scholarly journals Chloroquine Modulates HIV-1-Induced Plasmacytoid Dendritic Cell Alpha Interferon: Implication for T-Cell Activation

2009 ◽  
Vol 54 (2) ◽  
pp. 871-881 ◽  
Author(s):  
Jeffrey A. Martinson ◽  
Carlos J. Montoya ◽  
Xiomara Usuga ◽  
Rollie Ronquillo ◽  
Alan L. Landay ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Activation ◽  
Highly Active Antiretroviral Therapy ◽  
Cell Activation ◽  
Plasmacytoid Dendritic Cell ◽  
Chronic Phase ◽  
T Cell Response ◽  
Type I ◽  
Hiv 1

ABSTRACT Plasmacytoid dendritic cells (pDC) contribute to antiviral immunity mainly through recognition of microbial products and viruses via intracellular Toll-like receptor 7 (TLR7) or TLR9, resulting in the production of type I interferons (IFNs). Although interferons reduce the viral burden in the acute phase of infection, their role in the chronic phase is unclear. The presence of elevated plasma IFN-α levels in advanced HIV disease and its association with microbial translocation in chronic HIV infection lead us to hypothesize that IFN-α could contribute to immune activation. Blocking of IFN-α production using chloroquine, an endosomal inhibitor, was tested in a novel in vitro model system with the aim of characterizing the effects of chloroquine on HIV-1-mediated TLR signaling, IFN-α production, and T-cell activation. Our results indicate that chloroquine blocks TLR-mediated activation of pDC and MyD88 signaling, as shown by decreases in the levels of the downstream signaling molecules IRAK-4 and IRF-7 and by inhibition of IFN-α synthesis. Chloroquine decreased CD8 T-cell activation induced by aldrithiol-2-treated HIV-1 in peripheral blood mononuclear cell cultures. In addition to blocking pDC activation, chloroquine also blocked negative modulators of the T-cell response, such as indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PDL-1). Our results indicate that TLR stimulation and production of IFN-α by pDC contribute to immune activation and that blocking of these pathways using chloroquine may interfere with events contributing to HIV pathogenesis. Our results suggests that a safe, well-tolerated drug such as chloroquine can be proposed as an adjuvant therapeutic candidate along with highly active antiretroviral therapy to control immune activation in HIV-1 infection.

scholarly journals Better Viral Control despite Higher CD4+ T Cell Activation during Acute HIV-1 Infection in Zambian Women Is Linked to the Sex Hormone Estradiol

2020 ◽  
Vol 94 (16) ◽  
Author(s):  
Elina El-Badry ◽  
Gladys Macharia ◽  
Daniel Claiborne ◽  
Kelsie Brooks ◽  
Darío A. Dilernia ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Acute Infection ◽  
Chronic Phase ◽  
Cell Loss ◽  
Viral Control ◽  
Acute Hiv ◽  
17Β Estradiol ◽  
Hiv 1

ABSTRACT The influence of biological sex on disease progression in HIV-1-infected individuals has been focused on the chronic stage of infection, but little is known about how sex differences influence acute HIV-1 infection. We observed profound differences in viral load and CD4+ T cell activation from the earliest time points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a >2-fold higher rate of CD4+ T cell loss despite significantly lower viral loads (VL) than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4+ T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4+ T cells in the acute phase was significantly correlated with plasma levels of 17β-estradiol (E2). However, unlike in men, higher CD4+ T cell activation in women was not associated with higher VL. In contrast, a higher E2 level in early infection was associated with lower early and set-point VL in women. We attribute this to an inhibitory effect of estradiol on virus replication, which we were able to observe with relevant transmitted/founder viruses in vitro. Thus, estradiol plays a key role in defining major differences between men and women during early HIV-1 infection by contributing to both viral control and CD4+ T cell loss, an effect that extends into the chronic phase of the disease. IMPORTANCE Previous studies have identified sex-specific differences during chronic HIV-1 infection, but little is known about sex differences in the acute phase, or how disparities in the initial response to the virus may affect disease. We demonstrate that restriction of viral load in women begins during acute infection and is maintained into chronic infection. Despite this, women exhibit more rapid CD4+ T cell loss than men. These profound differences are influenced by 17β-estradiol, which contributes both to T cell activation and to reduced viral replication. Thus, we conclude that estradiol plays a key role in shaping responses to early HIV-1 infection that influence the chronic phase of disease.

scholarly journals Analysis of type I IFN response and T cell activation in severe COVID-19/HIV-1 coinfection

