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Abstract: Innate immune responses are critical in the defense against viral infections. NK cells, myeloid and plasmacytoid dendritic cells, and invariant CD1d-restricted NKT cells mediate both effector and regulatory functions in this early immune response. In chronic uncontrolled viral infections such as HCV and HIV-1, these essential immune functions are compromised and can become a double edged sword contributing to the immunopathogenesis of viral disease. In particular, recent findings indicate that innate immune responses play a central role in the chronic immune activation which is a primary driver of HIV-1 disease progression. HCV/HIV-1 co-infection is affecting millions of people and is associated with faster viral disease progression. Here, we review the role of innate immunity and chronic immune activation in HCV and HIV-1 infection, and discuss how mechanisms of innate immunity may influence protection as well as immunopathogenesis in the HCV/HIV-1 co-infected human host. [Copyright &y& Elsevier]

Abstract: The programmed death (PD)-1 interacts with its ligand (PDL-1) delivering a negative signal to T cells. During human immunodeficiency virus (HIV)-1 infection PD-1 and PDL-1 expressions are increased. Here we show that monocytes and CCR5+ T cells of HIV-uninfected donors upregulated PDL-1 upon in vitro exposure to HIV. HIV-induced PDL-1 required interferon (IFN)-α, but not IFN-γ, production. Inhibition of endocytosis, required for HIV-induced IFN-α production, prevented PDL-1 upregulation. IFN-α-inducing Toll-like receptor (TLR) agonists increased PDL-1 on monocytes and CCR5+ T cells. CD80 and CD86 were also increased on monocytes and CCR5+ T cells after HIV exposure, but only CD80 was IFN-α-dependent. IFN-α-receptor subunit 2 (IFNAR2), was expressed only by CCR5+ T cells and monocytes, explaining why these leukocytes responded to HIV-induced IFN-α. Finally, T cell proliferation was improved by PDL-1 blockade in HIV-treated PBMC. In the setting of HIV infection, IFN-α may negatively affect T cell responses by inducing PDL-1. [Copyright &y& Elsevier]

Individuals over the age of 65 comprise a substantial portion of the world population and become more susceptible to vaccine-preventable infections with age as vaccination response diminishes. The underlying reason for this impaired vaccine response in older individuals is not entirely clear. We evaluated potential differences in phenotypic and functional responses of B cells from healthy younger (22–45 years) and older (64–95 years) individuals that may associate with a diminished antibody response to influenza vaccination. We report that age is associated with expansion of atypical memory B cells (CD10 − CD20 + CD21 − CD27 − ) and an age-associated B cell (ABC, CD21 − T-bet + CD11c + ) phenotype. Reduced expression of PAX5 was also seen in older individuals. Poor influenza-specific antibody production following vaccination was associated with low PAX5 expression and a distinct composition of the ABC compartment. Collectively, these findings demonstrate that the characteristics of the ABC populations of older individuals are associated with antibody production following influenza vaccination. [ABSTRACT FROM AUTHOR]

Highly active antiretroviral therapy (HAART) for the treatment of HIV infection sustains viral suppression and increases CD4 + T cells in HIV patients. However, in 10–25% of subjects, known as immunological non-responders (INRs), HAART does not increase CD4 count. We investigated a potential role for galectin-9 and TIM-3 in INRs as galectin-9 and TIM-3 have been described to modulate NK and T cell function. PBMCs were isolated from healthy controls, HIV immunological responders (IRs, > 350 CD4 + cells/mm 3 ) and HIV INRs (< 350 CD4 + cells/mm 3 ) and TIM-3 and galectin-9 expressions on NK cell subsets and CD4 + T cells were assessed. HIV INRs and HIV IRs showed increased galectin-9 expression on CD16 − CD56 bright and CD16 + CD56 + NK cells and CD4 + T cells. Only HIV INRs showed a reduced frequency of TIM-3-expressing CD16 + CD56 + , CD16 + CD56 − and CD4 + cells, which correlated with low peripheral CD4 counts. These data suggest that TIM-3 expression may be characteristic for HIV INRs. [ABSTRACT FROM AUTHOR]

Alterations in the gut microbiota composition are associated with food allergy. Toll-like receptors (TLRs) respond to microbial stimuli. We studied the effects of the ligation of TLRs on intestinal epithelial cells (IECs) in preventing an allergic effector response. IEC monolayers (T84 cells) were co-cultured with CD3/28-activated PBMCs from healthy controls or atopic patients and simultaneously apically exposed to TLR2, TLR4 or TLR9 ligands. The barrier integrity of T84 cell monolayers was significantly reduced upon co-culture with PBMCs of food allergic subjects compared to healthy subjects. Apical exposure of IECs to a TLR9 ligand prevented PBMC-induced epithelial barrier disruption. Using PBMCs from food allergic subjects, apical TLR9 activation on IECs increased the IFN-γ/IL-13 and IL-10/IL-13 ratio, while suppressing pro-inflammatory IL-6, IL-8 and TNF-α production in an IEC-dependent manner. Hence, the activation of apical TLR9 on IECs, potentially by microbiota-derived signals, may play an important role in the prevention of allergic inflammation. [ABSTRACT FROM AUTHOR]

