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. 2016 Jan 14;12(1):e1005369.
doi: 10.1371/journal.ppat.1005369. eCollection 2016 Jan.

Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort

Affiliations

Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort

Elise Landais et al. PLoS Pathog. .

Abstract

Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.

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Conflict of interest statement

PPh and TW are employed by a commercial company, Monogram Biosciences, Inc. This affiliation does not alter our adherence to all the PLOS Pathogens policies on sharing data and materials. The other authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Evolution of broadly neutralizing antibody responses in plasma from Protocol C participants.
(A-C) Plasma from HIV-1 infected participants collected at various time points post infection were assessed for neutralizing activity on a predictive 6v-panel [16]. Neutralization score on the 6v-panel was calculated as indicated in Material and Methods (A) Best neutralization score across all time points tested for Protocol C participants. (B) Fraction of Protocol C individuals with the indicated plasma neutralization score at the indicated visits. Neutralization score is color-coded as indicated in (A). (C) Detailed evolution of neutralization score over time (months) for individual Protocol C best neutralizers (N = 46), organized by time to reach neutralization score ≥ 1 in months post infection (MPI). NT: Not Tested. ART: Participants was on Anti-Retroviral Therapy at this visit, OFF: Participant was off-study at this visit.
Fig 2
Fig 2. Correlation between clinical parameters and development of broadly neutralizing antibody responses.
(A) Bivariate and multivariable GLM correlation analyses between the listed variables, and the best neutralization score for the M48+ subset of Protocol C participants. Number of participants in each subgroup (N) is indicated. Estimated coefficients (EstCoef), p-values, q-values, odd ratios (ExpEst) upper (U95) and lower (L95) values of the 95% confidence interval are indicated. P-values are color coded as follows: 0.01< p-value < 0.05, in green; 0.001< p-value < 0.01, in yellow; 2E-16 < p-value <0.001, in red. Q-values below 0.1 are indicated in bold. (B) Kaplan Meier curves recording the time for Protocol C neutralizers (best neutralization score ≥ 0.5, N = 157) within the indicated subgroups to reach a neutralization score ≥ 0.5. Log-Rank test p-values are indicated. DC: Discordant couple, OHS: Other Heterosexual transmission, HSM: Women to Men Heterosexual transmission, HSW: Men to Women Heterosexual transmission, MSM: Men who have Sex with Men.
Fig 3
Fig 3. Correlation between total and antigen-specific IgG responses and development of broadly neutralizing antibody responses.
Correlations were assessed by Spearman analyses: p-values and r-values are indicated; (ns) not significant. Linear, semi-Log or Log-log regressions are also shown as dotted lines. Neutralization score corresponds to a participant’s best neutralization score on the 6-virus panel across all tested time points. (A,C) IgG binding activity to recombinant MN gp41 (Subtype B), BG505 gp120 (subtype A) and IAVIC22 gp120 (Subtype B) was assessed, by ELISA, in plasma samples of Protocol C participants (N = 61) from the M48+ subset, at visits matching development of bnAb responses (M24-72, mean = 36.6 mpi). (B) Avidity index for IAVIC22-gp120 IgG titers were calculated from high salt (1.5M or 3M NaSCN) ELISA experiments. (C) Total IgG titers were assessed by ELISA. (D) Total IgG titers in pre-infection (N = 27), ~4mpi (N = 56, M00, mean = 4.0 mpi) and ~36mpi (N = 61) M24-72) samples. (E) Total IgG titers in ~36mpi samples (M24-72). (F) ELISA binding ID50 and neutralization score from (A) were standardized to a reference concentration of 20mg/mL of total plasma IgG.
Fig 4
Fig 4. Specificities mediating neutralization breadth and potency in the top 42 Protocol C neutralizers.
(A) Samples are ranked by their neutralization score on the 37-virus panel (37vP) (S4 Fig in S1 Text and S2 Table in S1 Text). VC: Visit Code (months post infection). Symbols recapitulate the strength of the phenotypes tested using the different approaches detailed in this manuscript (S7-S11 Figures in S1 Text) to determine the Env epitope region targeted by the plasma broadly neutralizing activity: gp120 absorption of bnAb activity, effect of b6 competition in gp120 absorption experiments, RSC3 binding and neutralization competition, HIV-2 chimera neutralization, viruses produced in presence of kifunensine or bearing mutations. Absent (-), very weak (+/-), weak (+), moderate (++), strong (+++), phenotype was attributed based on i) the median fold or average percent decrease in ID50 and ii) the fraction of viruses which neutralization ID50 was decreased <2 fold, <10 <50 fold or <20%, <40%, <60%, <80%. Blank = not tested, NB: not binding. A dominant specificity was attributed for each sample based on results from all these experiments. UD: Undefined. (B) Overall distribution of dominant nAb specificities mediating plasma neutralization breadth in the top 42 Protocol C neutralizers as detailed in (A).

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