Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Abstract

Neutralizing antibody induction is a key feature of many effective vaccines and is the only immune response that has proven to be capable of completely blocking AIDS virus infection in animal models. Unfortunately, the extensive genetic variability and complex immune-evasion strategies of HIV-1 have thwarted all attempts to date at eliciting an effective neutralizing antibody response with candidate HIV-1 vaccine immunogens. Recent advances in our understanding of how these evasion strategies operate, coupled with growing progress in unravelling the structure and immunobiology of the viral envelope glycoproteins, are contributing to novel immunogen designs to overcome the many barriers to inducing protective antibodies against HIV-1. Keywordsantiretroviral therapy; HIV-1; host cell fusion; immunogen; neutralizing antibody induction Development of a safe, practical and effective HIV-1 vaccine is one of the highest priorities of the global scientific community [1,2]. Although antiretroviral therapy (ART) has dramatically prolonged the lives of HIV-1 infected patients, ART is not yet routinely available in developing countries, and the global rate of spread of HIV-1 continues unabated. If no effective AIDS vaccine is developed by 2010, the number of people infected world-wide with HIV-1 could exceed 60 million [3].In spite of more than 20 years of research, the types of immune responses needed to protect an immunized individual from HIV-1 infection are not known. Its is known that CD8 + cytotoxic T-cell responses can control HIV-1 replication to varying degrees in acute HIV-1 infection (AHI) [4,5], and when induced by immunogens, can control viral set point after simian immunodeficiancy virus (SIV) or simian HIV (SHIV) challenges in non-human primates [4]. Strong proliferative CD4 + T-cell responses to HIV-1 proteins have been demonstrated to correlate well with immune control of HIV-1 viral load [5]. Therefore, it is highly desirable for an HIV-1 vaccine co induce robust CD4 + and CD8 + T-cell responses in order to control virus replication and reduce the likelihood of subsequent transmission [4][5][6][7]. The potential for complete ('sterilizing') immunity from HIV-1 infection may depend on the presence of pre-existing neutralizing antibodies. We know that neutralizing antibodies can prevent the acquisition of AIDS virus infection after intravenous, vaginal, rectal and oral virus challenge in nonhuman primates [8][9][10][11][12]. This level of protection is highly attractive for a vaccine against a virus, such as HIV-1, which integrates genetically and forms latent viral reservoirs soon after infection. However, the diversity of transmitted HIV-1 genetic variants and the relative resistance of the majority of HIV-1 primary isolates to most types of inducible neutralizing antibodies have posed major hurdles to current vaccine efforts. Furthermore, the few rare broadly reactive neutralizing monoclonal antibodies (mAbs) that have been isolated from HIV-1 infected patients represent species of antibodies that...

Broad, high-magnitude and multifunctional CD4+ and CD8+ T-cell responses elicited by a DNA and modified vaccinia Ankara vaccine containing human immunodeficiency virus type 1 subtype C genes in baboons

“…The first, that a vaccine able to induce neutralizing antibodies will protect against infection or viral replication, has experimental support from both nonhuman primate and human trials (Veazey et al, 2003;Emini et al, 1992;Trkola et al, 2005). The goal for this approach is the generation of sufficiently potent neutralizing antibodies at the site of HIV transmission (Haynes & Montefiori, 2006). The challenge is designing an immunogen capable of inducing high titre, broadly cross-neutralizing antibodies to multiple clades of HIV.…”

Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface

“…4). Sequence variability, extensive glycosylation, and immunodominance of those exposed, largely variable segments subvert immune responsiveness (5,6).…”

HIV-1 Glycoprotein Immunogenicity

“…However, recent studies using chimeric pseudoviruses with epitopes in a context more closely related to the MPER structure ( figure 15B) suggest that MPER-specific NABs are relatively rare or absent during natural infection. Moreover, the fact that new NAbs are mapping to a different region in MPER than 2F5 and 4E10 provides hopes by suggesting that vaccine-induced neutralizing antibodies are achievable (Haynes and Montefiori, 2006;Li et al, 2006). To date, the lack of broadly neutralizing activity shown by MPER binding sera could be due to low titers or absence of NAbs.…”