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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic infection with HIV-1 has profound effects on host cell growth and function. We used subtractive hybridization cloning to identify genes whose expression is modulated by HIV-1 infection in the T leukemia cell line CEM. The gene encoding thymosin beta 4, a ubiquitous polypeptide associated with hematopoietic differentiation, showed two- to threefold reduced transcription in HIV-1-infected CEM cells and other HIV-1-infected T cells and macrophages in vitro. Solid-phase radioimmunoassay revealed about a threefold decrease in the level of thymosin beta 4 protein in lysates of infected cells. Northern blot analysis of RNA samples from lymphocytes of five AIDS patients reveals an up to fivefold reduction in the level of thymosin beta 4 mRNA. These results indicate that HIV-1 infection may directly influence the expression of certain physiologically important proteins.
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PMID:Modulation of cellular gene expression of HIV type 1 infection as determined by subtractive hybridization cloning: downregulation of thymosin beta 4 in vitro and in vivo. 788 7

Chronic infection with HIV type 1 is associated with alterations in macronutrient metabolism, specifically elevated plasma lipids, glucose and reduced insulin sensitivity. These alterations are most severe in patients at the later stages of AIDS, indicating a relationship with disease progression. Recently, a metabolic syndrome, termed lipodystrophy, has been described in successfully-treated HIV patients in whom the altered macronutrient metabolism of HIV infection appears to be amplified markedly, with concurrent alterations in adipose tissue patterning. This syndrome presents a paradox, as before the development of highly-active antiretroviral therapy (HAART) the most severe perturbations in metabolism were observed in the sickest patients. Now, the patients that respond well to therapy are showing metabolic perturbations much greater than those seen before. The implications of this syndrome are that, whilst life expectancy may be increased by reducing viral load, there are concomitant increases in the risk of cardiovascular disease, diabetes and pancreatitis within this patient population. The aetiology of the syndrome remains unclear. In a collaborative trial with the Chelsea and Westminster Hospital in London we have used stable-isotope-labelled fatty acids to examine the hypothesis that treatment with HAART causes a delayed clearance of dietary lipid from the circulation, resulting in the retention of lipid within plasma and the downstream changes in insulin and glucose homeostasis. This hypothesis would indicate a role for low-fat diets, exercise and drugs that reduce plasma lipid or insulin resistance, in modulating the response to antiretroviral therapy in HIV infection.
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PMID:The paradox of improved antiretroviral therapy in HIV: potential for nutritional modulation? 1200 87

Chronic HIV infection is associated with T cell abnormalities and altered effector function. Regulatory T cells (Treg) are CD4+ T cells that play a critical role in regulating the immune system. The impact of regulatory T cells on HIV infection and disease progression may be highly significant. We hypothesize that chronic antigenic stimulation from a persistent, high viraemic state may promote a population of Treg that contributes to HIV-associated immune dysfunction. We evaluated the pattern of Treg in chronically infected, HIV-positive individuals over a course of 6 months. Treg are depleted at a distinct rate from that of absolute CD4 cells and loss of Treg is slower in the presence of viral suppression. In vitro depletion of CD25+ CD4+ cells resulted in increased Gag-specific CD4 and CD8 responses. A significant correlation between ex vivo measurement of Treg and Gag-specific CD4 T cell responses was observed (r=-0 x 41, P=0 x 018) with a trend observed with Gag-specific CD8 T cell responses (P=0 x 07). The impact of HIV infection on the Treg population directly complicates the measured effect of Treg on the immune dysfunction although our data support the important role of Treg on modulating the effector T cell response in chronic infection.
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PMID:Peripheral CD4 loss of regulatory T cells is associated with persistent viraemia in chronic HIV infection. 1730 4

Chronic infection with HIV is associated with neuroinflammation. Prior diffusion tensor imaging (DTI) studies demonstrated increased mean diffusion (MD) and decreased fractional anisotropy (FA) in the white matter (WM) and subcortical brain regions of HIV patients. The current study aims to detect whether there are greater than age-related brain changes in HIV patients after a 1-year follow-up period using DTI. Thirty-nine antiretroviral-stable HIV subjects and 32 HIV-seronegative (SN) controls were evaluated, with neuropsychological tests and DTI, at baseline and after 1 year. MD and FA in the genu and splenium of the corpus callosum and in six other subcortical and white matter regions were evaluated bilaterally. Compared to SN controls, HIV subjects had significantly higher MD in the frontal WM (p = 0.0104) and lower FA in the parietal WM (p = 0.006). After 1 year, HIV subjects showed increase in MD in frontal and parietal WM, putamen, and genu; HIV subjects also showed greater increased genu diffusion than SN controls (p = 0.005). Changes in global cognitive deficit score correlated with changes in MD in the genu and FA in the parietal and frontal WM and putamen (multiple regression, p = 0.0008). Lastly, normal age-dependent changes in frontal WM diffusion and FA in genu and putamen were not observed in HIV subjects. Since increased MD may reflect increased neuroinflammation, our findings suggest greater than normal age-related inflammatory changes in the genu of these HIV patients, which may contribute to the cognitive deficits. Measurements of MD in the genu may be useful for monitoring disease progression in HIV brain infection.
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PMID:Greater than age-related changes in brain diffusion of HIV patients after 1 year. 1870 69

