Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients

Abstract

Objective: HAART largely decreases morbidity and mortality in chronic HIV-1-infected patients, but immune nonresponders (INRs) with full viral suppression still fail to reverse the immune deficiency. This study evaluated the safety and immunological responses of human umbilical cord mesenchymal stem cell (MSC) therapy in HIV-1-infected INRs.

Design and methods: A total of 13 HIV-1-infected INRs were enrolled in this pilot prospectively open-labeled controlled clinical trial. Seven patients were administered three umbilical cord-MSC transfusions at 1-month interval during 12-months of follow-up, whereas six control patients were treated with saline in parallel. Immunological parameters were monitored in these patients throughout the trial.

Results: All patients tolerated the umbilical cord-MSC transfusions well throughout the trial. The umbilical cord-MSC transfusions preferentially increased circulating naive and central memory CD4 T-cell counts and restored HIV-1-specific IFN-γ and IL-2 production in the INRs. These enhancements in immune reconstitution were also associated with the reduction of systemic immune activation and inflammation in vivo.

Conclusions: umbilical cord-MSC transfusions are well tolerated and can efficiently improve host immune reconstitution in INRs, suggesting that such treatments may be used as a novel immunotherapeutic approach to reversing immune deficiency in HIV-1-infected INRs (ClinicalTrials.gov identifier: NCT01213186).

Fig. 1. Longitudinal changes of peripheral CD4 T-cell counts in 13 enrolled patients before and after treatment

(a) CD4 T-cell counts. (b) Fold-increase in CD4 T-cell counts relative to baseline value at months 9 and 12. umbilical cord-mesenchymal stem cell (MSC) transfusions were initiated at month 0. Arrows in panel (a) indicate time-points of umbilical cord-MSC transfusions.

Fig. 2. Preferential increases of specific CD4 T-cell subsets in INR patients undergoing umbilical cord mesenchymal stem cell therapy

(a) Representative dot plots show the alteration of memory CD4 T-cell populations throughout the study in an INR patient receiving umbilical cord-mesenchymal stem cell (MSC) transfusions. Numbers within the plots indicate the percentage of each T-cell population: naive (T_naive, CD45RA+CD27+), central memory (T_cm; CD45RA−CD27+), effector memory (T_em, CD45RACD27−), terminally differentiated effector (T_emRA; CD45RA⁺CD27⁻). (b) Pooled data of percentages and absolute counts of memory CD4 T-cell subsets in treatment and control patients. (c–f) Pooled data of absolute counts of CD127⁺ CD4 T cells (c), CD25⁺CD127⁻ regulatory CD4 T cells (d), CD31⁺ CD4 T cells or recent thymic emigrants (e) and CD57⁺ senescent CD4 T cells (f) over time in umbilical cord-MSC-treated patients (dots) and control patients (circles). Means ± SD for each cohort are shown. *P < 0.05 vs. baseline data, Wilcoxon paired t test. ^#P < 0.05 vs. control; Mann–Whitney U test. umbilical cord-MSC transfusions were initiated at month 0.

Fig. 3. Effects of umbilical cord-mesenchymal stem cell therapy on HIV-1-specific T-cell functions

Pooled data of the counts of IFN-γ (a) and IL-2 (b) SFCs per million peripheral blood mononuclear cells upon stimulation with HIV-1 gag1, gag2, nef and CMVpp65 peptide pools in seven umbilical cord-mesenchymal stem cell (MSC)-treated patients (dots) and six control patients (circles). *P < 0.05 vs. baseline data in treated patients, Wilcoxon paired t test. ^#P < 0.05 vs. control, Mann-Whitney U test. umbilical cord-MSC transfusions were initiated at month 0.

Fig. 4. Effects of umbilical cord mesenchymal stem cell therapy on co-inhibitory molecules and activation markers on CD8 T cells

umbilical cord-mesenchymal stem cell (MSC) transfusions significantly downregulated PD-1 expression (a), upregulated BTLA expression (b), and reduced CD38 and HLA-DR (c) and Ki67 (d) expression on total CD4 and CD8 T cells as well as HIV-1-specific pentamer⁺ CD8 T cells in umbilical cord-MSC-treated patients (dots) and control patients (circles). Means ± SD for each cohort are shown. *P < 0.05 vs. baseline data, Wilcoxon paired t test. ^#P < 0.05 vs. control, Mann–Whitney U test. Umbilical cord-MSC transfusions were initiated at month 0.