Abstract
A chimeric vesicular stomatitis virus with the glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, is a potent viral vaccine vector that overcomes several of the limitations of wild-type VSV. Here, we evaluated the potential of VSV-GP as an HIV vaccine vector. We introduced genes for different variants of the HIV-1 envelope protein Env, i.e., secreted or membrane-anchored, intact or mutated furin cleavage site or different C-termini, into the genome of VSV-GP. We found that the addition of the Env antigen did not attenuate VSV-GP replication. All HIV-1 Env variants were expressed in VSV-GP infected cells and some were incorporated very efficiently into VSV-GP particles. Crucial epitopes for binding of broadly neutralizing antibodies against HIV-1 such as MPER (membrane-proximal external region), CD4 binding site, V1V2 and V3 loop were present on the surface of VSV-GP-Env particles. Binding of quaternary antibodies indicated a trimeric structure of VSV-GP incorporated Env. We detected high HIV-1 antibody titers in mice and showed that vectors expressing membrane-anchored Env elicited higher antibody titers than vectors that secreted Envs. In rabbits, Tier 1A HIV-1 neutralizing antibodies were detectable after prime immunization and titers further increased after boosting with a second immunization. Taken together, VSV-GP-Env is a promising vector vaccine against HIV-1 infection since this vector permits incorporation of native monomeric and/or trimeric HIV-1 Env into a viral membrane.
Highlights
Human immunodeficiency virus (HIV) infection is still a major health problem with around36.9 million people living with HIV worldwide [1]
It had been shown by others that full-length HIV Env is only poorly integrated into the wild-type envelope, butbythat truncated or Env/vesicular stomatitis virus glycoprotein (VSV-G)-C-term chimeric proteins
Using the model antigen ovalbumin, we previously have shown that VSV-GP is an excellent vaccine vector that can be used for homologous boosting [24]
Summary
Human immunodeficiency virus (HIV) infection is still a major health problem with around36.9 million people living with HIV worldwide [1]. HAART at the end of 2015 and the number of new infections is still high with ~2.1 million per year [1]. It is believed that high titers of broadly neutralizing antibodies (bnAbs) can protect from HIV infection. This was confirmed in preclinical studies showing that passive infusion of bnAbs results in protection of non-human primates from simian/human immunodeficiency virus (SHIV) [2,3]. All HIV vaccine candidates have so far failed to induce bnAbs and in the RV144 HIV vaccine trial, the only clinical trial that showed moderate protection, this protection was correlated with non-neutralizing
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