Chronic HIV infection is characterized by chronic immune activation and dysfunctional T cells with elevated intracellular cyclic AMP (cAMP), which inhibits the T cell activation capability. cAMP may be induced by prostaglandin E(2) following lipopolysaccharide (LPS)-induced upregulation of cyclooxygenase type 2 (COX-2) in monocytes due to the elevated LPS levels in patients with chronic HIV infection. This hypothesis was tested using celecoxib, a COX-2 inhibitor, for 12 weeks in HIV-infected patients without antiretroviral treatment in a prospective, open, randomized exploratory trial. Thirty-one patients were randomized in the trial; 27 completed the study, including 13 patients on celecoxib. Celecoxib reduced chronic immune activation in terms of CD38 density on CD8(+) T cells (-24%; P = 0.04), IgA levels (P = 0.04), and a combined score for inflammatory markers (P < 0.05). Celecoxib further reduced the inhibitory surface receptor programmed death 1 (PD-1) on CD8(+) T cells (P = 0.01), including PD-1 on the HIV Gag-specific subset (P = 0.02), enhanced the number of CD3(+) CD4(+) CD25(+) CD127(lo/-) Treg or activated cells (P = 0.02), and improved humoral memory recall responses to a T cell-dependent vaccine (P = 0.04). HIV RNA (P = 0.06) and D dimers (P = 0.07) tended to increase in the controls, whereas interleukin-6 (IL-6) possibly decreased in the treatment arm (P = 0.10). In conclusion, celecoxib downmodulated the immune activation related to clinical progression of chronic HIV infection and improved T cell-dependent functions in vivo.
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PMID:An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses. 2149 90

Chronic HIV infection is associated with persistent immune activation and inflammation even among patients virologically suppressed on antiretroviral therapy for years. Chronic immune activation has been associated with poor outcomes--both AIDS-defining and non-AIDS-defining clinical events--and persistent CD4 T-cell depletion. The cause of chronic immune activation in well-controlled HIV infection is unknown. Proposed drivers include residual viral replication, microbial translocation, and coinfecting pathogens. Therapeutic interventions targeting immune activation are emerging, from approaches that interfere directly with activation and inflammatory pathways to those that prevent microbial translocation or decrease the availability of host target cells for the virus. In the context of the disappointing results of the interleukin-2 trials, the main challenges to developing these disease-modifying therapies include identifying an adequate target population and choosing surrogate endpoints that will provide positive proof-of-concept that the interventions will translate into long-term clinical benefit before embarking on large clinical endpoint trials.
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PMID:Disease-modifying therapeutic concepts for HIV in the era of highly active antiretroviral therapy. 2179 65

Chronic HIV infection leads to the development of cognitive impairments, designated as HIV-associated neurocognitive disorders (HAND). The secretion of soluble neurotoxic factors by HIV-infected macrophages plays a central role in the neuronal dysfunction and cell death associated with HAND. One potentially neurotoxic protein secreted by HIV-1 infected macrophages is cathepsin B. To explore the potential role of cathepsin B in neuronal cell death after HIV infection, we cultured HIV-1(ADA) infected human monocyte-derived macrophages (MDM) and assayed them for expression and activity of cathepsin B and its inhibitors, cystatins B and C. The neurotoxic activity of the secreted cathepsin B was determined by incubating cells from the neuronal cell line SK-N-SH with MDM conditioned media (MCM) from HIV-1 infected cultures. We found that HIV-1 infected MDM secreted significantly higher levels of cathepsin B than did uninfected cells. Moreover, the activity of secreted cathepsin B was significantly increased in HIV-infected MDM at the peak of viral production. Incubation of neuronal cells with supernatants from HIV-infected MDM resulted in a significant increase in the numbers of apoptotic neurons, and this increase was reversed by the addition of either the cathepsin B inhibitor CA-074 or a monoclonal antibody to cathepsin B. In situ proximity ligation assays indicated that the increased neurotoxic activity of the cathepsin B secreted by HIV-infected MDM resulted from decreased interactions between the enzyme and its inhibitors, cystatins B and C. Furthermore, preliminary in vivo studies of human post-mortem brain tissue suggested an upregulation of cathepsin B immunoreactivity in the hippocampus and basal ganglia in individuals with HAND. Our results demonstrate that HIV-1 infection upregulates cathepsin B in macrophages, increases cathepsin B activity, and reduces cystatin-cathepsin interactions, contributing to neuronal apoptosis. These findings provide new evidence for the role of cathepsin B in neuronal cell death induced by HIV-infected macrophages.
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PMID:Dysregulation of macrophage-secreted cathepsin B contributes to HIV-1-linked neuronal apoptosis. 2269 52

