UMLS:C0019693 - FACTA Search

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

As pattern recognition receptors, TLRs signal and induce expression of multiple host defense genes including proinflammatory cytokines and chemokines. To investigate the mechanisms of up-regulation of proinflammatory cytokines and chemokines during SIV infection in rhesus macaques, we measured the relative levels of expression of TLRs 1-10 in lymphoid tissues during different stages of SIV infection. By real-time RT-PCR, TLR3 was determined to be up-regulated in macaque lymph nodes (LN) throughout the course of infection, whereas TLR9 was down-regulated during early stages of infection. CXCL9/Mig, CXCL10/IP-10, IFN-gamma, and IFN-alpha mRNAs were also increased during acute SIV infection and AIDS. Treatment of macaque spleen and LN cells with TLR3 and TLR9 ligands led to the induction of these same genes. TLR3 stimulation had disparate effects on viral transcription and viral replication, because poly(I:C), a model TLR3 ligand, stimulated the viral promoter but potently inhibited SIV replication in primary cultures of macaque spleen and LN cells. These findings identify roles for TLR3 inflammation in lymphoid tissues and in the immunopathogenesis of HIV-1/SIV, and suggest that TLR3 ligands could potentially be used to flush out latently infected cells that persist during antiretroviral therapies.
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PMID:Increased expression of TLR3 in lymph nodes during simian immunodeficiency virus infection: implications for inflammation and immunodeficiency. 1621 Jun 37

Encephalitis and dementia associated with acquired immunodeficiency syndrome (AIDS) are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, blood-brain barrier (BBB) disruption, and eventual loss of neurons. Little is known about whether human immunodeficiency virus 1 (HIV-1) infection of leukocytes affects their ability to transmigrate in response to chemokines and to alter BBB integrity. We now demonstrate that HIV infection of human leukocytes results in their increased transmigration across our tissue culture model of the human BBB in response to the chemokine CCL2, as well as in disruption of the BBB, as evidenced by enhanced permeability, reduction of tight junction proteins, and expression of matrix metalloproteinases (MMP)-2 and MMP-9. HIV-infected cells added to our model did not transmigrate in the absence of CCL2, nor did this condition alter BBB integrity. The chemokines CXCL10/interferon-gamma-inducible protein of 10 kDa, CCL3/macrophage inflammatory protein-1alpha, or CCL5/RANTES (regulated on activation normal T-cell expressed and secreted) did not enhance HIV-infected leukocyte transmigration or BBB permeability. The increased capacity of HIV-infected leukocytes to transmigrate in response to CCL2 correlated with their increased expression of CCR2, the chemokine receptor for CCL2. These data suggest that CCL2, but not other chemokines, plays a key role in infiltration of HIV-infected leukocytes into the CNS and the subsequent pathology characteristic of NeuroAIDS.
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PMID:CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. 1643 95

Chemokines play a key role in the regulation of central nervous system disease. CXCL10 over-expression has been observed in several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease and HIV-associated dementia. More recent studies by others and us have shown that CXCL10 elicits apoptosis in fetal neurons. The mechanism of CXCL10-mediated neurotoxicity, however, remains unclear. In this study, we provide evidence for the direct role of Ca(2+) dysregulation in CXCL10-mediated apoptosis. We demonstrate that treatment of fetal neuronal cultures with exogenous CXCL10 produced elevations in intracellular Ca(2+) and that this effect was modulated via the binding of CXCL10 to its cognate receptor, CXCR3. We further explored the association of intracellular Ca(2+) elevations with the caspases that are involved in CXC10-induced neuronal apoptosis. Our data showed that increased Ca(2+), which is available for uptake by the mitochondria, is associated with membrane permeabilization and cytochrome c release from this compartment. The released cytochrome c then activates the initiator active caspase-9. This initiator caspase sequentially activates the effector caspase-3, ultimately leading to apoptosis. This study identifies the temporal signaling cascade involved in CXCL10-mediated neuronal apoptosis and provides putative targets for pharmaceutical intervention of neurological disorders associated with CXCL10 up-regulation.
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PMID:CXCL10-induced cell death in neurons: role of calcium dysregulation. 1651 60

