We statement herein previous attempts and recent progress on the design and synthesis of BnAb-inducing, glycan-dependent epitopes toward the development of an effective HIV vaccine

We statement herein previous attempts and recent progress on the design and synthesis of BnAb-inducing, glycan-dependent epitopes toward the development of an effective HIV vaccine. the current state-of-the-art toward the development of fully synthetic HIV vaccines. Keywords: AIDS, HIV vaccine design, broadly neutralizing antibody (BnAb), gp120, synthetic antigen, carbohydrates, glycopeptides, glycosylation Introduction More than 60 million people worldwide have been infected by human immunodeficiency computer virus (HIV) since its discovery approximately 30 years ago as the cause of AIDS; over 25 million have died from the disease [1]. In 2012, an estimated 35.3 million people globally were living with HIV, including 2.3 million newly infected individuals, and the number of AIDS deaths in that year totaled 1.6 million [2]. Therefore, the development of a safe and effective prophylactic vaccine, ideally with elicitation of both T-cell mediated immunity and a broadly neutralizing antibody (BnAb) response, is usually of paramount importance. While HIV-specific cytotoxic T-lymphocytes (CTL) can identify and kill infected cells, classic CD8+ CTL with acknowledgement of HIV antigens in the context of MHC Class I molecules are not sufficient on their own to prevent HIV contamination and vaccines designed to elicit CD8+ T cell-mediated immune responses have provided no protection in efficacy trials [3]. However, atypical CD8 CTLs induced by HIV antigens in a cytomegalovirus vector identify simian immunodeficiency computer virus (SIV) antigens in the context of MHC class II, and have eliminated contamination in the setting of acute SIV contamination in rhesus macaques [4]. In contrast, passive immunization experiments in animal models have demonstrated that BnAbs can provide protection against viral challenge when present in sufficient plasma levels [5,6]. However, elicitation of such protective BnAbs by active immunization has, so far, not been possible with any vaccine candidate in clinical trials. For example, the candidate vaccine AIDSVAX, a genetically designed version of HIVs surface protein gp120, raised only poor neutralizing antibodies and showed no protection in humans in a phase III clinical trial [7]. The RV144 HIV trial, including more than 16,000 healthy individuals in Thailand, used a gp120-based ALVAC primary, AIDSVAX B/E boost HIV vaccine regime, and resulted in an estimated 31% protective efficacy in HIV transmission [8,9]. However, antibodies capable of neutralizing transmitted/founder viruses were not produced [10], and the protection induced was neither sufficiently strong for deployment, nor of sufficient durability for sustained vaccine efficacy. Thus, the development of GSK547 a successful HIV vaccine has, thus far, remained elusive. In the ideal case, vaccines capable of inducing the production of BnAbs as well as cellular immune responses in a synergistic manner represent the optimal approach. On this basis, new HIV vaccine design strategies should aim at incorporating both computer virus neutralizing and T-cell determinants, to GSK547 create synthetic polyepitope immunogens that include B- and T-cell epitopes for the activation GSK547 of BnAbs along with cytotoxic and T-helper cell responses [11]. The main scientific difficulties for the successful development of an HIV-1 vaccine have been attributed, GSK547 in part, to the wide variety of defense mechanisms by which the virus is able to evade the host immune system, including a high mutational rate of its genome, the large degree of glycosylation of the viral surface proteins and the considerable genetic diversity amongst HIV strains globally [12]. In addition, all BnAbs have unusual characteristics of antibodies that are limited by immune tolerance mechanisms [13], and some BnAbs have been shown to be deleted in bone marrow due to autoreactivity with host antigens [14]. Vaccine formulations utilized to date have been unable to induce potent and sustained immune responses with effective levels of neutralization to prevent the onset of HIV contamination. Thus, eliciting antibodies capable of broadly neutralizing HIV-1 strains (BnAbs) remains a high priority in designing an HIV vaccine [15], especially after the recent failure of FZD7 the DNA primary, recombinant (r) adenovirus type 5 (Ad5) HIV vaccine in human efficacy trials [16]. BnAbs have been isolated from HIV-1 chronically-infected subjects [17] and are directed to five general HIV-1 envelope (Env) glycoprotein targets [18,19]: the gp41 membrane proximal external region (MPER), the CD4 binding site (CD4bs) on gp120, the gp120 variable loop 1/2 (V1V2), the gp120 variable loop 3 (V3), and a conformational combined gp41-gp120 set of epitopes [20,21,22,23]. The HIV-1 envelope spike, critical for viral infectivity, consists of a trimer of the glycoproteins gp41 and gp120 [24]. It undergoes rapid development in each individual patient, resulting in sequence heterogeneity among individual isolates of HIV-1 [25,26]. Moreover, the considerable glycosylation of these envelope glycoproteins can mask underlying protein domains, forming a glycan shield that renders neutralization-sensitive polypeptide epitopes inaccessible to acknowledgement by the immune system [27]. As a result, the surface glycans of HIV envelope proteins have become interesting targets for the development of synthetic HIV vaccines based on carbohydrates and glycopeptides..