Early skewed differentiation and PD-1 expression in CD4+ T-cells relate to immune dysfunction and viral persistence in HIV+ subjects one year post-cART initiation

CÉSAR ARIEL TRIFONE; PEDRO CAHN; YANINA GHIGLIONE; ALEJANDRO CZERNIKIER; HORACIO SALOMÓN; NATALIA LAUFER; JIMENA SALIDO; MARÍA INÉS FIGUEROA; OMAR SUED; GABRIELA TURK

Ciudad de Mexico

Conferencia; Conferencia de la Sociedad International de SIDA (IAS 2019); 2019

International AIDS association

Achieving an HIV functional cure is a priority. Strategies such as adoptive cell transfer have been assayed, without success yet mainly due to immune dysfunctions observed among individuals. AIM: To determine the influence of early CD4 T-cell (CD4TC) responses in inflammation levels, viral reservoir, and HIV-specific CD8TC response post-cART.Samples from 25 HIV+ subjects were collected at diagnosis (baseline sample, BSL) and one year post-cART initiation (post-cART). At BSL, bulk and HIV-specific CD4 phenotype (CD45RO, CCR7, CD95 and PD1 expression) was assessed by flow cytometry after a short stimulation with HIV peptides. Also, proportion of CD4+/HLA-DR+/CD38+ cells was measured. At post-cART, HIV-specific CD8TCs were obtained after 2-week expansion with peptides. Phenotype and antiviral activity (VIA and VITAL assays) were evaluated post-expansion. Plasma CXCL10 (IP-10) was assessed by ELISA. Cell-associated HIV DNA (total and integrated) and unspliced (US) and multiply-spliced (MS) RNA were quantified by real-time PCR. Non-parametric statistics were applied.Early elevated PD-1 on CD4TCs inversely correlated with CD8TCs ability to differentiate post-cART: %CD4+/PD-1high correlated directly with the proportion of stem-cell (CD8TCSCM) and central memory (CD8TCCM) CD8TC subsets but indirectly with terminal effector (CD8TCTE), both in bulk (p=0.018, p=0.0018, p=0.010, respectively) and HIV-specific (p=0.040, p=0.012, p=0.028, respectively) compartments. Similarly, early skewed CD4TCs memory differentiation (CD4TCEM/(CD4TCEM+CD4TCTE)) positively correlated with the proportion of CD8TCCM (p=0.0096) and effector memory (CD8TCEM, p=0.0031) but inversely with CD8TCTE (p=0.0003) and with the %CD8+/PD-1+ (p=0.023), post-cART. BSL %CD4TCEM, %CD4+/PD-1+ and %CD4TCTE/PD1+ correlated directly with CXCL10 post-cART (p=0.037, p=0.0096, p=0.003, respectively). Also, early CD4TC phenotype and activation correlated with viral reservoir: %CD4TCEM inversely with both MS-RNA (p=0.008) and US-RNA (p=0.017); %CD4+/PD-1+ directly with total DNA (p