Loss of CD127 expression links immune activation and CD4+ T cell loss in HIV infection

ABSTRACT Macrophage dysfunction is associated with increased tuberculosis (TB) susceptibility in patients with human immunodeficiency virus (HIV) infection. However, the mechanisms underlying how HIV infection impairs macrophage function are unclear. Here, we found that levels of autoantibodies against red blood cells (RBCs) were significantly elevated in patients with HIV as determined by direct antiglobulin test (DAT). DAT positivity was significantly associated with TB incidence in both univariate and multivariate analyses (odds ratio [OR] = 11.96 [confidence interval {CI}, 4.68 to 30.93] and 12.65 [3.33 to 52.75], respectively). Ex vivo analysis showed that autoantibodies against RBCs enhanced erythrophagocytosis and thus significantly impaired macrophage bactericidal function against intracellular Mycobacterium tuberculosis. Mechanistically, autoantibody-mediated erythrophagocytosis increased heme oxygenase-1 (HO-1) expression, which inhibited M. tuberculosis-induced autophagy in macrophages. Silencing ATG5, a key component for autophagy, completely abrogated the effect of erythrophagocytosis on macrophage bactericidal activity against M. tuberculosis. In conclusion, we have demonstrated that HIV infection increases autoantibody-mediated erythrophagocytosis. This process impairs macrophage bactericidal activity against M. tuberculosis by inhibiting HO-1-associated autophagy. These findings reveal a novel mechanism as to how HIV infection increases TB susceptibility. IMPORTANCE HIV infection significantly increases TB susceptibility due to CD4 T-cell loss and macrophage dysfunction. Although it is relatively clear that CD4 T-cell loss represents a direct effect of HIV infection, the mechanism underlying how HIV infection dampens macrophage function is unknown. Here, we show that HIV infection enhances autoantibody-mediated erythrophagocytosis, which dampens macrophage bactericidal activity against TB by inhibiting HO-1-associated autophagy. Our findings reveal a novel mechanism explaining how HIV infection increases susceptibility to TB. We propose that DAT could be a potential measure to identify HIV patients who are at high TB risk and who would be suitable for anti-TB chemotherapy preventive treatment.

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CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract

Journal of Experimental Medicine ◽

10.1084/jem.20040874 ◽

2004 ◽

Vol 200 (6) ◽

pp. 749-759 ◽

Cited By ~ 1217

Author(s):

Jason M. Brenchley ◽

Timothy W. Schacker ◽

Laura E. Ruff ◽

David A. Price ◽

Jodie H. Taylor ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Immune Activation ◽

Cd4 T Cell ◽

Cell Depletion ◽

Collagen Deposition ◽

Hiv Disease ◽

Gi Tract ◽

T Cell Depletion

The mechanisms underlying CD4+ T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4+ and CD8+ T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4+ T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5+ CD4+ T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4+ T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5+ CD4+ T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation.

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HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients

The Journal of Immunology ◽

10.4049/jimmunol.1501588 ◽

2016 ◽

Vol 196 (4) ◽

pp. 1768-1779 ◽

Cited By ~ 17

Author(s):

Anjali Joshi ◽

Melina Sedano ◽

Bethany Beauchamp ◽

Erin B. Punke ◽

Zuber D. Mulla ◽

...

Keyword(s):

T Cell ◽

Immune Activation ◽

Cell Loss ◽

Cd4 T Cell ◽

Hiv Patients ◽

Hiv 1 ◽

Env Glycoprotein

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CD4 T-Cell Responses in Primary HIV Infection: Interrelationship with Immune Activation and Virus Burden

Frontiers in Immunology ◽

10.3389/fimmu.2016.00395 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 7

Author(s):

Mathieu F. Chevalier ◽

Céline Didier ◽

Pierre-Marie Girard ◽

Maria E. Manea ◽

Pauline Campa ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

Immune Activation ◽

T Cell Responses ◽

Cd4 T Cell ◽

Primary Hiv Infection ◽

Cell Responses

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Immune Activation Correlates Better Than HIV Plasma Viral Load with CD4 T-Cell Decline During HIV Infection

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/00126334-200108010-00010 ◽

2001 ◽

Vol 27 (4) ◽

pp. 389-397 ◽

Cited By ~ 50

Author(s):

Qibin Leng ◽

Gadi Borkow ◽

Ziva Weisman ◽

Miguel Stein ◽

Alexander Kalinkovich ◽

...

