IL-8 Alterations in HIV-1 Infected Children With Disease Progression

Pananghat, Ambili Nair; Aggarwal, Heena; Prakash, Sneha; Makhdoomi, Muzamil Ashraf; Singh, Ravinder; Lodha, Rakesh; Ali, Shakir; Srinivas, M; Das, Bimal Kumar; Pandey, Ravindra Mohan; Kabra, S. K.; Luthra, Kalpana

doi:10.1097/md.0000000000003734

Cited by 21 publications

(16 citation statements)

References 53 publications

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“…Increased IL-8 plasma levels in cancer patients predict increased disease severity [64][65][66][67]. Consistently, published data in HIV infection has shown that increased IL-8 levels correlate with mortality, reduced CD4 cell count and increased viral load [28][29][30][31][32][33]. In a study of HIV/tuberculosis coinfected patients, a direct association of plasma IL-8 levels was found with frequencies of granulocytes and their capacity to migrate in response to IL-8.…”

Section: Discussionsupporting

confidence: 62%

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High frequencies of PMN-MDSCs are associated with low suppressive capacity in advanced stages of HIV-1 infection

et al. 2020

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Background: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are an immature cell type that inhibits the effector functions of T lymphocytes in chronic HIV infection. A well-known immunological feature of the disease course is the development of immune exhaustion, which is correlated with excessive immune activation in late-stage disease. Here, we hypothesized that immune exhaustion would also affect PMN-MDSCs in late-stage HIV-1 infection. Methods: We evaluated untreated chronically HIV-infected patients (progressors, n = 10) and control groups (controllers, patients with non-small cell lung carcinoma and healthy controls, n = 16) with regard to levels of PMN-MDSCs and their inhibitory potential. Additionally, we studied CD8 T cell effector functions (interferon-gamma, TNF alpha, IL-2 and CD107) and parameters of CD8 T cell activation (CD38 and HLA-DR) and exhaustion (PD-1 and LAG-3) by flow cytometry. Plasma inflammation markers analyzed here were IL-6, IL-8, soluble CD14, highly sensitive CRP, and cystatin C. Results: Coincubation experiments with isolated PMN-MDSCs led to a significant inhibition of CD8 T cell proliferation (p < 0.0001), with a significant correlation between PMN-MDSC frequency and suppressive capacity: the higher the frequency of PMN-MDSCs was, the lower the suppressive capacity (rho = 0.51, p = 0.0082). Stratifying all study subjects into subgroups with PMN-MDSC frequencies above or below 2.5% resulted in a significantly increased suppressive capacity in patients with frequencies below 2.5% (p = 0.021). While there was no correlation with the cellular activation markers CD38 and HLA-DR, high IL-8 levels were significantly associated with high PMN-MDSC frequencies (rho = 0.52, p = 0.0074) and low suppressive capacity (rho = 0.47, p = 0.019). Conclusions: In this study, we demonstrate for the first time that PMN-MDSCs show limited effector functions in advanced disease stages of HIV infection. The hyperactive immune state is associated with this loss of function. However, we show an association with the proinflammatory cytokine IL-8, which is an important factor for the migration and adhesion of polymorphonuclear cells.

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Section: Discussionsupporting

confidence: 62%

“…IL-8 is an important factor for the migration and activation of polymorphonuclear cells, which include PMN-MDSCs. In the context of HIV infection, IL-8 has been studied extensively and has been shown to be a marker of immune activation in HIV disease with relevance to polymorphonuclear cells [27][28][29][30][31][32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

High frequencies of PMN-MDSCs are associated with low suppressive capacity in advanced stages of HIV-1 infection

et al. 2020

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“…Also observed was a higher expression of CXCL8 in untreated HIV-1-infected progressors and cART nonresponders compared to long-term nonprogressors and cART responders, respectively. Furthermore, a negative correlation of plasma levels of CXCL8 with CD4 counts was found in HIV-1-infected cART-naive subjects, whereas the CXCL8 levels positively correlated with viral load in the cART-treated children (27). These observations suggest a strong link between CXCL8 through its proinflammatory action to viral replication and disease progression.…”

