Diminished proportions of HLA-G⁺ CD4 and CD8 T cells in progressive HIV-1 infection.

<p>(A): Representative flow cytometry dot plots reflecting the proportions of HLA-G⁺ CD4 and CD8 T cells in indicated study subjects. FMO control reflects “fluorescence minus one” control condition without addition of HLA-G antibodies. (B): Box and Whisker plots summarizing the relative proportions and absolute numbers of HLA-G⁺ CD4 and CD8 T cells in indicated study cohorts. ANOVA followed by post-hoc analysis with Tukey's Multiple Comparison Test was used to determine significance. (C): Correlations between frequencies of HLA-G⁺ T cells and total CD4 T cell counts in controllers (n = 23), progressors (n = 27) and HIV seronegative individuals (n = 15). (D): Correlations between proportions of HLA-G⁺ Treg and CD8 T cell immune activation determined by surface expression of CD38 and HLA-DR in controllers (n = 19), progressors (n = 20), and HIV seronegative individuals (n = 15). (C/D): Spearman's correlation coefficient is shown.</p

HLA-G⁺ Treg reduce bystander activation of T cells.

<p>(A–B): Representative flow cytometry dot plots reflecting the surface expression of CD38 on Vβ13.1⁺ and Vβ13.1⁻ responder T cells following exposure to indicated CD4 (A) or CD8 (B) Treg cell populations or negative control CD4 or CD8 T cells from HIV-seronegative donors. (C–D): Cumulative data representing relative suppression of CD38, HLA-DR and CD69 on Vβ13.1⁺ and Vβ13.1⁻ responder T cells following exposure to indicated CD4 (C) or CD8 (D) Treg cell populations. Mean and standard deviation from n = 8 HIV-1 negative study subjects are shown. Significance was tested by paired T test.</p

Stable LILRB1 expression on T cells after “bystander activation”.

<p>(A) Representative dot plots demonstrating proportions of LILRB1-expressing Vβ13.1⁺ and Vβ13.1⁻ T cells after activation with SEB over indicated time course. (B): Fold change of LILRB1 expression on Vβ13.1⁺ or Vβ13.1⁻ T cells at indicated time points. Mean and standard error from 7 different HIV-1 negative donors are shown. Significance was tested by paired T test.</p

HLA-G⁺ Treg minimally inhibit proliferative activities of antigen-specific T cells.

<p>(A–B): Representative dot plots reflecting proliferative activities of HIV-1-, CMV-, or PHA-stimulated CD4 (A) or CD8 (B) T cells from HIV controllers following incubation with indicated autologous Treg subsets or HLA-G⁻ CD25⁻ control cells. (C–D): Cumulative data reflecting the Treg-mediated suppression of HIV-1-specific CD4 (C) or CD8 (D) T cell proliferation from n = 3 HIV-1 controllers. Significance was tested by paired T test.</p

Characteristics at baseline and at cART initiation in 34 elite Controllers (ECs) and 478 chronically viremic (VIRs) patients from the ANRS COPANA Cohort.

<p>Data are median [IQR] or n (%);</p><p>According to own cohort’s definitions of ECs;</p><p>SSA/Car/BA = Sub-Saharan African, Caribbean or African-American origin.</p

Estimated CD4 cell count dynamics in viremic patients (VIRs: n = 478) and elite controllers (ECs: n = 34) in mixed-effect linear models (mean CD4 T cells gain after 12 months of cART was significantly lower in ECs than in VIRs (p = 0.048)).

<p>Estimated CD4 cell count dynamics in viremic patients (VIRs: n = 478) and elite controllers (ECs: n = 34) in mixed-effect linear models (mean CD4 T cells gain after 12 months of cART was significantly lower in ECs than in VIRs (p = 0.048)).</p

Increased detection of Gag p24 specific responses using a 10 mer peptide set.

<p>IFN-γ ELISpot responses against Gag p24 elicited either by consensus B overlapping 18 mer or COT-M 10 mer peptide sets in 25 HIV-1 controllers (<b>A</b>) and 25 HIV-1 non-controllers (<b>B</b>) P-values reflect the increase in median breadth of responses when using 10 mer peptide sets instead the 18 mer peptides (two-tailed Wilcoxon matched paired test). Total magnitude of responses (<b>C</b>) and average magnitude of responses (<b>D</b>) to COT-M Gag p24 10 mer peptides are shown for 25 controllers and 25 non-controllers, respectively. Lines represent median values and indicated p values are based on Mann-Whitney t-tests.</p

High avidity responses are enriched in HIV-1 controllers and mediate superior variant recognition.

<p>(<b>A</b>) Comparison of functional avidity of all COT-M Gag p24 responses titrated in controllers (n = 219 responses) vs. non-controllers (n = 255 responses) (<b>B</b>) Comparison of functional avidities limited to responses targeting the same 10 mer OLP in the two groups (n = 52 responses, Wilcoxon). In (<b>C</b>) the total breadth (number) of the response to the tested COT-M Gag p24 variant peptides (n = 88) is indicated for controllers and non-controllers. (<b>D</b>) Shows the percentage of variant peptides that were reactive when the COT-M sequence elicited a response (“cross-reactive responses”) and (<b>E</b>) indicates responses to variant peptides for which the COT-M sequence did not elicit a response (“gained responses”). The association between functional avidity and cross-reactivity is shown in (<b>F</b>) where responses with functional avidities in either the first quartile of all titrated responses (SD50%<1,401 ng/ml) or the second or third quartile (SD50% 1,401–71,594 ng/ml) or the fourth quartile (SD50%>71,594 ng/ml) were defined as “high”, “intermediate” and low” avidity responses. The percentage of variants that elicited a response was compared between the three groups (Fishers Exact Test).</p

CE containing HLA-B14, -B27 and B57 restricted, protective CTL epitopes are predominantly targeted by HIV-1 controllers.

<p>(<b>A</b>) The total magnitude of responses to CE regions is compared between HIV controllers and non-controllers. (<b>B</b>) The frequency of recognition of the 7 different CE is shown for 25 HIV-1 controllers (C) and 25 non-controllers (NC), respectively. CE regions targeted by at least 50% more controllers than non-controllers are boxed and p-values indicated (T test). (<b>C</b>) Breadth of responses to the combination of CE 4+5+6 regions in controllers vs. non-controllers is shown. Horizontal lines represent median values and Mann-Whitney t-test p value is shown. (<b>D</b>) Correlation between the cumulative magnitude of responses to CE 4+5+6 and HIV viral loads in all 50 tested individuals is shown (Spearman's rank test).</p

Spearman correlation between LILRB2 binding strength and mVL in HIV-1-infected individuals.

<p>Spearman correlation between LILRB2 binding strength and mVL in HIV-1-infected individuals.</p