Authors: Anne-Sophie Beignon, Karine Mollier, Christelle Liard, Frederic Coutant, Sandie Munier, Julie Riviere, Philippe Souque, and Pierre Charneau

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 log10 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.

Introduction

The AIDS vaccination field is currently facing a drawback after the failure of the phase IIb test-of-concept STEP trial of the MERCK’s adenovirus serotype 5 (Ad5)-based vaccine candidate (8, 36, 52). There was no protection induced by the MRKAd5 human immunodeficiency virus type 1 (HIV-1) GAG/POL/NEF vaccine and no reduction of viremia in cases of infection, and it appears that HIV-1 incidence was even higher in vaccinated men with preexisting immunity to Ad5 (8, 36). There is therefore a pressing need to design and test new strategies, including new viral vectors. Many studies have highlighted the critical role played by CD8 T cells in controlling HIV infection (12, 27, 29, 41, 48, 50, 53) and suggested that an effective vaccine should induce vigorous, broad, and long-lasting CD8 T-cell responses (2, 5). However, no clear-cut immune correlates of protection have been described thus far, and yet several viral vectors shown to elicit specific SIV CD8 T-cell responses have subsequently failed to control viremia in SIV/macaques models (reviewed by Schoenly and Weiner [51]). One unique feature of HIV-1 and lentiviruses biology is their ability to infect nondividing cells through active nuclear import of their genome into the nucleus of the infected cell (59). This precious property was exploited for the design of lentivirus-derived retroviral vectors, which in contrast to classical Moloney retroviral vectors, efficiently transduce nondividing target cells, such as adult and embryonic stem cells, neurons, or hepatocytes. Lentiviral vectors constitute a major technological breakthrough in the field of gene transfer. Notably, a number of successful gene therapy preclinical studies have translated into an increasing number of approved or ongoing human clinical trials worldwide (http://www.wiley.co .uk/genmed/clinical/) including, among them, several in the AIDS field. When applied as vaccination tools, lentiviral vectors efficiently transduce dendritic cells (DC), enabling stable delivery of the antigen and thus sustained presentation by DC of the encoded antigen through the endogenous pathway (22). Lentiviral vector-mediated antigen presentation will persist for the whole in vivo lifetime of the DC, i.e., until they are eliminated by the innate (7) and adaptive immunity they have induced. This sustained endogenous antigen presentation probably accounts for the potent induction of high proportions of specific cytotoxic T cells and long-lasting memory T cells that we and others have reported after direct injection of lentiviral vector particles in various mice models (6, 9, 10, 21). It appears, in several comparative studies (14, 17, 22, 47, 58) that lentiviral vectors are more potent to elicit cellular protective immunity than other viral vectors (including adenoviral and pox vectors) or other vaccine strategies (such as DNA vaccine and peptidepulsed or mRNA electroporated DC). We assessed here whether HIV-1-derived lentiviral vectors could confer protective cellular immunity against simian immunodeficiency virus (SIV) infection and simian AIDS. We opted for the model of SIVmac251 infection of cynomolgus macaques, which displays viral load levels and a variety of progression rates similar to those seen in HIV-1 infection in humans (3, 28, 44, 54). We have recently shown that, unlike T cells or macrophages, nonhuman primate DC lack TRIM5- mediated restriction and are equally transduced by HIV-1- derived lentiviral vector such as human DC, allowing the use of Old World primates as vaccine models to test HIV-1-derived lentiviral vectors (1). We show that a prime/boost vaccination regimen using lentiviral vector encoding a nonoptimized SIV GAG antigen induced specific T-cell responses capable of controlling the early viral replication by reducing plasma viral loads at the peak of acute infection by 200-fold and by fully preventing the acute CD28 CD95 memory CD4 T-cell depletion.

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