Pulmonary infections and dysfunction are frequent outcomes during the development of immunodeficiency associated with human immunodeficiency virus type 1 (HIV-1) infection, and obtaining a better understanding of the immunologic changes that occur in lungs following HIV-1 infection will provide a foundation for the development of further intervention strategies. We sought here to identify changes in the pulmonary immune environment that arise during simian immunodeficiency virus (SIV) infection of rhesus macaques, which serves as an excellent model system for HIV-1 infection and disease. To examine the gene expression profiles of macaque lung tissues following infection with the pathogenic SIV/DeltaB670 isolate, we performed cDNA microarray hybridizations with lung total RNAs using two commercially available cDNA arrays and a custom-fabricated, immunologically focused macaque cDNA microarray. In situ hybridization and real-time RT-PCR were performed to provide additional analyses of gene expression. Among the genes exhibiting the highest level of induction in lung tissues were the IFN-gamma-inducible chemokines, CXCL10/IP-10 and CXCL9/Mig. In situ hybridization and real-time RT-PCR strongly supported these findings. Correlation analyses revealed that the levels of expression of IFN-gamma, CXCL9/Mig, and CXCL10/IP-10 mRNAs were all strongly positively correlated, and that CXCL10/IP-10 mRNA and Pneumocystis carinii rRNA were positively correlated. Taken together, these findings demonstrate that inflammatory chemokines are among the most differentially expressed mRNAs in macaque lung tissues during systemic SIV infection of rhesus macaques, and provide insight into the complicated events occurring in the lung tissues during HIV-1 infection in humans.
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PMID:Increased expression of interferon-inducible genes in macaque lung tissues during simian immunodeficiency virus infection. 1682 91

Changes in T-cell function are a hallmark of human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms leading to these changes are unclear. We examined the gene expression profiles in ex vivo human CD4+ and CD8+ T cells from untreated HIV-1-infected individuals at different clinical stages and rates of disease progression. Profiles of pure CD4+ and CD8+ T-cell subsets from HIV-1-infected nonprogressors with controlled viremia were indistinguishable from those of individuals not infected with HIV-1. Similarly, no gene clusters could distinguish T cells from individuals with early infection from those seen in chronic progressive HIV-1 infection, whereas differences were observed between uninfected individuals or nonprogressors versus early or chronic progressors. In early and chronic HIV-1 infection, three characteristic gene expression signatures were observed. (i) CD4+ and CD8+ T cells showed increased expression of interferon-stimulated genes (ISGs). However, some ISGs, including CXCL9, CXCL10, and CXCL11, and the interleukin-15 alpha receptor were not upregulated. (ii) CD4+ and CD8+ T cells showed a cluster similar to that observed in thymocytes. (iii) More genes were differentially regulated in CD8+ T cells than in CD4+ T cells, including a cluster of genes downregulated exclusively in CD8+ T cells. In conclusion, HIV-1 infection induces a persistent T-cell transcriptional profile, early in infection, characterized by a dramatic but potentially aberrant interferon response and a profile suggesting an active thymic output. These findings highlight the complexity of the host-virus relationship in HIV-1 infection.
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PMID:Distinct transcriptional profiles in ex vivo CD4+ and CD8+ T cells are established early in human immunodeficiency virus type 1 infection and are characterized by a chronic interferon response as well as extensive transcriptional changes in CD8+ T cells. 1725

