Severe Immune Dysregulation Affects CD4+CD25hiFoxP3+ Regulatory T Cells in HIV-Infected Patients With Low-level CD4 T-Cell Repopulation Despite Suppressive Highly Active Antiretroviral Therapy

Abstract

We hypothesized that CD4(+)CD25(hi)FoxP3(+) regulatory T cells (Tregs) could be involved in the high immune activation existing in patients with low-level CD4 T-cell repopulation under suppressive high active antiretroviral therapy (hereafter, "LLR patients"). Sixteen LLR patients, 18 human immunodeficiency virus (HIV)-infected controls (hereafter, "HIV controls"), and 16 healthy subjects were included. The frequency of CD4(+)CD25(hi)FoxP3(+) and HIV-specific Treg suppressive function were assessed. Relationships between Treg and CD4/CD8 activation (HLA-DR/CD38) and the frequency of naive CD4 T-cells were assessed. Low-level patients showed a higher Treg frequency but reduced HIV-specific immunosuppressive functions than HIV controls. Whereas in healthy subjects a strong negative correlation between Tregs and activated CD8 T cells emerged (r = -0.75, P < .001), it appeared disrupted in both HIV-infected groups (r = -0.06 and P = .83 for LLR patients; r = -0.11 and P = .68 for and HIV controls). Nevertheless, in LLR patients, Tregs negatively correlated with naive CD4 T cells (r = -0.60, P = .01), whereas there was no such correlation in HIV controls (r = -0.19, P = .46) or healthy subjects (r = -0.10, P = .73). Remarkably, a higher ratio of Tregs to naive CD4 T cells was observed in LLR patients than in HIV controls (P = .001) and healthy subjects (P < .001). We conclude that LLR patients have important alterations in immunoregulation involving CD4(+)CD25(hi)FoxP3(+) Tregs. In this scenario, the role of Tregs seems to be more related to the control of the naive CD4 T-cell homeostatic proliferation, rather than to the immune activation.

HIV Infection Deregulates the Balance Between Regulatory T Cells and IL-2–Producing CD4 T Cells by Decreasing the Expression of the IL-2 Receptor in Treg

“…Additionally, our previous data suggest that a suppressor antiretroviral treatment could not be able to restore such Treg-associated disturbance because the balance between Treg and IL-2-producing CD4 T cells was also found to be disrupted in aviremic HIVinfected patients, who had been treated for at least 2 years. 12 Future designs are encouraged to test whether this disturbance could also be contributing to the residual hyperactivation of successfully treated HIV-infected patients. Numerous authors report that decreased absolute counts of Treg in HIV-infected patients were correlated with rising markers of immune activation.…”

“…12 Briefly, Treg-depleted PBMC were stained with 5-(and -6)-carboxyfluorescein diacetate succinimidyl ester, then stimulated with phytohemagglutinin, and restimulated 5 days later for 4 additional hours in the presence of Brefeldin A. CD4 + proliferating cells (CFSElow) were analyzed by flow cytometry for intracellular IL-2 expression. Data are expressed as the percentage of IL-2 + T cells in CD4-gated T cells, and this percentage was correlated with the percentage of peripheral Treg (defined as CD4 + CD25 highFoxP3 + ) measured in each patient.…”

Immunodiscordant responses to HAART – mechanisms and consequences

“…Immunodiscordant patients show higher frequencies of Treg in the CD4 T-cell compartment [60], but lower frequency in the whole lymphocyte population [35]; however, their role in immune reconstitution remains unknown. One hypothesis could be that persistent low levels of Tregs in the lymphocyte population could be unable to turn off immune activation in immunodiscordant subjects [35].…”

“…One hypothesis could be that persistent low levels of Tregs in the lymphocyte population could be unable to turn off immune activation in immunodiscordant subjects [35]. However, within the CD4 T-cell compartment, in which higher frequencies are observed, Treg might control the naïve CD4 T-cell homeostatic proliferation and impact on immune reconstitution rather than immune activation [60].…”

CD4+CD25+CD127− assessment as a surrogate phenotype for FOXP3+ regulatory T cells in HIV‐1 infected viremic and aviremic subjects

“…Considering the potential clinical interest of monitoring Tregs during HIV infection (18)(19)(20), and the need to further investigate their role in the different steps of disease progression, (especially during the phase of viremia), the objective of the present study was to assess in fresh samples the correlation between frequencies of CD4þCD25þCD127À and CD4þCD25þFOXP3þ lymphocytes in viremic and matched-aviremic HIV infected patients.…”