1. Th17-related cytokines altered after HIV infection
Antiretroviral treatment did not restore functionality of cervical mucosal cells for
Th17-related cytokines altered after HIV infection
M.P. Caruso, M.P. Holgado, J. Falivene, J. Salido, D.H. Zurita, A. Nico, V. Fink, N. Laufer, H.M. Perez, P. Cahn, O. Sued, G. Turk, M.M. Gherardi.
Groups of study
Th17 and Treg cells play a key role in HIV infection and mucosal defenses. A reduction of Th17 cells in female genital mucosa (FGM) of HIV positive women has been previously described.
To analyze the effects of antiretroviral treatment (ART) in these T-cell subsets in FGM
Cervical mononuclear cells (CMCs) and ectocervical swabs from FGM were obtained. Cytokines secreted by CMCs after stimulation with PMA+Ionomycin and chemokines in ectocervical swabs were quantified by Cytometric Bead Array.
Background
Th17 and Treg cells play a key role in HIV infection and mucosal defenses. A reduction of Th17 cells in the female genital mucosa (FGM) of HIV+ women has been previously described. Aim: To analyze the effects of antiretroviral treatment (ART) in these T-cell subsets in FGM in different groups of individuals.
Methods
Cervical mononuclear cells (CMCs) and exocervical swabs from FGM were obtained from the following groups: HIV- (n=21), HIV+ART+ (n=32) and HIV+ART- (n=12). Cytokines (CKs) secreted by CMCs after stimulation with PMA+Ionomycin and chemokines in exocervical swabs were quantified by Cytometric Bead Array.
Results
CMCs production of Th17-related-CKs (IL17A, IL17F, IL21 and IL22) and Treg-related-CKs (IL10 and TGF-β1) were evaluated. HIV+ART- group showed diminished proportions of positive responses for Th17-related-CKs compared to HIV- (IL17A, IL17F and IL21:p<0.01). Minor proportions were still found in HIV+ART+ group (IL17A and IL17F:p<0.05). In Treg-related-CKs, reduction was only found for IL10 in both HIV+ groups (p<0.05).
CMCs production of Th17-related-cytokines (IL-17A, IL-17F, IL-21 and IL-22) and Treg-related-cytokines (IL-10 and TGF-β1) were evaluated.

2. Global patterns of Th17-related-cytokines
Global pattern of Treg-related-cytokines 5%
33%
63%
17%
p = 0,0219
p = 0,0281
Thirteen different inflammatory chemokines were evaluated in ectocervical swabs:
Analysis of global pattern of secretion of Th17-related-cks, indicated that in HIV+ART- the secretion pattern was severely modified (p=0.0297)señalarlo.
In HIV+ART+ group the Th17-related-cks pattern tend to be restored.
However, after treatment, still a significant lower percentage of samples secreted 4 Th17-related-CKs (HIV-:62.5% vs HIV+ART+:16.67%; p=0.0281). And on the other hand, an increased proportions of samples with NO Th17-CK production was observed.
In contrast, when Treg-related-CKs pattern was compared none significant differences were found between the different groups.
Thirteen different chemokines were evaluated in exocervical swabs. Differences in both HIV+ groups vs HIV- were detected: minor levels of CXCL5 and CXCL1 (neutrophil recruitment); major levels of CCL17 (homing of Treg-cells).

3. HIV+ART+ group was divided in two according to the number of Th17-related-cytokines secreted by the CMCs: “at least 3” or “1 or less”
To inquire if CMCs function deterioration in relation to Th17-related-cytokines could be related with the minor chemokine levels observed, HIV+ART+ group was divided in two according to the number of Th17-related-CKs secreted: “at least 3CKs“ and “1 or less CKs”.
Interestingly, for CXCL5 and CXCL1, significant lower levels were found in the “1 or less” group (compared to HIV- and to “at least 3”, all p<0.05).
Also in HIV+ART+, positive correlations were found between logCXCL5 vs logIL17A (r=0.5666, p=0.0241), logCXCL1 and logIL17A (r=0.7273, p=0.0006) and logCCL17 vs logIL10 (r=0.5700, p=0.0186).
Conclusion
These results suggest that HIV infection severely affects the functionality of cervical mucosal cells, and ART was not able to totally restore it. Earlier ART start might mitigate this HIV infection effect.
These results suggest that HIV infection severely affects the functionality of cervical mucosal cells mainly in relation to Th17-related-cytokines.
ART could not totally restore Th17-related immune functions at the female mucosal level.
HIV+ART+ women with lower quantities of Th17-related-cytokines had decreased levels of CXCL5 and CXCL1 chemokines.
It should be evaluated if earlier ART start can prevent this HIV infection effect.