Envelope-Specific Recognition Patterns of HIV Vaccine-Induced IgG Antibodies Are Linked to Immunogen Structure and Sequence

Abstract

Background: A better understanding of the parameters influencing vaccine-induced IgG recognition of individual antigenic regions and their variants within the HIV Envelope protein (Env) can help to improve design of preventive HIV vaccines. Methods: Env-specific IgG responses were mapped in samples of the UKHVC003 Standard Group (UK003SG, n = 11 from UK) and TaMoVac01 (TMV01, n = 17 from Tanzania) HIV vaccine trials. Both trials consisted of three immunizations with DNA, followed by two boosts with recombinant Modified Vaccinia Virus Ankara (MVA), either mediating secretion of gp120 (UK003SG) or the presentation of cell membrane bound gp150 envelopes (TMV01) from infected cells, and an additional two boosts with 5 μg of CN54gp140 protein adjuvanted with glucopyranosyl lipid adjuvant (GLA). Env immunogen sequences in UK003SG were solely based on the clade C isolate CN54, whereas in TMV01 these were based on clades A, C, B, and CRF01AE. The peptide microarray included 8 globally representative Env sequences, CN54gp140 and the MVA-encoded Env immunogens from both trials, as well as additional peptide variants for hot spots of immune recognition. Results: After the second MVA boost, UK003SG vaccinees almost exclusively targeted linear, non-glycosylated antigenic regions located in the inter-gp120 interface. In contrast, TMV01 recipients most strongly targeted the V2 region and an immunodominant region in gp41. The V3 region was frequently targeted in both trials, with a higher recognition magnitude for diverse antigenic variants observed in the UK003SG ( p < 0.0001). After boosting with CN54gp140/GLA, the overall response magnitude increased with a more comparable recognition pattern of antigenic regions and variants between the two trials. Recognition of most immunodominant regions within gp120 remained significantly stronger in UK003SG, whereas V2-region recognition was not boosted in either group. Conclusions: IgG recognition of linear antigenic Env regions differed between the two trials particularly after the second MVA boost. Structural features of the MVA-encoded immunogens, such as secreted, monomeric gp120 vs. membrane-anchored, functional gp150, and differences in prime-boost immunogen sequence variability most probably contributed to these differences. Prime-boosting with multivalent Env immunogens during TMV01 did not improve variant cross-recognition of immunodominant peptide variants in the V3 region.

Induction of Identical IgG HIV-1 Envelope Epitope Recognition Patterns After Initial HIVIS-DNA/MVA-CMDR Immunization and a Late MVA-CMDR Boost

“…IgG antibodies to the HIV-1 Env variable (V) regions V1 and V2, as well as V3, were found to correlate with a reduced risk of HIV-1 infection, while the presence of IgA Env-binding antibodies was associated with an increased risk of infection (9,10). Antibody responses to other linear epitopes of the HIV-1 Env gp120 did not correlate with infection risk (10), which might be due to the fact that many of these regions are not accessible on a native HIV-1 Env trimer (11). Viral sieve analyses showed that the RV144 vaccine regimen induced selection of viral variants with point mutations in the V2 and V3 regions, indicating that strain-specific V2 and V3 antibodies drove viral mutation to escape the vaccine-induced immune response against HIV-1 (12,13).…”

“…The peptide array design has been previously described in detail by our group (11). In brief, gp120 and gp41 sequences of 8 recently transmitted HIV primary isolates of different subtypes (A, B, C, CRF01_AE and CRF02_AG) were selected for inclusion in the peptide array design to represent the HIV Env variants of the current global pandemic.…”

“…Additionally, two HIV Env vaccine sequences-CN54gp140 (subtype C) and CMDR (subtype AE)-were incorporated in the array. Previously identified hot spots of IgG recognition on the envelope (10,11) Plasma from 20 HIVIS03/06 volunteers was analyzed using the peptide microarrays according to the manufacturer's instructions with minor modifications (www.jpt.com) as described elsewhere (11). Briefly, after initial blocking of the FIGURE 2 | Maps of linear IgG epitopes along the HIV-1 Env targeted by HIVIS03/06 vaccinees with frequency of responders (A) and mean FI (B) given for each time point tested.…”

“…Maximum likelihood phylogenetic trees of the peptide variants corresponding to HxB2 amino acid positions 163 and 304 were generated using MEGA. The FI of each peptide variant included in the Env peptide array for the V3 and V2 tip (HxB2 163 and 305) has been linked with their phylogenetic relationship as described previously (11). The mean FI of all vaccinees for each peptide variant is color coded and the frequency of occurrence of a given peptide variant in the global HIV epidemic (www.hiv.lanl.gov) is depicted by its icon size.…”

“…Recognition Patterns Are Detected After the Late 3rd MVA-CMDR Boost and the Original HIVIS-DNA/MVA-CMDR Vaccination Inclusion of additional peptide variants at previously identified hot spots of IgG recognition of the HIV-1 Env in the peptide array design allowed fine mapping of the vaccination-induced IgG responses of the V2 and V3 tip (11), both correlated with a decreased risk of HIV-1 infection (10). This thereby enables a direct comparison of the variant recognition after the initial combined HIVIS-DNA/MVA-CMDR vaccination and the late 3rd MVA-CMDR boost.…”