High expression of CD8 in the tumor microenvironment is associated with PD-1 expression and patient survival in high-grade serous ovarian cancer.

Objective: The current study assesses programmed death-1 (PD-1) receptor expression and CD3, CD4, and CD8 tumor-infiltrating lymphocytes (TILs) in high-grade serous ovarian cancer (HGSOC) and associates our results with neoadjuvant chemotherapy history and disease prognosis.

Materials And Methods: We included cases diagnosed with primary HGSOC with biopsy or surgical resection materials in this study. The immunoreactivity of CD3, CD4, CD8, and PD1 was assessed immunohistochemically in tumor tissue.

MeCP2 deficiency impairs motor cortical circuit flexibility associated with motor learning.

Loss of function mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2) cause Rett syndrome (RTT), a postnatal neurological disorder. The loss of motor function is an important clinical feature of RTT that manifests early during the course of the disease. RTT mouse models with mutations in the murine orthologous Mecp2 gene replicate many human phenotypes, including progressive motor impairments.

Reinforcing locally led solutions for universal health coverage: a logic model with applications in Benin, Namibia and Uganda.

Development assistance for health programmes is often characterised as donor-led models with minimal country ownership and limited sustainability. This article presents new ways for low-income and middle-income countries to gain more control of their development assistance programming as they move towards universal health coverage (UHC). We base our findings on the experience of the African Collaborative for Health Financing Solutions (ACS), an innovative US Agency for International Development-funded project.

Vaginal epithelioid malignant peripheral nerve sheath tumor nearly misdiagnosed as advanced cervical cancer: A case report.

A 56-year-old woman was referred to our hospital with a pathological diagnosis of squamous cell carcinoma of the cervix. We performed a re-biopsy of the vaginal mass and cervical conization. The mass was originally reported as an epithelioid MPNST after re-biopsy.

Using electronic medication monitoring to guide differential management of tuberculosis patients at the community level in China.

Background: In settings such as China, where universal implementation of directly observed therapy (DOT) is not feasible, innovative approaches are needed to support patient adherence to TB treatment. The electronic medication monitor (EMM) is one of the digital technologies recommended by the World Health Organization (WHO), but evidence from implementation studies remains sparse. In this study, we evaluated acceptance of the EMM among health care workers and patients while implementing the device for differential TB patient management at the community level.

The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands.

The programmed death (PD)-1 molecule and its ligands (PD-L1 and PD-L2), negative regulatory members of the B7 family, play an important role in peripheral tolerance. Previous studies have demonstrated that PD-1 is up-regulated on T cells following TCR-mediated activation; however, little is known regarding PD-1 and Ag-independent, cytokine-induced T cell activation. The common gamma-chain (gamma c) cytokines IL-2, IL-7, IL-15, and IL-21, which play an important role in peripheral T cell expansion and survival, were found to up-regulate PD-1 and, with the exception of IL-21, PD-L1 on purified T cells in vitro.

CD25+ regulatory T cells isolated from HIV-infected individuals suppress the cytolytic and nonlytic antiviral activity of HIV-specific CD8+ T cells in vitro.

HIV infection is characterized by CD4(+) T cell depletion and progressive immune dysfunction; particularly impacted are HIV-specific T cell responses. An important component of immune-mediated control of HIV replication, killing of infected cells, appears to be impaired, in part due to poor cytolytic activity of HIV-specific cytotoxic T cells (CTL). In vitro, several functions of HIV-specific T cells, such as cytokine production, can be enhanced by the depletion of the immunosuppressive CD25(+) FoxP3(+) CD4(+) regulatory (Treg) cell subset.

Suppression of HIV-specific T cell activity by lymph node CD25+ regulatory T cells from HIV-infected individuals.

CD25(+) CD4(+) FoxP3(+) regulatory T (Treg) cells isolated from the peripheral blood of asymptomatic HIV-infected individuals have been demonstrated to significantly suppress HIV-specific immune responses in vitro. CD25(+) Treg cell suppressor activity in the peripheral blood seems to diminish with progression of HIV disease, and it has been suggested that loss of Treg cells contributes to aberrant immune activation and disease progression. However, phenotypic studies suggest that Treg cells may migrate to, and be maintained or even expanded in, tissue sites of HIV replication.

Correlates of preserved CD4(+) T cell homeostasis during natural, nonpathogenic simian immunodeficiency virus infection of sooty mangabeys: implications for AIDS pathogenesis.

In contrast to HIV-infected humans, naturally SIV-infected sooty mangabeys (SMs) very rarely progress to AIDS. Although the mechanisms underlying this disease resistance are unknown, a consistent feature of natural SIV infection is the absence of the generalized immune activation associated with HIV infection. To define the correlates of preserved CD4(+) T cell counts in SMs, we conducted a cross-sectional immunological study of 110 naturally SIV-infected SMs.

Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection.

In this study, we demonstrate that the in vitro interactions between a CD56(neg)/CD16(pos) (CD56(neg)) subset of natural killer (NK) cells and autologous dendritic cells (DCs) from HIV-1-infected viremic but not aviremic individuals are markedly impaired and likely interfere with the development of an effective immune response. Among the defective interactions are abnormalities in the process of reciprocal NK-DC activation and maturation as well as a defect in the NK cell-mediated editing or elimination of immature DCs (iDCs). Notably, the lysis of mature DCs (mDCs) by autologous NK cells was highly impaired even after the complete masking of major histocompatibility complex I molecules, suggesting that the defective elimination of autologous iDCs is at the level of activating NK cell receptors.

Identification of NKG2A and NKp80 as specific natural killer cell markers in rhesus and pigtailed monkeys.

Investigations of natural killer (NK) cells in simian models of disease have been hampered by a lack of appropriate phenotypic markers and by an inadequate understanding of the regulation of NK cell activities. In the present study, a panel of monoclonal antibodies (mAbs) specific for various human NK receptors was screened for cross-reactivity with NK cells from rhesus macaques and pigtailed macaques. Flow cytometric analyses using anti-human NKG2A and anti-human NKp80 mAbs individually, and particularly in combination with anti-CD16 mAb, allowed for the identification of the entire NK cell population in both species.

Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals.

Natural killer (NK) cells are an important component of the innate immune response against viral infections. NK cell-mediated cytolytic activity is defective in HIV-infected individuals with high levels of viral replication. In the present study, we examined the phenotypic and functional characteristics of an unusual CD56(-)/CD16(+) (CD56(-)) NK subset that is greatly expanded in HIV-viremic individuals.

Contrasting effects of low-dose IL-2 on vaccine-boosted simian immunodeficiency virus (SIV)-specific CD4+ and CD8+ T cells in macaques chronically infected with SIVmac251.

IL-2, the first cytokine discovered with T cell growth factor activity, is now known to have pleiotropic effects on T cells. For example, it can promote growth, survival, and differentiation of Ag-selected cells, or facilitate Ag-induced cell death of T cells when Ag persists, and in vivo, it is thought to contribute to the regulation of the size of adaptive T cell response. IL-2 is deficient in HIV-1 infection and has been used in the management of HIV-1-infected individuals undergoing antiretroviral therapy.

Neonatal natural killer cells produce chemokines and suppress HIV replication in vitro.

The innate immune system may be critical in the prevention of perinatal HIV infection. Since neonates have limited immunological experience, they may rely more on the ability of the innate immune system to defend against infection than their adult counterparts. To assess the potential of human neonatal natural killer (nNK) cells to suppress HIV infection in a noncytolytic manner, we evaluated their ability to secrete chemokines and inhibit HIV replication in vitro.

CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status.

Human immunodeficiency virus (HIV) disease is associated with loss of CD4(+) T cells, chronic immune activation, and progressive immune dysfunction. HIV-specific responses, particularly those of CD4(+) T cells, become impaired early after infection, before the loss of responses directed against other antigens; the basis for this diminution has not been elucidated fully. The potential role of CD25(+)CD4(+) regulatory T cells (T reg cells), previously shown to inhibit immune responses directed against numerous pathogens, as suppressors of HIV-specific T cell responses was investigated.

Productive HIV infection of resting CD4+ T cells: role of lymphoid tissue microenvironment and effect of immunomodulating agents.

The ability of resting CD4+ T cells to support HIV replication is relevant to understanding how the reservoir of HIV-1-infected resting CD4+ T cells is generated, maintained and, hopefully, how it might be reduced or eliminated. We have utilized a tonsillar histoculture system to demonstrate that HIV, particularly X4 strains, can productively infect phenotypically resting CD4+ T cells in vitro and that this event is largely dependent on the lymphoid tissue microenvironment. Highly purified CD4+ tonsillar T cells that lack expression of both cell surface and nuclear antigens characteristic of classic T cell activation produce X4 HIV-1 mRNA, p24, and infectious virus while maintaining a resting phenotype when cultured in a tonsillar tissue microenvironment; in contrast, comparable purified resting CD4+ tonsillar T cells that have been exposed to X4 HIV do not support HIV replication when cultured in the absence of a lymphoid tissue microenvironment.

HIV envelope induces virus expression from resting CD4+ T cells isolated from HIV-infected individuals in the absence of markers of cellular activation or apoptosis.

Resting CD4(+) T cells containing integrated HIV provirus constitute one of the long-lived cellular reservoirs of HIV in vivo. This cellular reservoir of HIV had been thought to be quiescent with regard to virus replication based on the premise that HIV production in T cells is inexorably linked to cellular activation as determined by classical activation markers. The transition of T cells within this HIV reservoir from a resting state to an activated HIV-producing state is believed to be associated with a shorten life span due to susceptibility to activation-associated apoptosis.

