologous virus neutralization in primates, we immunized RMs with sequential CH505 Env gp140C trimers (Bonsignori et al, 2017b) primed with CH505 TF gp145 DNA delivered by electroporation (Table S1).…”

Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer

“…While NHP HIV protein immunization studies have been done for over 20 years, significant Tier 2 neutralizing antibody responses in immunized non-human primates have only been reported in two studies, published recently (Hessell et al, 2016; Sanders et al, 2015). In a first study of four rhesus macaques (RM) immunized with BG505 SOSIP.664, some animals developed low levels of autologous Tier 2 neutralizing antibodies, whereas in the same study BG505 gp120 immunized macaques did not (Sanders et al, 2015).…”