Section: Discussionmentioning

confidence: 77%

HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood

Hocini

Bonnabau

Lacabaratz

et al. 2019

J Virol

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HIV controllers (HIC) maintain control of HIV replication without combined antiretroviral treatment (cART). The mechanisms leading to virus control are not fully known. We used gene expression and cellular analyses to compare HIC and HIV-1-infected individuals under cART. In the blood, HIC are characterized by a low inflammation, a downmodulation of natural killer inhibitory cell signaling, and an upregulation of T cell activation gene expression. This balance that persists after stimulation of cells with HIV antigens was consistent with functional analyses showing a bias toward a Th1 and cytotoxic T cell response and a lower production of inflammatory cytokines. Taking advantage of the characterization of HIC based upon their CD8+ T lymphocyte capacity to suppress HIV-infection, we show here that unsupervised analysis of differentially expressed genes fits clearly with this cytotoxic activity, allowing the characterization of a specific signature of HIC. These results reveal significant features of HIC making the bridge between cellular function, gene signatures, and the regulation of inflammation and killing capacity of HIV-specific CD8+ T cells. Moreover, these genetic profiles are consistent through analyses performed from blood to peripheral blood mononuclear cells and T cells. HIC maintain strong HIV-specific immune responses with low levels of inflammation. Our findings may pave the way for new immunotherapeutic approaches leading to strong HIV-1-specific immune responses while minimizing inflammation. IMPORTANCE A small minority of HIV-infected patients, called HIV controllers (HIC), maintains spontaneous control of HIV replication. It is therefore important to identify mechanisms that contribute to the control of HIV replication that may have implications for vaccine design. We observed a low inflammation, a downmodulation of natural killer inhibitory cell signaling, and an upregulation of T-cell activation gene expression in the blood of HIC compared to patients under combined antiretroviral treatment. This profile persists following in vitro stimulation of peripheral blood mononuclear cells with HIV antigens, and was consistent with functional analyses showing a Th1 and cytotoxic T cell response and a lower production of inflammatory cytokines. These results reveal significant features of HIC that maintain strong HIV-specific immune responses with low levels of inflammation. These findings define the immune status of HIC that is probably associated with the control of viral load.

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“…Disease progression in HIV-1 infection involves a complex set of interactions between viral and host factors leading to a chronic immune activation state. Inflammation has been shown to be a contributing factor, in addition to T cell activation, towards disease progression and mortality ( 13 ). In viremic individuals, it has long been recognized that viral replication may not solely be responsible for disease progression; immune activation status being an important determinant too ( 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…The pediatric model affords several advantages for studying virus-host interactions, including the information on virus source and time of exposure ( 11 ). In infants who are exposed to HIV-1, innate immunity is of particular relevance in conferring protection since the adaptive immune system is still under development ( 12 , 13 ). There is a paucity of information on the interactions between innate and adaptive immune response in HIV-1 infection that influences disease progression in infected children.…”

Section: Introductionmentioning

confidence: 99%

Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children

et al. 2017

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Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10–20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naïve children and 25 seronegative controls were recruited. Based on the CD4 counts and years post-infection, infected children were categorized as long-term non-progressors (LTNPs) (n = 20) and progressors (n = 18). Eight of these progressors were followed up at 6–12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naïve progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1-infected children.

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IL-8 Alterations in HIV-1 Infected Children With Disease Progression

Abstract: Supplemental Digital Content is available in the text

Cited by 21 publications

References 53 publications

High frequencies of PMN-MDSCs are associated with low suppressive capacity in advanced stages of HIV-1 infection

High frequencies of PMN-MDSCs are associated with low suppressive capacity in advanced stages of HIV-1 infection

HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood

Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children

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