There were no vaccine-related serious AE, discontinuation due to AE, intercurrent HIV infection, or significant decreases in CD4 count. AE were mild. The most common vaccine-related adverse event was injection site pain. There were no vaccine-related severe AE, discontinuation due to AE, intercurrent HIV contamination, or significant decreases in CD4 count. By the final vaccination, all vaccine recipients developed antibodies against IHV01 and exhibited anti-CD4i epitope antibodies. The elicited antibodies reacted with CD4 non-liganded Env antigens from diverse HIV-1 strains. Antibody-dependent cell-mediated cytotoxicity against heterologous infected cells or gp120 bound to CD4+ cells was obvious in all cohorts as were anti-gp120 T-cell responses. IHV01 vaccine was safe, well tolerated, and immunogenic at all doses tested. The vaccine raised broadly reactive humoral responses against conserved CD4i epitopes on gp120 Etofylline that mediates antiviral functions. Keywords: HIV, Vaccine, Chimeric subunit vaccine, Full-length single chain (FLSC), CD4i 1.?Introduction Despite more than three decades of research, a highly effective preventative vaccine against the human immunodeficiency computer virus 1 (HIV-1) is still not available. A vaccine that elicits antibody responses to the viral envelope spike is usually expected to be protective. Such responses could prevent or suppress contamination by direct neutralization or Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, or trogocytosis [1], [2], [3]. However, a major challenge to this concept stems from the capacity of HIV to evolve mutational escape from humoral immunity. Antigenic domains around the surfaces of free virions Rabbit Polyclonal to MUC7 readily acquire such changes in the face of immune pressure. Potential opportunities to overcome this hurdle are offered by the nature of HIV attachment and access. HIV virions express surface heterotrimers comprised of two components, gp120 and gp41. During attachment, the gp120 component of the envelope spike forms a transition state structure upon virion binding to the host cell CD4 receptor. This structure is usually distinguished by the presentation of extremely conserved, CD4-induced (CD4i) epitopes, some of which perform the critical role of binding to cell coreceptors (primarily CCR5) that trigger membrane fusion and viral access [4], [5]. CD4i epitopes can be immunoreactive in multiple scenarios during spreading contamination. For example, allosteric mechanisms propagate the expression of CD4i epitopes across virion surfaces after host cell attachment occurs [6], [7]. Further, CD4i epitopes are expressed at the contact interfaces of fusing infected and uninfected cells and across the surfaces post-fusion cell pairs [8], [9], [10]. Consequently, antibodies realizing CD4i epitopes have opportunities to be broadly antiviral if present before exposure, holding potential power for HIV vaccine development. In accordance with this concept, anti-CD4i antibodies are known to mediate neutralizing activity as well as numerous Fc-mediated effector functions including ADCC, phagocytosis and trogocytosis [10], [11], [12], [13], [14], [15], [16], [17]. The structural basis for the translation of anti-CD4i antibody binding into antiviral activity has been studied extensively [11], [13], [14], [18], [19], [20]. CD4i epitopes are naturally immunogenic, frequently eliciting antibody titers in HIV-infected persons [21], [22], [23], [24], [25], [26]. Anti-CD4i antibody responses fortuitously raised by HIV envelope-based vaccines in human trials were linked with reduced risk of contamination [27], Etofylline [28], [29]. In addition, similar responses correlated with protection or control of viremia in HIV envelope-vaccinated macaques challenged with simian immunodeficiency viruses (SIV) or chimeric SIV expressing the HIV envelope (SHIV) [30], [31]. A full-length single chain (FLSC) of gp120-CD4 chimera subunit vaccine was developed to exploit the potential vulnerabilities of transition state/CD4i envelope structures. FLSC is usually a subunit vaccine encoded by a synthetic gene expressing a human codon-optimized, full-length HIV (BaL isolate) gp120 sequence joined at its C terminus to the N terminus of domains 1 and 2 of human CD4 Etofylline (CD4D1D2) via a flexible 20 amino acid linker that covalently links.