Immunogenicity and efficacy of immunodeficiency virus-like particles pseudotyped with the G protein of vesicular stomatitis virus

Abstract

Vaccination with exogenous antigens such as recombinant viral proteins, immunodeficiency virus-derived whole inactivated virus particles, or virus-like particles (VLP) has generally failed to provide sufficient protection in animal models for AIDS. Pseudotyping VLPs with the vesicular stomatitis virus G protein (VSV-G), which is known to mediate entry into dendritic cells, might allow more efficient stimulation of immune responses. Therefore, we pseudotyped noninfectious immunodeficiency virus-like particles with VSV-G and carried out a preliminary screen of their immunogenicity and vaccination efficacy. Incorporation of VSV-G into HIV-1 VLPs led to hundred-fold higher antibody titers to HIV-1 Gag and enhancement of T cell responses in mice. Repeated vaccination of rhesus monkeys for 65 weeks with VSV-G pseudotyped simian immunodeficiency virus (SIV)-like particles (VLP[G]) provided initial evidence for efficient suppression of viral load after mucosal challenge with the SIVmac239 virus. Challenge of monkeys after a 28 week vaccination regimen with VLP[G] led to a reduction in peak viremia, but persistent suppression of viral load was not achieved. Due to limitations in the number of animals available for this study, improved efficacy of VSV-G pseudotyped VLPs in nonhuman primates could not be demonstrated. However, mouse experiments revealed that pseudotyping of VLPs with fusion-competent VSV-G clearly improves their immunogenicity. Additional strategies, particularly adjuvants, should be considered to provide greater protection against a challenge with pathogenic immunodeficiency virus.

Functional Virus-Like Particles Production Using Silkworm and Their Application in Life Science

“…As a result of this, the VLPs can be easily collected from the supernatant [29]. Using this approach, many proteins that are difficult to express and study are being pseudo typed on VLPs [30]. This has led to development of many vaccine candidates undergoing clinical trials [31].…”

Pseudotyped Single-Cycle Simian Immunodeficiency Viruses Expressing Gamma Interferon Augment T-Cell Priming Responses In Vitro

“…This ensures efficient antigen entry and delivery into exogenous and endogenous presentation pathways for Band T-cell activation (34,39), mimicking infections of cells with live attenuated SIVs without the potential pathogenicity due to virus replication. In contrast to lentiviral vectors developed for gene therapy applications where viral genes were minimally retained (32), our intent was to preserve as many immunogens as possible while ensuring a single round of infection.…”

“…VSV-G-pseudotyped HIVs have been shown to be 20-to 130-fold more infectious than nonpseudotyped viruses due to CD4-independent entry and broad cell tropism (2). This led to the induction of antibody titers to HIV-1 Gag that were a hundredfold higher as well as increases in T-cell responses to HIV-1 peptides in immunized mice (34). Thus, antigen expression and presentation in target cells are likely to be enhanced.…”

HIV-1 Virus-Like Particles Produced by Stably Transfected Drosophila S2 Cells: a Desirable Vaccine Component

“…However, in macaque challenge models definitive proof of protection has not been clearly demonstrated. Immunization with simian immunodeficiency virus (SIV)/HIV VLP elicited an anamnestic response to HIV-1 gp120, which correlated with accelerated clearance of SHIV (34); immunization with single cycle SIV elicited broad SIVspecific T cell responses and significantly reduced viral loads after intravenous SIV challenge (22); repeated vaccination with VSV-G-pseudotyped SIV VLP significantly reduced peak viremia after mucosal SIV challenge, but persistent suppression of viral load was not achieved (25); and vaccination with chemically inactivated SIV particles elicited both SIV envelope-specific binding and neutralizing antibody responses and significantly reduced viral loads after intravenous homologous SIV challenge but failed to resist subsequent heterologous SIV challenge (26). In contrast, immune responses elicited by VLP alone or by heterologous poxvirus-VLP prime-boost did not protect macaques from SHIV or SIV challenge (33,50).…”