This trimeric glycoprotein mediates receptor binding and viral entry through its interactions with both CD4 and CCR5/CXCR4. These characteristics make Env a logical candidate as a component of an HIV-1 vaccine. Such a vaccine will likely need to elicit broadly cross-neutralizing antibodies to be effective. However, due to extensive intra- and inter-subtype sequence variability of Env, anti-Env antibody response are generally isolate-specific. To be effective against diverse isolates, the NAbs induced by a prospective vaccine will need to recognize multiple Env variants, as patients are unlikely to encounter viruses that match the vaccine strain during natural infection. Therefore, the ideal method of generating a broad, cross-reactive NAb response would be to target highly conserved regions in Env. Unfortunately, many conserved epitopes of Env are occluded or Vismodegib transiently exposed, and therefore are poorly immunogenic. Several monoclonal antibodies have been isolated from patients with broad, potent-neutralizing activity, however attempts to elicit similarly potent and broadly NAbs by vaccination using recombinant forms of Env as antigens have, at best, met limited success. The antibodies generated in this manner are primarily strain-specific and have limited breadth in their neutralizing activity. Designing immunogens that are able to elicit antibodies that are broadly cross-neutralizing is a challenge as accessible immunodominant variable regions redirect antibody responses away from the desired, but often masked conserved regions. Thus, many studies involving Env have focused on attempting to dampen the immunogenicity of the highly variable regions and/or to increase the immunogenicity of the desired conserved epitopes. One such conserved region that has been under evaluation is the conformational epitope that Env forms upon binding with the receptor CD4. This CD4-induced epitope is highly conserved. In fact, many CD4i antibodies are quite potent, even against the highly divergent HIV-2, in the presence of sCD4, indicating the conserved nature of this epitope. This make the CD4i epitope an AP24534 in vivo attractive target for vaccine development. A potential concern that CD4i antibodies, as whole IgG, face steric hindrance in accessing the epitope and hence not effective in neutralizing primary isolates remain. However, broadly crossreactive neutralizing antibodies were elicited in rhesus macaques by using covalently cross-linked HIV-1 Env-CD4 receptor complexes. DeVico et al. also showed in a SHIV-challenged model that antibodies to CD4i sites in HIV-1 gp120 correlated with the control of SHIV challenge in macaques vaccinated with cross-linked and single-chain gp120�CCD4 complexes. Importantly, it was shown recently that humans infected with HIV-1 generate CD4i antibodies during the course of infection.