Frequency of Circulating Regulatory T Cells Increases during Chronic HIV Infection and Is Largely Controlled by Highly Active Antiretroviral Therapy

Abstract

Regulatory T cells (Tregs) act by suppressing the activation and effector functions of innate and adaptive immune responses. HIV infection impacts Treg proportion and phenotype, although discrepant results have been reported depending on the patient population and the way Tregs were characterized. The effects of highly active antiretroviral therapy (HAART) on Treg frequency have not been thoroughly documented. We performed a detailed longitudinal analysis of Treg frequency and phenotype in 11 HIV-infected individuals enrolled in a single, prospective clinical trial, in which all patients underwent the same treatment protocol and were sampled at the same time points. Tregs were characterized for their expression of molecules associated with activation, cell cycle, apoptosis, or function, and compared to circulating Tregs from a group of age-matched healthy individuals.Our results revealed increased proportions, but reduced absolute numbers of circulating CD3+CD4+FOXP3+ Tregs in chronically infected HIV-infected patients. Treg frequency was largely normalized by HAART. Importantly, we show that similar conclusions were drawn regardless of the combination of markers used to define Tregs. Our results also showed increased expression of cell cycle markers (Ki67 and cyclin B) in Tregs from untreated infected individuals, which were decreased by HAART. However, the Treg phenotype in untreated patients was not consistent with a higher level of generalized activation, as they expressed very low levels of CD69, slightly elevated levels of HLA-DR and similar levels of GARP compared to Tregs from uninfected donors. Moreover, none of these markers was significantly changed by HAART. Treg expression of CTLA-4 and cytotoxic molecules was identical between patients and controls. The most striking difference in terms of functional molecules was the high expression of CD39 by Tregs in untreated patients, which HAART only partially controlled.

CD25+FoxP3+Memory CD4 T Cells Are Frequent Targets of HIV InfectionIn Vivo

“…Although frequencies of CD25 ϩ FoxP3 ϩ CD4 T cells were slightly elevated in viremic, HIV ϩ subjects, absolute cell numbers of this subset were significantly depleted, which confirms previously published data (50,52,66). A greater proportion of CD25 ϩ FoxP3 ϩ memory CD4 T cells from HIV ϩ subjects expressed Ki67 ϩ , with almost one-third of these cells "cycling" at any given time.…”

Homeostasis and Function of Regulatory T Cells in HIV/SIV Infection

“…Furthermore, the same antibody did not increase effector immune responses during the acute phase (17). Recently, we and others found an upregulation of CD39 expression by Tregs of HIV-infected subjects (63,71,80). Blockade of CD39 relieved, although not completely, the suppressive effect of Tregs on effector T cells (63).…”

“…In agreement with this hypothesis, we and other groups have reported increased Ki67 expression in circulating Tregs from untreated, chronically infected patients. This increase was controlled by HAART (12, 50,71,98). Of note, a direct effect of HIV on Treg expansion has been hypothesized, as direct interaction of HIV with Tregs induced their expansion and promoted the expression of FOXP3, CD25, and CTLA-4 (3).…”

“…In addition to their role in controlling peripheral tolerance, Tregs promote the establishment of multiple persistent infections (viral, bacterial, parasitic, and fungal) (reviewed in reference 10). In most studies, Treg frequency was found to be substantially increased during the chronic phase of HIV infection (4,7,12,19,28,63,65,71,80,82,96). Thus, Tregs may contribute substantially to inefficient CMI during HIV infection.…”

Immunological Function Restoration with Lopinavir/Ritonavir Versus Efavirenz Containing Regimens in HIV-Infected Patients: A Randomized Clinical Trial

“…+ T cells, [21][22][23] thymic recent emigrants, 24 and CD127 (IL-7 receptor involved in T cell homeostasis) expression on T cells, 25,26 as well as a decrease of effector memory T cells, 27 Treg cells, 28 and markers of activation, senescence, exhaustion, and apoptosis. [13][14][15]29 However, as reported previously by our group and other authors, cART did not have an effect on lymph node fibrosis after 1 year of treatment.…”