To exert their cytotoxic function, cytotoxic T-lymphocytes (CTL) must be recruited into infected lymphoid tissue where the majority of human immunodeficiency virus (HIV) replication occurs. Normally, effector T cells exit lymph nodes (LNs) and home to peripheral sites of infection. How HIV-specific CTL migrate into lymphoid tissue from which they are normally excluded is unknown. We investigated which chemokines and receptors mediate this reverse homing and whether impairment of this homing could contribute to CTL dysfunction as HIV infection progresses. Analysis of CTL chemokine receptor expression in the blood and LNs of untreated HIV-infected individuals with stable, chronic infection or advanced disease demonstrated that LNs were enriched for CXCR3(+) CD8 T cells in all subjects, suggesting a key role for this receptor in CTL homing to infected lymphoid tissue. Compared to subjects with chronic infection, however, subjects with advanced disease had fewer CXCR3(+) CD8 T cells in blood and LNs. CXCR3 expression on bulk and HIV-specific CD8 T cells correlated positively with CD4 count and negatively with viral load. In advanced infection, there was an accumulation of HIV-specific CD8 T cells at the effector memory stage; however, decreased numbers of CXCR3(+) CD8 T cells were seen across all maturation subsets. Plasma CXCL9 and CXCL10 were elevated in both infected groups in comparison to the levels in uninfected controls, whereas lower mRNA levels of CXCR3 ligands and CD8 in LNs were seen in advanced infection. These data suggest that both CXCR3(+) CD8 T cells and LN CXCR3 ligands decrease as HIV infection progresses, resulting in reduced homing of CTL into LNs and contributing to immune dysfunction.
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PMID:Decreased CXCR3+ CD8 T cells in advanced human immunodeficiency virus infection suggest that a homing defect contributes to cytotoxic T-lymphocyte dysfunction. 1755 94

There is increasing cumulative evidence that activated mononuclear phagocytes (macrophages/microglia) releasing inflammatory mediators in the CNS are a better correlate of HIV-associated dementia (HAD) than the actual viral load in the brain. Earlier studies on simian HIV/rhesus macaque model of NeuroAIDS confirmed that pathological changes in brains of macaques with encephalitis were associated with up-regulation of platelet-derived growth factor (PDGF) and the chemokine, CXCL10. Because the complex interplay of inflammatory mediators released by macrophages often leads to the induction of neurotoxins in HAD, we hypothesized that PDGF could interact with IFN-gamma to modulate the expression of CXCL10 in these primary virus target cells. Although PDGF alone had no effect on the induction of CXCL10 in human macrophages, in conjunction with IFN-gamma, it significantly augmented the expression of CXCL10 RNA & protein through transcriptional and posttranscriptional mechanisms. Signaling molecules, such as JAK and STATs, PI3K, MAPK, and NF-kappaB were found to play a role in the synergistic induction of CXCL10. Furthermore, PDGF via its activation of p38 MAPK was able to increase the stability of IFN-gamma-induced CXCL10 mRNA. Understanding the mechanisms involved in the synergistic up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.
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PMID:PDGF synergistically enhances IFN-gamma-induced expression of CXCL10 in blood-derived macrophages: implications for HIV dementia. 1770 85

gammadelta T lymphocytes are involved in the defence from viral and mycobacterial infections; however they are also responsible for autoimmune reactions. Herein, we discuss the characteristics of these cells, focusing on the mechanism(s) underlying extravasation and tissue localization. We show that Vdelta1 and Vdelta2 gammadeltaT cells display differential expression of adhesion molecules and chemokine receptors, the former being preferentially PECAM-1(+)CXCR4(+), the latter expressing NKRP1A and CXCR3. The two cell populations transmigrate across endothelial cells by activation of distinct kinase pathways and in response to interferon-gamma-inducing protein-10 (IP-10/CXCL10) or stromal-derived factor-1 (SDF-1/CXCL12) according to the expression of the specific receptors CXCR3 and CXCR4. IP-10/CXCL10 and SDF-1/CXCL12-induced transmigration are phosphoinositide-3 kinase (PI-3K) and Akt/PKB-dependent. In addition, occupancy of CXCR3, but not of CXCR4, leads to CAMKII activation; blocking of CAMKII decreases IP-10/CXCL10 and 6Ckine/SLC/CCL21-driven transmigration. We report that HIV-1-infected patients have an increased number of circulating Vdelta1 T cells possibly due to the interference of Tat protein on the function of chemokine receptors. In turn, patients with relapsing-remitting multiple sclerosis (MS), display an increase in peripheral Vdelta2 gammadelta T cells and this is related to interleukin-12-mediated upregulation of NKRP1A. Finally, the possible role of gammadelta T lymphocytes in post-transplantation immune reconstitution is discussed.
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PMID:Adhesion molecules and kinases involved in gammadelta T cells migratory pathways: implications for viral and autoimmune diseases. 1822 Jul 50

