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. 2017 Dec:26:25-37.
doi: 10.1016/j.ebiom.2017.11.001. Epub 2017 Nov 3.

Evaluation of Different Parameters of Humoral and Cellular Immune Responses in HIV Serodiscordant Heterosexual Couples: Humoral Response Potentially Implicated in Modulating Transmission Rates

María Julia Ruiz  1 , Jimena Salido  1 , Lorena Abusamra  2 , Yanina Ghiglione  1 , Cintia Cevallos  1 , Gabriel Damilano  1 , Ana María Rodriguez  1 , César Trifone  1 , Natalia Laufer  3 , Luis D Giavedoni  4 , Omar Sued  5 , Horacio Salomón  1 , María Magdalena Gherardi  1 , Gabriela Turk  6
Affiliations

Evaluation of Different Parameters of Humoral and Cellular Immune Responses in HIV Serodiscordant Heterosexual Couples: Humoral Response Potentially Implicated in Modulating Transmission Rates

María Julia Ruiz et al. EBioMedicine. 2017 Dec.

Abstract

As the HIV/AIDS pandemic still progresses, understanding the mechanisms governing viral transmission as well as protection from HIV acquisition is fundamental. In this context, cohorts of HIV serodiscordant heterosexual couples (SDC) represent a unique tool. The present study was aimed to evaluate specific parameters of innate, cellular and humoral immune responses in SDC. Specifically, plasma levels of cytokines and chemokines, HIV-specific T-cell responses, gp120-specific IgG and IgA antibodies, and HIV-specific antibody-dependent cellular cytotoxicity (ADCC) activity were assessed in nine HIV-exposed seronegative individuals (ESN) and their corresponding HIV seropositive partners (HIV+-P), in eighteen chronically infected HIV subjects (C), nine chronically infected subjects known to be HIV transmitters (CT) and ten healthy HIV- donors (HD). Very low magnitude HIV-specific cellular responses were found in two out of six ESN. Interestingly, HIV+-P had the highest ADCC magnitude, the lowest IgA levels and the highest IgG/IgA ratio, all compared to CT. Positive correlations between CD4+ T-cell counts and both IgG/IgA ratios and %ADCC killing uniquely distinguished HIV+-P. Additionally, evidence of IgA interference with ADCC responses from HIV+-P and CT is provided. These data suggest for the first time a potential role of ADCC and/or gp120-specific IgG/IgA balance in modulating heterosexual transmission. In sum, this study provides key information to understand the host factors that influence viral transmission, which should be considered in both the development of prophylactic vaccines and novel immunotherapies for HIV-1 infection.

Keywords: ADCC; HIV-1; HIV-1 transmission; Serodiscordant couples.

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Figures

FIG. 1
Fig. 1
CD4+ T-cell counts (A) and plasma viral loads (VL, B) of enrolled HIV subjects per study group. Inclusion criteria for subjects enrolled are explained in Materials and Methods. Horizontal lines stand for median values. HIV+-P: HIV positive partners, ESN: Exposed HIV seronegative individuals, CT: Chronically HIV transmitters subjects C: Chronics. P values were calculated using a Mann-Whitney U test. Asterisks denote different p values: ***, p < 0.005,
FIG. 2
Fig. 2
Differential plasma cytokine/chemokine levels among groups. A. Macrophage-derived chemokine (MDC) levels (pg/ml) in plasma from exposed HIV seronegative individuals (ESN) versus healthy donors (HD). B. sCD40L levels (pg/ml) in plasma from HIV positive partners (HIV+-P) versus Chronics (C). P values were calculated using a Mann-Whitney U test. Asterisks denote different p values: *, p < 0.05, **, p < 0.001. After applying the FDR procedure, adjusted p value was > 0.1.
FIG. 3
Fig. 3
ELISPOT screening of HIV-specific T-cell response magnitude and breadth in HIV+-P, ESN and Chronics. A. Magnitude (SFU/106 PBMC, left panel) and breadth (contribution of each antigen relative to the total HIV response, right panel) of the HIV-specific T-cell responses in HIV+-P and Chronics. In the case of the magnitude, results corresponding to the CEF control peptide pool (Cytomegalovirus, Epstein Bar, Influenza) are also shown. Horizontal lines within boxes represent the median values. Whiskers extend from min to max values. B. Magnitude (SFU/106 PBMC) of the HIV-specific and CEF-specific responses in three ESN individuals, obtained in the “fresh” (conventional) and “expanded” (14-day stimulation) ELISPOT protocol. Bars represent the media ± SD from triplicate conditions.
FIG. 4
Fig. 4
A. ADCC responses in Serodiscordant Couples (HIV+-P and ESN), HIV chronically infected individuals (C) and HIV chronically infected transmitter subjects (CT), measured by RFADCC assay. Zebra plots for one representative subject per study group. A PKH26-versus-CFSE plot was generated to determine the percentage of ADCC killing, defined as the proportion of cells that remained PKH26high but lost the viability dye (CFSEneg). Percentages shown in each plot correspond to results obtained after calculating and subtracting the background (%ADCC killing for uncoated target cells) from the media of triplicate conditions. B. Percentages of ADCC killing corresponding to a 1/1000 plasma dilution for HIV+-P, C and CT, and to a 1/100 plasma dilution for HD and ESN. %ADCC killing data correspond to background subtracted values. Horizontal lines stand for median values. Statistical analysis was performed using Kruskal-Wallis test followed by Dunn's multiple comparisons post-test. # When the outlier identified within the CT group was removed, the statistical significance was lost (p = 0.07). C. Gp120-specific IgG antibodies (log10(nanograms per milliliter), left panel), gp120-specifc IgA titers (middle panel) and IgG/IgA ratios (right panel) per study group. Horizontal lines stand for median values. Statistical analysis was performed using Kruskal-Wallis test followed by Dunn's multiple comparisons post-test. HIV+-P: HIV positive partners, ESN: Exposed HIV seronegative individuals, CT: Chronically HIV transmitters subjects C: Chronics. HD: Healthy donors.
FIG. 5
Fig. 5
A. Correlations between %ADCC Killing versus IgG/IgA ratios, IgG/IgA ratios versus CD4+ T-cell counts and CD4+ T-cell counts versus %ADCC killing in HIV +-P (left panels) and CT (right panels) individuals. r and p values were determined by Spearman's test. ns: non-significant. r and p values shown between brackets correspond to those obtained after the removal of the ADCC outlier data point identified within the CT group. B. Percentage of ADCC killing evaluated in IgA-depleted (grey bars) and non-depleted (black bars) plasma at 1/1000 dilutions. Plasma was obtained from representative HIV +-P and CT individuals. ADCC was evaluated in triplicates and data was analyzed by t-test.
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