Increased Sensitivity of CD4+ T-Effector Cells to CD4+CD25+ Treg Suppression Compensates for Reduced Treg Number in Asymptomatic HIV-1 Infection

Abstract

BackgroundIn HIV infection, uncontrolled immune activation and disease progression is attributed to declining CD4+CD25+FoxP3+ regulatory T-cell (Treg) numbers. However, qualitative aspects of Treg function in HIV infection, specifically the balance between Treg cell suppressive potency versus suppressibility of effector cells, remain poorly understood. This report addresses this issue.Methodology/Principal FindingsA classic suppression assay to measure CD4+CD45RO+CD25hi Treg cells to suppress the proliferation of CD4+CD45RO+CD25− effectors cells (E) following CD3/CD28 polyclonal stimulation was employed to compare the suppressive ability of healthy volunteers (N = 27) and chronic, asymptomatic, treatment naïve, HIV-infected subjects (N = 14). HIV-infected subjects displayed significantly elevated Treg-mediated suppression compared to healthy volunteers (p = 0.0047). Cross-over studies comparing Treg cell potency from HIV-infected versus control subjects to suppress the proliferation of a given population of allogeneic effector cells demonstrated increased sensitivity of CD4+CD25− effector cells from HIV-infected subjects to be suppressed, associated with reduced production of the Treg counter-regulatory cytokine, IL-17, rather than an increase in the suppressive potential of their CD4+CD25+ Treg cells. However, compared to controls, HIV+ subjects had significantly fewer absolute numbers of circulating CD4+CD25+FoxP3+ Treg cells. In vitro studies highlighted that one mechanism for this loss could be the preferential infection of Treg cells by HIV.Conclusions/SignificanceTogether, novel data is provided to support the contention that elevated Treg-mediated suppression may be a natural host response to HIV infection

Impact of HIV Infection and HAART Therapy on CD4 T Helper Cell Subset Expression and Function

“…However, it has been demonstrated that the relative frequency of Treg cells within the CD4 T cell population as a whole appears to increase during HIV infection while at the same time, the absolute numbers of Tregs decline(Schulze Zur, Thomssen et al, 2011). This is supported by several studies which indicated a gradual decline in Treg absolute numbers during HIV pathogenesis (Jiao, Fu et al, 2009;Prendergast, Prado et al, 2010;Thorborn, Pomeroy et al, 2010;Cao, Jamieson et al, 2009). In particular, in primary HIV infection in untreated individuals, HIV-specific Treg cells and suppressive activity decreased over a 24 month follow-up period (Kared, Lelievre et al, 2008).…”

The split personality of regulatory T cells in HIV infection

“…55,90 Most studies, however, were not able to discriminate the actual Treg potency from the sensitivity of effector cells to Treg suppression. To address this question, Treg activity was tested in both autologous and allogeneic systems in which Tregs from patients and healthy donors were cocultured with effector cells from a unique donor and vice versa.…”

HIV Nef Expression Favors the Relative Preservation of CD4+ T Regulatory Cells That Retain Some Important Suppressive Functions

“…Such a relative expansion of Treg accompanied by their depletion in absolute number has been described in HIV infection (7,(36)(37)(38)(39)(40). However, controversial findings have been reported on percentages and numbers of Treg in HIV-1-infected humans or SIV-infected macaques (reviewed in Refs.…”

“…[2][3][4][5][6]. Some groups found a lower frequency and absolute number (7)(8)(9)(10) of circulating Treg, whereas others reported them to be increased (11)(12)(13). Contrasting results were also obtained for Treg in lymphoid organs (2,14).…”