Background
Residual immune activation/inflammation is a hallmark of treated HIV. Dual (2DR) regimens are efficacious in maintaining viral suppression, however, their effect on T-cell homeostasis and mitochondrial damage, is ill-defined.
Methods
PLWH switching from viro-suppressive, three drug (3DR) cART to an INSTI-based 2DR with sample availability (at switch and approximately 12 months from switch) were studied. We evaluated T-cell surface maturation (CD127/CD45RA) and activation (CD38/CD45RO) by flow cytometry, plasma gut barrier dysfunction (E-cadherin, I-FABP) and microbial translocation (sCD14, LBP, ELISA;16S rDNA, qPCR). In an unselected subgroup of 16 PLWH, we also assessed total intracellular HIV DNA, and circulating cell-free mitochondrial DNA (ccf-mtDNA, qPCR). Wilcoxon test for statistics.
Results
We enrolled 60 PLWH (Table1). Switching to 2DR led to significant CD4 increases (32% [27-39] vs 35% [30-40]; p=0.0001), reduction in CD8 (40% [34-45] vs 37% [30-42]; p<0.0001) and rise in CD4/CD8 (0.83 [0.65- 0.91] vs 0.96 [0.76-1.3]; p=0.0007). Moreover, switch to 2DR resulted in a decrease of naïve T cells (CD4/CD45RA: 11% [8-17] vs 10% [6-13], p<0.0001; CD8/CD45RA: 18% [15-22] vs 17% [12-20], p=0.002), and significant expansion of central memory phenotypes (CD4/CD127: 28% [24-33] vs 32% [26-37], p<0.0001; CD8/CD127: 30% [24-34] vs 32% [26-36], p=0.01). We also observed a marked reduction in activation (CD8/CD38: 5% [4-8] vs 3% [2-5], p<0.0001, Fig1A; CD8/CD45RO: 7% [4-11] vs 6 [3-8], p=0.03); CD8/CD38/CD45RO: 1% [0-1] vs 0% [0-1], p<0.0001). No changes in markers of intestinal damage, microbial translocation, bacterial 16S rDNA and total HIV DNA were detected, whereas a significant increase in ccf-mtDNA was noted after the switch (Fig.1B). The same trend was observed when the two ccf-mtDNA genes were analysed separately (ND-1 gene: 5,87E+06 cp/ml [8,52E+05-3,18E+07] vs 2,55E+07 cp/ml [2,75E+06-9,90E+07], p=0.03; D-Loop gene: 6,21E+06 cp/ml [8,75E+05-3,16E+07] vs 2,80E+07 cp/ml [3,46E+06-7,97E+07], p=0.03). No correlations were found between ccf-mtDNA and T-cell activation (pre-switch: r=0.02, p=0.9; post-switch: r=0.03, p=0.8).
Conclusions
By maintaining the control over viral reservoir and microbial translocation, 12-month switch to INSTI-based dual cART contribute to T-cell activation containment, and yet fails to revert cellular stress as measured by circulating mitochondrial DNA. The effects of longer 2DR to contain the enduring HIV-driven cell stress needs further investigation.
Table or Figure