The effect of elective cesarean delivery and intrapartum infection on fetal lymphocyte activation and susceptibility to HIV infection.

Objective: Mother-to-child transmission of the human immunodeficiency virus may be reduced with elective cesarean delivery before labor. Because immune activation enhances the human immunodeficiency virus infection, we hypothesized that fetal lymphocytes that are obtained at elective cesarean delivery may be less activated, therefore less susceptible to human immunodeficiency virus infection than cells that are obtained after normal spontaneous vaginal delivery at term. A second hypothesis was that intrapartum infection correlates with increased lymphocyte activation and susceptibility to human immunodeficiency virus infection.

Interleukin (IL)-4 inhibits phorbol-ester induced HIV-1 expression in chronically infected U1 cells independently from the autocrine effect of endogenous tumour necrosis factor-alpha, IL-1beta, and IL-1 receptor antagonist.

The anti-inflammatory cytokine interleukin 4 (IL-4) has shown both inductive and inhibitory effects on the replication of the human immunodeficiency virus type 1 (HIV-1) in primary CD4+ T cells and mononuclear phagocytes. In this study, IL-4 did not induce virus production, but inhibited phorbol esters (PMA)-stimulated HIV expression in chronically infected promonocytic U1 cells. This effect, however, was not accounted for by a decreased secretion of endogenous TNF-alpha induced by phorbol myristate acetate (PMA).

Interleukin-6 and glucocorticoids synergistically induce human immunodeficiency virus type-1 expression in chronically infected U1 cells by a long terminal repeat independent post-transcriptional mechanism.

Background: Glucocorticoids (GC) such as dexamethasone (Dex) can directly upregulate human immunodeficiency virus type-1 (HIV-1) replication in acutely infected cells and potentiate HIV expression from chronically infected promonocytic U1 cells stimulated with tumor necrosis factor-alpha (TNF-alpha). We have here investigated the potential effect of Dex in U1 cells stimulated with interleukin-6 (IL-6), a cytokine inducing virus expression by acting mostly at a post-transcriptional level on the virus life cycle.

Materials And Methods: Virus production in culture supernatants was evaluated by reverse transcriptase (RT) activity.

Chemokines, cytokines and HIV: a complex network of interactions that influence HIV pathogenesis.

The important role of chemokine receptors in HIV pathogenesis is becoming increasingly apparent. The level at which certain chemokine receptors that serve as HIV co-receptors are available influences the susceptibility of a CD4+ cell to viral infection and to certain HIV envelope-induced alterations in cellular function. Numerous pathogens, including HIV, can stimulate the production of chemokines and cytokines from a variety of cell types.

Interactions of CCR5 and CXCR4 with CD4 and gp120 in human blood monocyte-derived dendritic cells.

Dendritic cells (DC) and macrophages play an important role in the generation of immune responses and transmission of HIV infection. It has been recently found that, in the presence of gp120, CD4 can be efficiently coimmunoprecipitated by anti-CXCR4 antibodies from lymphocytes and monocytes but not from blood monocyte-derived macrophages. The gp120-CD4-CXCR4 complex formation paralleled the ability for these cell types to support X4 (LAV) HIV-1 envelope glycoprotein (Env)-mediated fusion.

Differential effects of CD40 ligand/trimer stimulation on the ability of dendritic cells to replicate and transmit HIV infection: evidence for CC-chemokine-dependent and -independent mechanisms.

The role of exogenous stimulation of CD40 by CD40 ligand (CD40L) in dendritic cell (DC) maturation, CC-chemokine production, and CCR5 receptor expression was examined using a soluble trimeric CD40L agonist protein (CD40LT). Stimulation of monocyte-derived DCs with CD40LT enhanced the production of the CC-chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and RANTES and diminished surface expression of CCR5. Based on these findings, the functional role of CD40LT stimulation on the ability of DCs to replicate and transmit HIV viral infection was studied.

Peripheral blood-derived CD34+ progenitor cells: CXC chemokine receptor 4 and CC chemokine receptor 5 expression and infection by HIV.

The present study demonstrates cell surface expression of both CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5), major coreceptors for T cell-tropic and macrophage-tropic strains of HIV, respectively, on CD34+ progenitor cells derived from the peripheral blood. CD34+ progenitor cells were susceptible to infection by diverse strains of HIV, and infection could be sustained for prolonged periods in vitro. HIV entry into CD34+ progenitor cells could be modulated by soluble CD4, HIV gp120 third variable loop neutralizing mAb and the cognate ligands for the CXCR4 and CCR5 HIV coreceptors.