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Recognition Patterns of the C1/C2 Epitopes Involved in Fc-Mediated Response in HIV-1 Natural Infection and the RV114 Vaccine Trial.

ABSTRACT: Antibodies (Abs) specific for CD4-induced envelope (Env) epitopes within constant region 1 and 2 (C1/C2) were induced in the RV144 vaccine trial, where antibody-dependent cellular cytotoxicity (ADCC) correlated with reduced risk of HIV-1 infection. We combined X-ray crystallography and fluorescence resonance energy transfer-fluorescence correlation spectroscopy to describe the molecular basis for epitopes of seven RV144 Abs and compared them to A32 and C11, C1/C2 Abs induced in HIV infection. Our data indicate that most vaccine Abs recognize the 7-stranded β-sandwich of gp120, a unique hybrid epitope bridging A32 and C11 binding sites. Although primarily directed at the 7-stranded β-sandwich, some accommodate the gp120 N terminus in C11-bound 8-stranded conformation and therefore recognize a broader range of CD4-triggered Env conformations. Our data also suggest that Abs of RV144 and RV305, the RV144 follow-up study, although likely initially induced by the ALVAC-HIV prime encoding full-length gp120, matured through boosting with truncated AIDSVAX gp120 variants.IMPORTANCE Antibody-dependent cellular cytotoxicity (ADCC) correlated with a reduced risk of infection from HIV-1 in the RV144 vaccine trial, the only HIV-1 vaccine trial to date to show any efficacy. Antibodies specific for CD4-induced envelope (Env) epitopes within constant region 1 and 2 (cluster A region) were induced in the RV144 trial and their ADCC activities were implicated in the vaccine efficacy. We present structural analyses of the antigen epitope targets of several RV144 antibodies specific for this region and C11, an antibody induced in natural infection, to show what the differences are in epitope specificities, mechanism of antigen recognition, and ADCC activities of antibodies induced by vaccination and during the course of HIV infection. Our data suggest that the truncated AIDSVAX gp120 variants used in the boost of the RV144 regimen may have shaped the vaccine response to this region, which could also have contributed to vaccine efficacy.

SUBMITTER: Tolbert WD

PROVIDER: S-EPMC7327165 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:HIV Vaccine Trials Network (HVTN) 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection yet enhanced HIV infection risk for others. Here, we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four FCGR2C single-nucleotide polymorphism [SNP] sites) (hazard ratio [HR] = 9.79, P = 0.035) but not among participants without the haplotype (HR = 0.86, P = 0.67); the interaction of vaccine and haplotype effect was significant (P = 0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3 FCGR3B SNPs) (HR = 2.78, P = 0.058) but not among participants without the haplotype (HR = 0.73, P = 0.44); again, the interaction of vaccine and haplotype was significant (P = 0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8+ T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an FCGR2A SNP and two FCGR2B SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination.IMPORTANCE By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines.

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Recognition Patterns of the C1/C2 Epitopes Involved in Fc-Mediated Response in HIV-1 Natural Infection and the RV114 Vaccine Trial.

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