Glycosylation of HIV Env Impacts IgG Subtype Responses to Vaccination

Abstract

The envelope protein (Env) is the only surface protein of the human immunodeficiency virus (HIV) and as such the exclusive target for protective antibody responses. Experimental evidences from mouse models suggest a modulating property of Env to steer antibody class switching towards the less effective antibody subclass IgG1 accompanied with strong TH2 helper responses. By simple physical linkage we were able to imprint this bias, exemplified by a low IgG2a/IgG1 ratio of antigen-specific antibodies, onto an unrelated antigen, namely the HIV capsid protein p24. Here, our results indicate the glycan moiety of Env as the responsible immune modulating activity. Firstly, in Card9−/− mice lacking specific C-Type lectin responsiveness, DNA immunization significantly increased the IgG2a/IgG1 ratio for the Env-specific antibodies while the antibody response against the F-protein of the respiratory syncytial virus (RSV) serving as control antigen remained unchanged. Secondly, sequential shortening of the Env encoding sequence revealed the C2V3 domain as responsible for the strong IgG1 responses and TH2 cytokine production. Removing all potential N-glycosylation sites from the C2V3 domain by site-specific mutagenesis reversed the vaccine-induced immune response towards a Th1-dominated T-cell response and a balanced IgG2a/IgG1 ratio. Accordingly, the stretch of oligomannose glycans in the C2V3 domain of Env might mediate a specific uptake and/or signaling modus in antigen presenting cells by involving interaction with an as yet unknown C-type lectin receptor. Our results contribute to a deeper understanding of the impact of Env glycosylation on HIV antigen-specific immune responses, which will further support HIV vaccine development.

Modulation of Vaccine-Induced HIV-1-Specific Immune Responses by Co-Electroporation of PD-L1 Encoding DNA

“…In HIV-1 infected patients, humoral immune responses against Env protein are largely restricted to the IgG1 isotype [27][28][29][30]. Vaccination studies on mice demonstrated that the immune response against Env-in contrast to envelope proteins of other viruses-is strongly T H 2-biased, which is partly caused by its unique glycosylation profile [11,12,22]. At the same time, T H 1 associated Env-specific antibodies are correlating with an efficient virus control in elite controllers [1,3,7,31,32].…”

“…Previously we reported that immunization of mice against HIV-1 Env with both protein and DNA vaccines induces a T H 2-associated immune response leading to IgG1 Env-specific Ab responses with reduced effector functions [11,12,22]. Here we investigated whether this pattern might be switched to the T H 1-associated IgG2a subclass by blocking immune checkpoints.…”

“…However, in contrast to the surface proteins of RSV and Influenza A, i.m. EP of plasmids encoding for HIV-1 Env elicits an antibody response strongly biased towards the T H 2-associated IgG1 subclass in mice [11,12].…”

Conjugation of Native-Like HIV-1 Envelope Trimers onto Liposomes Using EDC/Sulfo-NHS Chemistry: Requirements and Limitations

“…The low number of Env trimers per liposome achieved by our tag-free EDC/Sulfo-NHS-based conjugation approach may thus be very well sufficient for an enhanced activation of Env-specific/Env-reactive B cells by B-cell receptor crosslinking (BCR crosslinking). Moreover, the high molar ratio of incorporated T helper cell peptides to surface-displayed Env trimers may be well suited to improve/modulate Env antibody responses by intrastructural help [ 65 , 68 ]. Investigating the immunogenicity and the potential of the prepared Env-liposome conjugates (T helper liposomes) to shape the immune response against the surface-displayed Env trimers is of particular importance but was beyond the scope of the present methodological paper.…”

“…First steps towards the development of liposome-based vaccines capable of harnessing intrastructural help date back to the early 1990′s [ 61 , 62 , 63 ]. Recent studies that involved particle-based vaccines (virus-like particles and calcium phosphate nanoparticles) have provided additional proof of concept for this type of strategy within the context of HIV-1 [ 64 , 65 , 66 , 67 , 68 ]. Recent independent reports on liposome-based vaccines (against HIV-1, malaria, group A streptococci and ErbB-2 overexpressing breast cancer) utilizing the same principle are also very encouraging [ 69 , 70 , 71 , 72 ].…”