Abstract
HIV-1 envelope glycoprotein (Env) remains the most relevant target for the elicitation of functional antibodies to HIV by vaccination. However, soluble Env antigens often do not elicit the desired immune responses. Delivering subunit antigens on particulate nanoparticles is an established approach to improve their immunogenicity. In this study the sequence encoding Zera®, a proline-rich domain derived from the γ-zein storage protein, was fused to either the C- or N-terminus of the superinfecting HIV-1 CAP256 gp140 envelope: Zera® generally induces the formation of protein bodies (PBs), which can significantly improve both the immunogenicity and yields of the partner protein. The expression of gp140-Zera® and Zera®-gp140 (N- and C-terminal fusions respectively) in mammalian cells was confirmed by western blot analysis and immunostaining. However, isopycnic ultracentrifugation showed that neither gp140-Zera® nor Zera®-gp140 accumulated in characteristic electron-dense PBs. gp140-Zera® elicited higher binding antibody titers in rabbits to autologous gp140 and V1V2 scaffold than Zera®-gp140. Rabbit anti-gp140-Zera® sera also had significantly higher Tier 1A neutralizing antibody titers than anti-Zera®-gp140 sera. Neither gp140-Zera® nor Zera®-gp140-specific sera neutralized Tier 1B or autologous Tier 2 viruses. These results showed that HIV-1 gp140 tagged with Zera® at either the N- or C-termini elicited high titers of gp140 and V1V2 binding antibodies, and low levels of Tier 1 neutralizing antibodies in rabbits.
Highlights
An effective prophylactic vaccine remains an urgent priority to combat the HIV-1 pandemic
We evaluated if Zera R -induced protein bodies (PBs) in cells expressing Zera R gp140, gp140-Zera R, or Zera R -enhanced green fluorescent protein (eGFP) could be isolated by isopycnic gradient ultracentrifugation
We evaluated the production of protein bodies (PBs) by fusing the sequence encoding Zera R, a proline-rich domain derived from the γ -zein storage protein, to either the C- or N-terminus of HIV1 CAP256 gp140
Summary
An effective prophylactic vaccine remains an urgent priority to combat the HIV-1 pandemic. A preventative vaccine could work by inducing high titers of antibodies against the HIV-1 envelope glycoprotein (Env) with the capacity to neutralize the virus, and/or mediate effector functions to kill infected cells (Rerks-Ngarm et al, 2009; McCoy and Weiss, 2013; Burton and Hangartner, 2016; Alter and Barouch, 2018). The protective efficacy conferred by vaccine-induced polyfunctional effector functions of nNAbs do not negate the need to design immunogens that elicit bNAb responses, but suggest that both nNAbs and bNAbs activities could produce synergistic effects in the development of protective responses against HIV-1 acquisition (Alter and Barouch, 2018; Lee and Kent, 2018)
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