Lentiviral Vector-Based Prime/Boost Vaccination against AIDS: Pilot Study Shows Protection against Simian Immunodeficiency Virus SIVmac251 Challenge in Macaques

Abstract

AIDS vaccination has a pressing need for more potent vaccination vectors capable of eliciting strong, diversified, and long-lasting cellular immune responses against human immunodeficiency virus (HIV). Lentiviral vectors have demonstrated efficiency not only as gene delivery vehicles for gene therapy applications but also as vaccination tools. This is likely due to their ability to transduce nondividing cells, including dendritic cells, enabling sustained endogenous antigen presentation and thus the induction of high proportions of specific cytotoxic T cells and long-lasting memory T cells. We show in a first proof-of-concept pilot study that a prime/boost vaccination strategy using lentiviral vectors pseudotyped with a glycoprotein G from two non-cross-reactive vesicular stomatitis virus serotypes elicited robust and broad cellular immune responses against the vector-encoded antigen, simian immunodeficiency virus (SIV) GAG, in cynomolgus macaques. Vaccination conferred strong protection against a massive intrarectal challenge with SIVmac251, as evidenced both by the reduction of viremia at the peak of acute infection (a mean of over 2 log 10 fold reduction) and by the full preservation of the CD28 ؉ CD95 ؉ memory CD4 ؉ T cells during the acute phase, a strong correlate of protection against pathogenesis. Although vaccinees continued to display lower viremia than control macaques during the early chronic phase, these differences were not statistically significant by day 50 postchallenge. A not-optimized SIV GAG antigen was chosen to show the strong potential of the lentiviral vector system for vaccination. Given that a stronger protection can be anticipated from a modern HIV-1 antigen design, gene transfer vectors derived from HIV-1 appear as promising candidates for vaccination against HIV-1 infection.

Lentiviral Vectors Targeted to MHC II Are Effective in Immunization

“…This stimulates CD8-positive and CD4-positive T-cell responses and antibodies against the LV-encoded transgene (Esslinger et al, 2003;Palmowski et al, 2004;Rowe et al, 2006;Dai et al, 2009). LVs are effective as antitumor or antiviral vaccines in mice (Coutant et al, 2008;Loisel-Meyer et al, 2009), and a similar vector based on simian immunodeficiency virus is an effective antiviral vaccine in macaques (Beignon et al, 2009).…”

Replication-Competent Influenza A Virus That Encodes a Split-Green Fluorescent Protein-Tagged PB2 Polymerase Subunit Allows Live-Cell Imaging of the Virus Life Cycle

“…MDCK cells were grown in modified Eagle's medium (MEM) supplemented with 5% FBS. The A549-GFP1-10 and MDCK-GFP1-10 cells were generated by lentiviral transduction, as described by Beignon et al (2). Vero cells were grown in MEM supplemented with 10% FBS.…”

Pseudotyping Lentiviral Vectors with Lymphocytic Choriomeningitis Virus Glycoproteins for Transduction of Dendritic Cells andIn VivoImmunization

“…This is consistent with these routes being the best to target skinderived DCs (Dai et al, 2009). One advantage of LVs is low antivector immunity since LVs do not induce vector-specific immunity, but only weak host immunity against the pseudotyping envelope (Beignon et al, 2009). Pinschewer et al (2004) studied the mechanisms underlying vector-specific nAb responses and found that the impact of the viral glycoprotein, but not the viral backbone, is critical in determining nAb kinetics.…”