In addition, we can also connect the immune-enhancing IgG Fc fragment [86, 87] to RSC3 in order to enhance the immunogenicity of RBD epitope

In addition, we can also connect the immune-enhancing IgG Fc fragment [86, 87] to RSC3 in order to enhance the immunogenicity of RBD epitope. from AIDS related causes [1]. Unfortunately, there is no effective preventive vaccine in the world. Therefore, whether we can get safe and effective preventive vaccines is a hotspot and difficulty in the field of current international Rabbit Polyclonal to THBD AIDS research. So far, AIDS vaccine development has followed three major trends. The first wave of candidate vaccines was designed of envelope proteins and synthetic peptides mimicking gp120 epitomes, mainly aimed at inducing neutralizing antibodies (Nabs) [2]. However, induction of potent and broadly cross-reactive neutralizing antibody responses remains a major challenge confronting the development of HIV vaccines because of the high diversity of gp120. The high glycosylation, large conformational changes, and steric restriction of the epitopes in gp120 during receptor binding and membrane fusion processes prevent antibodies from accessing the potentially vulnerable sites [3]. AIDSVAX, VaxGen’s gp120-based AIDS vaccine, failed in clinical trials, raising questions about the strategy of using viral Env protein to induce neutralizing antibody responses. The second wave of candidate vaccines was designed of vectors, such as weakened adenovirus that encodes the HIV-1 proteins Gag, Pol, and Nef, to stimulate HIV-1-specific cellular immunity. One such vaccine candidate is V520 developed by the researchers at Merck & Co. [4C6]. Although this vaccine could elicit strong immune response and showed protection in animal models, the clinical trial for V520 (STEP) was discontinued in 2007 because this vaccine did not provide protection in vaccinated human subjects and was even associated with increased risk of HIV infection in KN-62 some recipients [7C9]. The third wave of candidate vaccines was aimed at induction of both humeral and cell-mediated immune responses with heterogonous priming-booster strategies [3, 10]. One representative vaccine is the combination of AIDSVAX, as noted above, and Sanofi Pasteur’s vector-based vaccine, ALVAC. The results from the phase III clinical trial (RV144) for ALVAC/AIDSVAX showed modest efficacy (31.2% reduction of HIV infection rates compared with those in the placebo group) [11]. Further analysis of the clinical samples revealed that induction of antibodies against gp120 by the vaccine may contribute to the protection of the participants from HIV-1 infection. For example, some study in order to identify the risk of HIV-1 infection in RV144, two sequential sets of analyses of plasma specimens shown that the levels of IgG antibodies (Abs) specific for gp120 V2 were correlated with decreased the risk of infection, the level of IgA Abs reactive with envelope glycoproteins correlated with decreased vaccine efficacy [12]. And four monoclonal antibodies (CH58, CH59, HG107, and HG120) from RV144 vaccines have been described [13]. CH58 and CH59 could bind to gp120 vaccine antigen and also to a HIV-1 envelope variable region 2 peptide. Epitope mapping showed that they could recognize KN-62 the residues of lysine (K) at position 169. When the vaccine envelope at residue 169 was mutated, the neutralization was reduced or abrogated. In the case of the RV144 vaccine, the variable region as the target for antibodies correlated with increased vaccine efficacy. It has been demonstrated in the past that broadly neutralizing antibodies can bind glycans and variable region (V1 and V2) residues around position 169 [14]. The crystal structures of the CH58 and CH59 showed that they recognize similar V2 residues in completely different conformations. It is suggested that the V2 regions may exist in multiple conformations. These promising results have encouraged researchers to refocus on the studies of structure, function, antigenicity, and immunogenicity of gp120 in order to identify the critical functional regions containing relatively conserved neutralizing epitopes that may induce potent and broadly cross-reactive neutralizing antibodies. In previous studies, we have attempted to use the receptor binding site KN-62 (RBD) of the virus such as MERS-CoV [15C17], SARS [18, 19], and avian influenza A virus [20, 21] models as an antigen for vaccine design. In KN-62 practice, this strategy has achieved very good results: it induced high titers of neutralizing antibodies and provided the effective protection for animals attacked by virus in animal experiments. At the same time, the full-length virus envelope S protein as immunogen may cause the immune system to overreact, which leads to negative effects such as aggravation of illness; thus a shorter RBD area can effectively avoid this problem, such as SARS vaccine [22]. The same strategy may also be suitable for HIV vaccine design, especially after the finding of HIV RBD neutralizing antibody VRC01, VRC-PG04, 3BNC60, and the HJ16; the conservative area of.