Abstract: T-regulatory cell (T-reg) frequency is increased in HIV infection and with aging. We evaluated the effect of age on total, memory and naïve T-reg percentages in untreated HIV infection. Older HIV+ subjects had a total T-reg percent that is 2.8% (p =0.02) higher than among younger HIV+, older HIV− and younger HIV− subjects. In HIV+ subjects, the total T-reg percentage is inversely correlated with the lymphocyte proliferative responses to tetanus (r =−0.45, p =0.002) and Candida (r =−0.43, p =0.003) antigens. Similar correlations were seen between memory T-reg percentages and the lymphocyte proliferative response to tetanus and Candida in HIV+ subjects. T-reg percentages did not correlate consistently with markers of immune activation. T-reg percentages are increased in the older HIV+ population and may play a role in the accelerated disease progression seen in older HIV-infected persons. [Copyright &y& Elsevier]

Abstract: The frequency, subsets and activation status of peripheral blood invariant NKT (iNKT) cells were evaluated in pulmonary tuberculosis (TB) patients and in chronically HIV-1-infected subjects. The absolute numbers of iNKT cells were significantly decreased in TB patients and in HIV-1+ individuals who were antiretroviral therapy naive or had detectable viremia despite receiving HAART. iNKT cell subset analysis demonstrated a decreased percentage of CD4+ iNKT cells in HIV-1+ subjects, and a decreased percentage of double negative iNKT cells in TB patients. Peripheral blood iNKT cells from HIV-1+ and TB patients had significantly increased expression of CD69, CD38, HLA-DR, CD16, CD56, and CD62L. The expression of CD25 was significantly increased only on iNKT cells from TB patients. These findings indicate that peripheral blood iNKT cells in these two chronic infections show an up-regulated expression of activation markers, suggesting their role in the immune response to infection. [Copyright &y& Elsevier]

Abstract: Dendritic cells (DC) at mucosal surfaces mature when exposed to “danger” signals such as LPS. Bacterial vaginosis (BV) is a prevalent alteration of the vaginal bacterial flora associated with preterm childbirth and increased risk for HIV acquisition. We examined the effect of mucosal fluid from women with BV or healthy flora on DC function. IL-12, IL-23 and p40 production by monocyte-derived dendritic cells (MDDC) were all induced by BV samples. Activation/maturation markers HLA-DR, CD40 and CD83 on MDDC incubated with BV CVL were also induced. BV CVL also decreased the endocytic ability of MDDC and increased proliferation of T cells in allogeneic MLR. Plasmacytoid dendritic cell (pDC) CD86 expression was induced by BV CVL. Healthy flora CVL had little effect in any of the tests. This study suggests that BV, but not healthy flora, affects local dendritic cell function in vivo suggesting a mechanism through which BV affects mucosal immunity. [Copyright &y& Elsevier]

Abstract: The mechanisms involved in controlling the establishment of HIV-1 infection are not fully understood. In particular, the role of innate immunity in natural resistance exhibited by individuals who are continuously exposed to HIV-1 but remain seronegative (ESN) has not been thoroughly evaluated. We determined the frequency and function of peripheral blood innate immune cells (plasmacytoid and myeloid dendritic cells, monocytes, NK cells, CD3+/CD56+ cells and invariant NKT cells) in ESN, chronically HIV-1-infected and low-risk HIV-1 seronegative individuals. ESN demonstrated a similar frequency of innate immune cells in comparison to controls and a higher frequency of dendritic cells, NK and invariant NKT cells compared to HIV-1-infected subjects. Incubation of mononuclear cells with stimulatory CpG ODN induced CD86 and CD69 up-regulation to a similar degree on innate cells from the three study groups. CpG ODN-stimulated secretion of cytokines was also similar between ESN and controls, while secretion of IFN-α was significantly decreased in HIV-1+ individuals. Importantly, expression of IFN-γ by PMA/Ionomycin-activated CD56bright NK cells and CD3+/CD56+ cells was significantly higher in ESN when compared with controls. The anti-viral effects of IFN-γ are well established, and so our results suggest that IFN-γ production by innate immune cells might be one of the multiple factors involved in controlling the establishment of sexually transmitted HIV-1 infection. [Copyright &y& Elsevier]