Increased ex vivo cell death of central memory CD4 T cells in treated HIV infected individuals with unsatisfactory immune recovery

Abstract

BackgroundHigh levels of ex vivo CD4 T-cell death and the accumulation of highly differentiated and/or immunosenescent T cells have been associated with poor CD4 T-cell recovery in treated HIV-infected individuals. However, the relationship between cell death and T-cell differentiation is still unclear.MethodsWe have analyzed cell death, immunosenescence and differentiation parameters in HAART-treated subjects (VL <50 copies/mL for more than 2 years) with CD4 T-cell count <350 cells/μL (immunodiscordant, n = 23) or >400 cells/μL (immunoconcordant, n = 33). We included 11 healthy individuals as reference.ResultsAs expected, suboptimal CD4 T-cell recovery was associated with low frequencies of naïve cells, high frequencies of transitional and effector memory cells and a subsequent low ratio of central/transitional memory cells in the CD4 compartment. These alterations correlated with spontaneous CD4 T-cell death. A deeper analysis of cell death in CD4 T-cell subsets showed increased cell death in memory cells of immunodiscordant individuals, mainly affecting central memory cells. Immunosenescence was also higher in immunodiscordant individuals albeit unrelated to cell death. The CD8 compartment was similar in both HIV-infected groups, except for an underrepresentation of naïve cells in immunodiscordant individuals.ConclusionImmunodiscordant individuals show alterations in memory CD4 T-cell differentiation associated with a short ex vivo lifespan of central memory cells and an in vivo low central/transitional memory cell ratio. These alterations may contribute to poor CD4 T-cell repopulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0601-2) contains supplementary material, which is available to authorized users.

Preserved immune functionality and high CMV-specific T-cell responses in HIV-infected individuals with poor CD4+ T-cell immune recovery

“…This study provides an analysis of T-cell functionality in a group of HIV-infected individuals with different CD4 + T-cell recovery upon virologically suppressive cART. Our data show that even thought immunodiscordant individuals have a skewed T-cell maturation profile 10 – 13 , T-cell polyfunctionality, assessed by cytokine production after polyclonal and HIV-specific stimulation, is preserved in those individuals. In addition, we have observed that the magnitude of CMV-specific response was differentially associated with state of CD4 + T-cell maturation in immunodiscordant and immunoconcordant or HIV-negative groups, likely related to a more frequent or intense subclinical CMV reactivation from latency in immunodiscordant individuals (Gómez-Mora et al .…”

“… 4 ), among others altered thymic production 5 , 6 , low nadir CD4 counts 7 , older age 8 , high levels of immune activation 5 , 7 , 9 and increased cell death 5 , 7 . Additionally, immunodiscordant individuals show a skewed T-cell maturation profile 10 – 13 , increased expression of markers of replicative senescence (CD28 + CD57 + ) 6 , 13 , 14 and high frequencies of programmed cell death protein-1 (PD-1)-expressing CD4 + T-cells 5 , 15 , a phenotype associated with immune exhaustion, and defined by loss of effector functions and proliferative capacity. However, it is unclear how these changes affect the functional diversity (i.e.…”

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

“…also found that activated CD4 + T cells were significantly inversely correlated with current and nadir CD4 + T‐cell counts . It was reported that INRs showed increased levels of immune activation, mainly in CD4 + T cells; increased levels of proliferation; and increased rates of spontaneous CD4 + T‐cell death by apoptosis . These studies indicate that activated‐mediated CD4 + T‐cell hyperproliferation and spontaneous cell death may impede immune recovery in HIV‐1‐infected individuals.…”

“…Total CD4 + T-cell count > 400 cells/µl at 2 years after ART initiation, with plasma HIV RNA < 50 copies/ml. 48,105,106,241 Total CD4 + T-cell count < 350 cells/µl and/or increase in the CD4 + T-cell count < 30% from baseline at 1-10 years after ART initiation, with an undetectable plasma VL.…”

Dissecting How CD4 T Cells Are Lost During HIV Infection

“…Importantly, a subset of these patients is classified as “immunological nonresponders.” Despite the introduction of antiretroviral therapy, CD4 T cell counts remain low in these individuals. They also are distinguished by higher-than-expected levels of inflammation and immune activation (Gazzola et al, 2009; Massanella et al, 2015; Robbins et al, 2009). Thus, paradoxically, systemic inflammation in HIV-infected patients appears to persist in these individuals even when viral replication is effectively suppressed.…”