Medicine ◽  
2020 ◽  
Vol 99 (36) ◽  
pp. e21803 ◽  
Author(s):  
Gabriella d’Ettorre ◽  
Gregorio Recchia ◽  
Marco Ridolfi ◽  
Guido Siccardi ◽  
Claudia Pinacchio ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Type I ◽  
Type I Ifn ◽  
Hiv 1

scholarly journals Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression

2015 ◽  
Vol 112 (12) ◽  
pp. E1480-E1489 ◽  
Author(s):  
Daniel T. Claiborne ◽  
Jessica L. Prince ◽  
Eileen Scully ◽  
Gladys Macharia ◽  
Luca Micci ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
T Cell Activation ◽  
Immune Activation ◽  
Cell Activation ◽  
Viral Reservoir ◽  
Replicative Fitness ◽  
Cell Decline ◽  
Protective Genes ◽  
Hiv 1

HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1–induced immunopathology and subsequent CD4+ T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8+ T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4+ T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1–related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.

scholarly journals Sex-Based Differences in Human Immunodeficiency Virus Type 1 Reservoir Activity and Residual Immune Activation

2018 ◽  
Vol 219 (7) ◽  
pp. 1084-1094 ◽  
Author(s):  
Eileen P Scully ◽  
Monica Gandhi ◽  
Rowena Johnston ◽  
Rebecca Hoh ◽  
Ainsley Lockhart ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
T Cell Activation ◽  
Immune Activation ◽  
Cell Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in women are lower early in untreated HIV-1 infection compared with those in men, but women have higher T-cell activation and faster disease progression when adjusted for viral load. It is not known whether these sex differences persist during effective antiretroviral therapy (ART), or whether they would be relevant for the evaluation and implementation of HIV-1 cure strategies. We prospectively enrolled a cohort of reproductive-aged women and matched men on suppressive ART and measured markers of HIV-1 persistence, residual virus activity, and immune activation. The frequency of CD4+ T cells harboring HIV-1 DNA was comparable between the sexes, but there was higher cell-associated HIV-1 RNA, higher plasma HIV-1 (single copy assay), and higher T-cell activation and PD-1 expression in men compared with women. These sex-related differences in immune phenotype and HIV-1 persistence on ART have significant implications for the design and measurement of curative interventions.

scholarly journals Chronic CD4+ T-Cell Activation and Depletion in Human Immunodeficiency Virus Type 1 Infection: Type I Interferon-Mediated Disruption of T-Cell Dynamics

2007 ◽  
Vol 82 (4) ◽  
pp. 1870-1883 ◽  
Author(s):  
Ahmad R. Sedaghat ◽  
Jennifer German ◽  
Tanya M. Teslovich ◽  
Joseph Cofrancesco ◽  
Chunfa C. Jie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Type I Interferon ◽  
Type I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The mechanism of CD4+ T-cell depletion during chronic human immunodeficiency virus type 1 (HIV-1) infection remains unknown. Many studies suggest a significant role for chronic CD4+ T-cell activation. We assumed that the pathogenic process of excessive CD4+ T-cell activation would be reflected in the transcriptional profiles of activated CD4+ T cells. Here we demonstrate that the transcriptional programs of in vivo-activated CD4+ T cells from untreated HIV-positive (HIV+) individuals are clearly different from those of activated CD4+ T cells from HIV-negative (HIV−) individuals. We observed a dramatic up-regulation of cell cycle-associated and interferon-stimulated transcripts in activated CD4+ T cells of untreated HIV+ individuals. Furthermore, we find an enrichment of proliferative and type I interferon-responsive transcription factor binding sites in the promoters of genes that are differentially expressed in activated CD4+ T cells of untreated HIV+ individuals compared to those of HIV− individuals. We confirm these findings by examination of in vivo-activated CD4+ T cells. Taken together, these results suggest that activated CD4+ T cells from untreated HIV+ individuals are in a hyperproliferative state that is modulated by type I interferons. From these results, we propose a new model for CD4+ T-cell depletion during chronic HIV-1 infection.

scholarly journals High CD8+ T Cell Activation Marks a Less Differentiated HIV-1 Specific CD8+ T Cell Response that Is Not Altered by Suppression of Viral Replication

PLoS ONE ◽  
2009 ◽  
Vol 4 (2) ◽  
pp. e4408 ◽  
Author(s):  
Jason D. Barbour ◽  
Lishomwa C. Ndhlovu ◽  
Qi Xuan Tan ◽  
Terence Ho ◽  
Lorrie Epling ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
T Cell Activation ◽  
Cell Response ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Hiv 1
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