A Comparative Immunogenicity Study of HIV-1 Virus-Like Particles Bearing Various Forms of Envelope Proteins Particles Bearing no Envelope and soluble monomeric gp120

摘要

To assess the potential of native Envelope glycoprotein (Env) trimers as neutralizing antibody vaccines, we immunized guinea pigs with three types of VLPs and soluble gp120. Particles included “SOS-VLPs” (bearing disulfide-shackled functional trimers), “UNC-VLPs” (bearing uncleaved nonfunctional Env), and “naked VLPs” (bearing no Env). The SOS-VLPs were found to have a density of about 27 native trimers per particle, about twice that of live inactivated HIV-1 preparations. As immunogens, UNC- and SOS-VLP rapidly elicited anti-gp120 antibodies. Gp120-specific antibodies were focused on the V3 loop and the gp120 coreceptor binding site. Reactivity to the gp41 immunodominant domain was absent in SOS-VLP sera, presumably because gp120-gp41 association is stabilized. Gp120 immune sera were less focused on the V3 loop, and reacted with the receptor binding sites of gp120. Some Env-VLP sera neutralized primary isolates at modest titers. Neutralization activity was found to be affected by the cell lines used. Depending on the assay particulars, non-Env specific antibodies in VLP sera could enhance infection, or nonspecifically neutralized. However, we found that the TZM-BL neutralization assay was clear of these effects. We also report a native trimer shift assay that eliminates nonspecific effects and confirm the neutralization activity. Overall, our results suggest that a major focus of VLP sera was against components of particles other than Env trimers, including nonfunctional gp120/gp41 monomers. To make progress toward a more effective VLP vaccine, we will need to find ways to refocus the attention of B cells on native trimers.