Abstract
The HIV-1 envelope glycoprotein (Env) trimer is located on the surface of the virus and is the target of broadly neutralizing antibodies (bNAbs). Recombinant native-like soluble Env trimer mimetics, such as SOSIP trimers, have taken a central role in HIV-1 vaccine research aimed at inducing bNAbs. We therefore performed a direct and thorough comparison of a full-length unmodified Env trimer containing the transmembrane domain and the cytoplasmic tail, with the sequence matched soluble SOSIP trimer, both based on an early Env sequence (AMC011) from an HIV+ individual that developed bNAbs. The structures of the full-length AMC011 trimer bound to either bNAb PGT145 or PGT151 were very similar to the structures of SOSIP trimers. Antigenically, the full-length and SOSIP trimers were comparable, but in contrast to the full-length trimer, the SOSIP trimer did not bind at all to non-neutralizing antibodies, most likely as a consequence of the intrinsic stabilization of the SOSIP trimer. Furthermore, the glycan composition of full-length and SOSIP trimers was similar overall, but the SOSIP trimer possessed slightly less complex and less extensively processed glycans, which may relate to the intrinsic stabilization as well as the absence of the membrane tether. These data provide insights into how to best use and improve membrane-associated full-length and soluble SOSIP HIV-1 Env trimers as immunogens.
Highlights
The HIV-1 envelope glycoprotein (Env) trimer is the target of broadly neutralizing antibodies that arise during HIV-1 infection and is, an attractive immunogen for vaccine design
HIV-1 envelope glycoprotein (Env) trimer is the primary antigenic target for neutralizing antibodies. It is the focus of subunit vaccine design efforts that aim to recapitulate the structure and native antigenic profile in a soluble, stable form capable of eliciting neutralizing antibody responses
To allow for a direct structural, antigenic and biophysical comparison between SOSIP.664 and full-length trimers, we selected the AMC011 clade B env gene, which is a consensus sequence of early Env sequences from an HIV-infected individual enrolled in the Amsterdam Cohort Studies on HIV/AIDS (ACS) [24,25]
Summary
The HIV-1 envelope glycoprotein (Env) trimer is the target of broadly neutralizing antibodies (bNAbs) that arise during HIV-1 infection and is, an attractive immunogen for vaccine design. One approach to induce protective bNAbs is the use of Envbased vaccines that mimic native Env on the virus. Soluble SOSIP trimers from different clades have been described and characterized biophysically and biochemically [4,7,8,9,10,11]. Soluble SOSIP Env trimers have been tested as immunogens in animals and elicited neutralizing antibody (NAb) responses against the autologous viruses but generally not against heterologous Tier-2 viruses [10,18,19,20,21,22]
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