The mechanisms of resistance to AIDS development in HIV-1-infected chimpanzees have remained elusive. Unique among chimpanzees naturally or experimentally infected with HIV, several animals of the Yerkes cohort have progressed to clinical AIDS with selection of isolates showing increased pathogenicity for chimpanzees. We compared progressors vs. nonprogressors among the HIV-infected chimpanzees that made up this cohort, eight of which have been infected with HIV-1 for over 14 years. The additional two progressors were infected de novo with chimpanzee-pathogenic HIV, rapidly leading to a progressor status. Nonprogressors were characterized by normal CD4(+) T cell counts and the absence of detectable viremia. In contrast, progressor chimpanzees had relatively high plasma viral loads associated with a dramatic loss of CD4(+) T cells. The analysis of immune responses showed a similar amplitude and breadth of ELISPOT T cell responses in both groups. HIV-specific proliferative responses were, however, absent in the progressor animals, which also exhibited increased levels of immune activation characterized by elevated levels of the circulating chemokines IP-10 and MCP-1. Of interest was the conservation of potent NK cell activity in all animals, potentially contributing to the extended symptom-free survival of progressor animals. Modest anti-HIV antibody titers were detectable in the nonprogressor group, but these antibodies exhibited good neutralizing activity. In progressors, however, two sets of data were noted: in animals that gradually selected for pathogenic isolates, or that were superinfected, very high neutralizing antibody titers were observed, although none to the pathogenic HIV. In contrast, two animals infected de novo with chimpanzee pathogenic HIV failed to mount an extensive humoral response and both failed to develop neutralizing antibodies to the virus. Taken together, pathogenic HIV infection in chimpanzees is associated with rapid loss of CD4(+) T cells and proliferative responses as well as higher levels of immune activation.
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PMID:Analysis of the immune responses in chimpanzees infected with HIV type 1 isolates. 1842 37

HIV encephalitis (HIVE), the pathologic correlate of HIV-associated dementia (HAD) is characterized by astrogliosis, cytokine/chemokine dysregulation, and neuronal degeneration. Increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD. In fact, the severity of HAD/HIVE correlates more closely with the presence of activated glial cells than with the presence and amount of HIV-infected cells in the brain. Astrocytes, the most numerous cell type within the brain, provide an important reservoir for the generation of inflammatory mediators, including interferon-gamma inducible peptide-10 (CXCL10), a neurotoxin and a chemoattractant, implicated in the pathophysiology of HAD. Additionally, the proinflammatory cytokines, IFN-gamma and TNF-alpha, are also markedly increased in CNS tissues during HIV-1 infection. In this study, we hypothesized that the interplay of host cytokines and HIV-1 could lead to enhanced expression of the toxic chemokine, CXCL10. Our findings demonstrate a synergistic induction of CXCL10 mRNA and protein in human astrocytes exposed to HIV-1 and the proinflammatory cytokines. Signaling molecules, including JAK, STATs, MAPK (via activation of Erk1/2, AKT, and p38), and NF-kappaB were identified as instrumental in the synergistic induction of CXCL10. Understanding the mechanisms involved in HIV-1 and cytokine-mediated up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.
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PMID:Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes. 1898 32

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