scholarly journals Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8+T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

2015 ◽  
Vol 89 (7) ◽  
pp. 3723-3736 ◽  
Author(s):  
Kiera L. Clayton ◽  
Matthew B. Douglas-Vail ◽  
A. K. M. Nur-ur Rahman ◽  
Karyn E. Medcalf ◽  
Irene Y. Xie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Disease Progression ◽  
Human Plasma ◽  
Soluble Form ◽  
Hiv Disease ◽  
Cell Exhaustion ◽  
Domain 3 ◽  
Chronic Hiv Infection

ABSTRACTChronic HIV infection results in a loss of HIV-specific CD8+T cell effector function, termed “exhaustion,” which is mediated, in part, by the membrane coinhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized, and its role in HIV disease is unknown. Here, we show that Tim-3 is shed from the surface of responding CD8+T cells by the matrix metalloproteinase ADAM10, producing a soluble form of the coinhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma and was significantly elevated during early and chronic untreated HIV infection, but it was not found differentially modulated in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects or in elite controllers compared to HIV-uninfected subjects. Plasma sTim-3 levels were positively correlated with HIV load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8+T cells in terms of gamma interferon production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis, with implications for novel therapeutic interventions.IMPORTANCEDespite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression.

scholarly journals TIMs: central regulators of immune responses

2008 ◽  
Vol 205 (12) ◽  
pp. 2699-2701 ◽  
Author(s):  
David A. Hafler ◽  
Vijay Kuchroo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Viral Infections ◽  
Opportunistic Infections ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Responses ◽  
Chronic Viral Infections ◽  
Chronic Hiv Infection

Exhaustion of T cell responses during chronic viral infections has been observed in both mouse and man and has been attributed to up-regulation of PD-1 on the surface of exhausted T cells. In patients with chronic human HIV infection, T cell exhaustion leads to opportunistic infections associated with AIDS. However, not all the exhausted T cells express PD-1, suggesting that other molecules may be involved in the phenotype. A new study now demonstrates a central role for T cell immunoglobulin and mucin domain–containing protein-3 (TIM-3) in T cell exhaustion during chronic HIV infection and suggests that TIM-3 may be a novel therapeutic target in chronic viral diseases.

scholarly journals The combination of CXCL9, CXCL10 and CXCL11 levels during primary HIV infection predicts HIV disease progression

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiaowan Yin ◽  
Zhuo Wang ◽  
Tong Wu ◽  
Meichen Ma ◽  
Zining Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Cell Count ◽  
Disease Progression ◽  
Risk Score ◽  
Point Group ◽  
Clinical Information ◽  
Hiv Disease ◽  
Set Point ◽  
Primary Hiv Infection

Abstract Background Chemokines are small chemotactic cytokines involved in inflammation, cell migration, and immune regulation in both physiological and pathological contexts. Here, we investigated the profile of chemokines during primary HIV infection (PHI). Methods Fifty-four participants with blood samples before and during HIV infection and clinical information available were selected from an HIV-negative man who have sex with men (MSM) prospective cohort. Thirty chemokines and 10 cytokines were measured pre- and post-HIV infection in the same individuals using a Bio-Plex Pro™ Human Chemokine Panel. Results Levels of 18 chemokines/cytokines changed significantly during PHI relative to pre-HIV infection levels; 14 were up-regulated and 4 down-regulated. Among them, CXCL9, CXCL10, and CXCL11 were the most prominently raised. Levels of CXCL9 and CXCL10 were much higher in the high-set point group (log viral load (lgVL) ≥ 4.5) than those in the low-set point group (lgVL < 4.5) and levels of CXCL9, CXCL10, and CXCL11 were higher in the low-CD4+ T-cell count group (CD4+ T-cell count ≥ 500). A formula to predict HIV disease progression using a combination panel comprising CXCL9, CXCL10, and CXCL11 was developed, where risk score = 0.007 × CXCL9 + 0.004 × CXCL10 − 0.033 × CXCL11 − 1.724, with risk score values higher than the cutoff threshold (0.5211) indicating more rapid HIV disease progression. Conclusions A panel of plasma CXCL9, CXCL10, and CXCL11 measured during primary HIV-1 infection could predict long-term HIV disease prognosis in an MSM group and has potential as a novel biomarker in the clinic.

scholarly journals CD8 T cells targeting adapted epitopes in chronic HIV infection promote dendritic cell maturation and CD4 T cell trans-infection

2019 ◽  
Vol 15 (8) ◽  
pp. e1007970 ◽  
Author(s):  
Kai Qin ◽  
Sushma Boppana ◽  
Victor Y. Du ◽  
Jonathan M. Carlson ◽  
Ling Yue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Dendritic Cell Maturation ◽  
Cd4 T Cell ◽  
Cell Maturation ◽  
Trans Infection ◽  
Chronic Hiv Infection

Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 4928-4938 ◽  
Author(s):  
Patricia Ribeiro-dos-Santos ◽  
Emma L. Turnbull ◽  
Marta Monteiro ◽  
Agnès Legrand ◽  
Karen Conrod ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Cell Functions ◽  
Chronic Hiv Infection

Abstract CD8 T cells lose the capacity to control HIV infection, but the extent of the impairment of CD8 T-cell functions and the mechanisms that underlie it remain controversial. Here we report an extensive ex vivo analysis of HIV-specific CD8 T cells, covering the expression of 16 different molecules involved in CD8 function or differentiation. This approach gave remarkably homogeneous readouts in different donors and showed that CD8 dysfunction in chronic HIV infection was much more severe than described previously: some Ifng transcription was observed, but most cells lost the expression of all cytolytic molecules and Eomesodermin and T-bet by chronic infection. These results reveal a cellular mechanism explaining the dysfunction of CD8 T cells during chronic HIV infection, as CD8 T cells are known to maintain some functionality when either of these transcription factors is present, but to lose all cytotoxic activity when both are not expressed. Surprisingly, they also show that chronic HIV and lymphocytic choriomeningitis virus infections have a very different impact on fundamental T-cell functions, “exhausted” lymphocytic choriomeningitis virus-specific cells losing the capacity to secrete IFN-γ but maintaining some cytotoxic activity as granzyme B and FasL are overexpressed and, while down-regulating T-bet, up-regulating Eomesodermin expression.

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

2004 ◽  
Vol 200 (6) ◽  
pp. 749-759 ◽  
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.

scholarly journals Overexpression of a Novel Lymphocyte Population, Positive for an Intracellular CD14-Like Antigen, in Patients Positive for Human Immunodeficiency Virus Type 1

2004 ◽  
Vol 11 (6) ◽  
pp. 1040-1044 ◽  
Author(s):  
Dan Turner ◽  
Michael Hoffman ◽  
Israel Yust ◽  
Mordechai Fried ◽  
Margalit Bleiberg ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Population ◽  
Human Peripheral Blood ◽  
Soluble Form ◽  
Lymphocyte Population ◽  
Cellular Marker ◽  
Immunodeficiency Virus

ABSTRACT CD14, originally recognized as a lipopolysaccharide (LPS) receptor, has recently been implicated in the process of T-cell suppression and apoptosis. Its soluble form has been shown to bind, in vitro, to human T cells, a process that may carry a negative signal onto these cells. We recently described a novel lymphocyte population in human peripheral blood, a population that expresses an intracellular CD14-like antigen. This novel T-cell population, composed mainly of CD8 cells and of very few CD4 cells, was found to be greatly enhanced in asymptomatic, untreated human immunodeficiency virus (HIV)-positive individuals. In the present study, we further characterized this cell population and found that it differed from other CD8 subpopulations associated with HIV infection such as CD8/CD38. In addition, we followed HIV patients under conditions of highly active antiretroviral therapy (HAART) and observed two groups of patients: patients in whom the CD14-like positive-testing T cells returned to normal within 1 to 3 months, and patients in whom it did not, in spite of a significant plasma HIV-RNA viral load decrease. Thus, this new CD14-like positive-testing lymphocyte population may represent an interesting and important component of the cellular events associated with HIV infection. On the basis of its modulation following HAART, we speculate that it may be used, in the future, as a drug-monitoring cellular marker in antiretroviral treatment.

scholarly journals HIV-Resistant and HIV-Specific CAR-Modified CD4+ T Cells Mitigate HIV Disease Progression and Confer CD4+ T Cell Help In Vivo

2020 ◽  
Vol 28 (7) ◽  
pp. 1585-1599 ◽  
Author(s):  
Colby R. Maldini ◽  
Kevin Gayout ◽  
Rachel S. Leibman ◽  
Derrick L. Dopkin ◽  
Joshua P. Mills ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Hiv Disease ◽  
Cd4 T Cell Help ◽  
T Cell Help

PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression

Nature ◽  
2006 ◽  
Vol 443 (7109) ◽  
pp. 350-354 ◽  
Author(s):  
Cheryl L. Day ◽  
Daniel E. Kaufmann ◽  
Photini Kiepiela ◽  
Julia A. Brown ◽  
Eshia S. Moodley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals Reduction of Immune Activation with Chloroquine Therapy during Chronic HIV Infection

2010 ◽  
Vol 84 (22) ◽  
pp. 12082-12086 ◽  
Author(s):  
Shannon M. Murray ◽  
Carrie M. Down ◽  
David R. Boulware ◽  
William M. Stauffer ◽  
Winston P. Cavert ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Immune Activation ◽  
Hiv Disease ◽  
Activated T Cells ◽  
Ki 67 ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Highly Correlated ◽  
Chronic Hiv Infection

ABSTRACT Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune activation during HIV infection. We found that the frequency of CD38+ HLA-DR+ CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain groups of HIV-infected individuals.

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