Chronic HIV infection, which is primarily characterized by the progressive depletion of total CD4(+) T cells, also causes persistent inflammation and immune activation. This is followed by profound changes in cellular and tissue microenvironments that often lead to prolonged immune dysfunction. The global nature of this immune dysfunction suggests that factors that are involved in immune cell survival, proliferation, differentiation and maturation are all affected. Of particular interest is the transcriptional factor Foxo3a that regulates a number of genes that are critical in the development and the maintenance of T and B cells, dendritic cells (DCs) and macrophages. Alterations in the microenvironment mediated by HIV infection cause significant increase in the transcriptional activity of Foxo3a; this has major impact on T cell and B cell immunity. In fact, recent findings from HIV infected individuals highlight three important points: (1) the alteration of Foxo3a signaling during HIV infection deregulates innate and adaptive immune responses; (2) Foxo3a-mediated effects are reversible and could be restored by interfering with the Foxo3a pathway; and (3) down-regulation of Foxo3a transcriptional activity in elite controllers (ECs) represents a molecular signature, or a correlate of immunity, associated with natural protection and lack of disease progression. In this review, we will discuss how HIV-infection altered microenvironments could result in impaired immune responses via the Foxo3a signaling pathway. Defining precisely the molecular mechanisms of how persistent inflammation and immune activation are able to influence the Foxo3a pathway could ultimately help in the development of novel approaches to improve immune responses in HIV infected subjects.
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PMID:Foxo3a: an integrator of immune dysfunction during HIV infection. 2274 38

Chronic HIV infection leads to increased risk of non-Hodgkin B-cell lymphoma. However, only few recent data are available about their current management and prognosis in HIV-infected children since the advent highly active antiretroviral therapy (HAART). This multicenter retrospective study describes the 12 cases of B-cell non-Hodgkin lymphoma diagnosed in HIV-infected children in France between 1996 and 2009. All children had moderate to severe immunosuppression and high viral load at the time of diagnosis. Nine children had extracerebral primary sites and 3 had a primary central nervous system lymphoma. Eight patients had Burkitt lymphoma; 4 had diffuse large B-cell lymphoma. Concomitantly with HAART, all children with extracerebral lymphoma received intensive chemotherapy according to LMB protocol, those with primary central nervous system lymphoma received high-dose methotrexate. No toxicity-related deaths occurred. Ten patients entered complete remission (CR), 2 died of tumor progression despite a second line of therapy. No relapses occurred after CR (median follow-up, 72 mo). Thus, prognosis of patients unresponsive to first-line lymphoma treatment remains poor, but relapse seems to be rare when CR is achieved. Children without severe comorbidities can tolerate intensive chemotherapy with a mandatory HAART treatment, taking into account drug interactions.
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PMID:Characteristics and prognosis of B-cell lymphoma in HIV-infected children in the HAART era. 2293 59

Chronic HIV infection induces significant changes in the trafficking of circulating endothelial progenitor cells (EPCs). Specifically, it causes marked depletion of proangiogenic hematopoietic cells, the so-called colony-forming unit-endothelial cells (CFU-ECs). In this study we evaluated CFU-ECs in two subjects with acute HIV infection. We found that both patients already had a low CFU-EC level at the time of diagnosis. Nevertheless, after 6 months of antiretroviral therapy, the CFU-EC concentration reverted to normal values in both cases. HIV significantly depletes the CFU-EC compartment even in the early phase of infection, while 6-month therapy appears to be able to restore it.
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PMID:Short communication: proangiogenic hematopoietic cells in acute HIV infection. 2314 16


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