Keyword(s):

Viral Load ◽

T Cell ◽

Hiv Infection ◽

Immune Activation ◽

Plasma Viral Load ◽

Cd4 T Cell ◽

Cell Decline ◽

Better Than

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Immune Activation Correlates Better Than HIV Plasma Viral Load with CD4 T-Cell Decline During HIV Infection

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/00042560-200108010-00010 ◽

2001 ◽

Vol 27 (4) ◽

pp. 389-397 ◽

Cited By ~ 21

Author(s):

Qibin Leng ◽

Gadi Borkow ◽

Ziva Weisman ◽

Miguel Stein ◽

Alexander Kalinkovich ◽

...

Keyword(s):

Viral Load ◽

T Cell ◽

Hiv Infection ◽

Immune Activation ◽

Plasma Viral Load ◽

Cd4 T Cell ◽

Cell Decline ◽

Better Than

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Microbial Translocation Does Not Drive Immune Activation in Ugandan Children Infected With HIV

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy495 ◽

2018 ◽

Vol 219 (1) ◽

pp. 89-100 ◽

Cited By ~ 8

Author(s):

Felicity C Fitzgerald ◽

Edouard Lhomme ◽

Kathryn Harris ◽

Julia Kenny ◽

Ronan Doyle ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

Immune Activation ◽

Microbial Translocation ◽

Molecular Techniques ◽

Cd4 T Cell ◽

Median Baseline ◽

Cell Percentage ◽

Percentage Points ◽

Cluster 2

Abstract Objective Immune activation is associated with morbidity and mortality during human immunodeficiency virus (HIV) infection, despite receipt of antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children. Methods Nineteen markers of immune activation and inflammation were measured over 96 weeks in HIV-infected Ugandan children in the CHAPAS-3 Trial and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques, including next-generation sequencing. Results Of 249 children included, 142 were infected with HIV; of these, 120 were ART naive, with a median age of 2.8 years (interquartile range [IQR], 1.7–4.0 years) and a median baseline CD4+ T-cell percentage of 20% (IQR, 14%–24%), and 22 were ART experienced, with a median age of 6.5 years (IQR, 5.9–9.2 years) and a median baseline CD4+ T-cell percentage of 35% (IQR, 31%–39%). The control group comprised 107 children without HIV infection. The median increase in the CD4+ T-cell percentage was 17 percentage points (IQR, 12–22 percentage points) at week 96 among ART-naive children, and the viral load was <100 copies/mL in 76% of ART-naive children and 91% of ART-experienced children. Immune activation decreased with ART use. Children could be divided on the basis of immune activation markers into the following 3 clusters: in cluster 1, the majority of children were HIV uninfected; cluster 2 comprised a mix of HIV-uninfected children and HIV-infected ART-naive or ART-experienced children; and in cluster 3, the majority were ART naive. Immune activation was low in cluster 1, decreased in cluster 3, and persisted in cluster 2. Blood microbial DNA levels were negative or very low across groups, with no difference between clusters except for Enterobacteriaceae organisms (the level was higher in cluster 1; P < .0001). Conclusion Immune activation decreased with ART use, with marker clustering indicating different activation patterns according to HIV and ART status. Levels of bacterial DNA in blood were low regardless of HIV status, ART status, and immune activation status. Microbial translocation did not drive immune activation in this setting. Clinical Trials Registration ISRCTN69078957.

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