Abstract
BackgroundAlthough vaccines are important in preventing viral infections by inducing neutralizing antibodies (nAbs), HIV-1 has proven to be a difficult target and escapes humoral immunity through various mechanisms. We sought to test whether HIV-1 Env mimics may serve as immunogens.Methodology/Principal FindingsUsing random peptide phage display libraries, we identified the epitopes recognized by polyclonal antibodies of a rhesus monkey that had developed high-titer, broadly reactive nAbs after infection with a simian-human immunodeficiency virus (SHIV) encoding env of a recently transmitted HIV-1 clade C (HIV-C). Phage peptide inserts were analyzed for conformational and linear homology using computational analysis; some peptides mimicked various domains of the original HIV-C Env, such as conformational V3 loop epitopes and the conserved linear region of the gp120 C-terminus. Next, we devised a novel prime/boost strategy to test the immunogenicity of such phage-displayed peptides and primed mice only once with HIV-C gp160 DNA followed by boosting with mixtures of recombinant phages.Conclusions/SignificanceThis strategy, which was designed to focus the immune system on a few Env epitopes (immunofocusing), not only induced HIV-C gp160 binding antibodies and cross-clade nAbs, but also linked a conserved HIV Env region for the first time to the induction of nAbs: the C-terminus of gp120. The identification of conserved antigen mimics may lead to novel immunogens capable of inducing broadly reactive nAbs.
Highlights
HIV-1 continues to spread and has become a pandemic with more than 34 million infected people and 14,000 new infections per day [1]
We have identified a cohort of rhesus macaques infected with simianhuman immunodeficiency virus (SHIV)-1157ip, a chimera that encodes env of a recently transmitted HIV-1 clade C (HIV-C) strain, or the related SHIV-1157ipd3N4 [33] that developed high-titer neutralizing antibodies (nAbs) responses against homologous SHIV-C as well as heterologous primary strains of HIV-1 of different clades
High nAb titers were detected against the early SHIV-C (SHIV-1157ip), the late isolate SHIV1157ipd3N4 [33], as well as against a heterologous R5 SHIV-C generated in our group (SHIV-2873Nip)
Summary
HIV-1 continues to spread and has become a pandemic with more than 34 million infected people and 14,000 new infections per day [1]. Largescale phase III clinical trials with candidate AIDS vaccines have been disappointing (reviewed in [2,3]); such trials involved an attempt to generate neutralizing antibody (nAb) response-based vaccines based upon the surface subunit gp120 as well as a vaccine strategy designed to induce cytotoxic T-lymphocyte (CTL) responses with recombinant adenovirus vectors. The viral envelope glycoproteins, non-covalently linked trimers consisting of three gp120 and three gp subunits, divert the immune system with variable loops which cover neutralization-sensitive Env regions [4,5]. Env glycoproteins frequently change their amino acid sequence in response to selective pressure exerted by the immune system, presenting the host with ever new antigens. Vaccines are important in preventing viral infections by inducing neutralizing antibodies (nAbs), HIV1 has proven to be a difficult target and escapes humoral immunity through various mechanisms. We sought to test whether HIV-1 Env mimics may serve as immunogens
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