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

Species-specific innate resistance against viral infections offers novel avenues for antiviral therapeutic and prophylactic approaches. The retroviral and lentiviral restriction factors Ref1 and Lv1 are variants of the tripartite motif protein TRIM5alpha, a component of cytoplasmic bodies. TRIM5alpha severely restricts productive retroviral infections at the postentry and preintegration steps by destabilizing the incoming viral capsid via ubiquitination. Using this approach, resistance to HIV-1 infection could be conferred by TRIM5alpha(rh) expression in otherwise susceptible cells. Here we show that stable expression of simian TRIM5alpha(rh) via a lentiviral vector in a permissive cell culture line, Magi-CXCR4, conferred resistance to HIV-1. To translate these findings into a stem cell gene therapy setting, the TRIM5alpha(rh) transgene was stably introduced into CD34(+) hematopoietic progenitor cells to derive transgenic macrophages. Upon viral challenge, TRIM5alpha(rh)-expressing macrophages were highly resistant to HIV-1 infection compared to control cells. Human macrophages expressing TRIM5alpha(rh) were also found to be phenotypically and functionally normal, expressing the characteristic surface markers CD14, CD4, CCR5, CXCR4, MHC II, and B7.1. These results demonstrate that the species-specific restriction factor TRIM5alpha(rh) is effective in conferring HIV-1 resistance in a stem cell setting, thus paving the way for its application in AIDS gene therapy.
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PMID:TRIM5alpharh expression restricts HIV-1 infection in lentiviral vector-transduced CD34+-cell-derived macrophages. 1608 21

We show in this study that acute exposure of PBMCs derived from HIV-infected subjects to IL-13 results in increased recall T cell lymphoproliferative responses against HIV-1 p24 (n = 30, p < 0.0001) and other recall Ags (influenza, n = 43, p < 0.0001; purified protein derivative tuberculin, n = 6, p = 0.0299). This effect is due to a mechanism that acutely targets APC function in the adherent monocyte subset, as shown by the expansion of CD4(+) T cell responses following coculture of IL-13-treated enriched CD14(+) monocytes with donor-matched enriched CD4(+) T cells and Ag. Exposure to IL-13 over 18-72 h resulted in a significant enhancement of monocyte endocytosis (n = 11, p = 0.0005), CD86 expression (n = 12, p = 0.001), and a significant decrease in spontaneous apoptosis (n = 8, p = 0.008). Moreover, IL-13 exposure induced a significant decrease of significantly elevated constitutive levels of PBMC-secreted TNF-alpha (n = 14, p < 0.001) and IL-10 (n = 29, p < 0.001) within 18 h of exposure ex vivo, also reflected by decreased gene expression in the adherent cell population. Our data show that IL-13 is able to acutely enhance the function of the CD14(+) cell subset toward supporting Ag-specific cell-mediated responses in chronic HIV-1 infection.
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PMID:IL-13 acutely augments HIV-specific and recall responses from HIV-1-infected subjects in vitro by modulating monocytes. 1621 Jun 62

Tuberculosis (TB) enhances human immunodeficiency virus-1 (HIV-1) activity in patients with dual HIV-1/TB infection. Therapies that control augmentations of HIV-1 activity at sites of Mycobacterium tuberculosis (MTB) infection may be useful in inhibition of viral expansion. Regulated upon activation, normal T-cell expressed and secreted (RANTES) analogues (AOP and NNY) are potent in inhibiting the entry of primary HIV-1 isolates into host mononuclear cells. These analogues were used to inhibit MTB-induced HIV-1 entry in blood monunuclear cells (PBMC) from patients with pulmonary TB, and pleural fluid mononuclear cells (PFMC) from patients with pleural TB. PBMC or PFMC were cultured with and without MTB in presence and absence of RANTES analogues. HIV-1 strong stop DNA was assessed by real-time polymerase chain reaction (PCR) as a measure of infection. CCR5 mRNA was assessed by real-time reverse transcription (RT)-PCR and by immunostaining and FACS analysis. HIV-1 infection was induced by MTB in vitro in PBMC from the majority (14 of 20) of HIV-1/TB subjects, and new infection was inhibited by AOP- or NNY-RANTES. HIV-1 infection was also inhibited by these reagents in MTB-induced PFMC from three of three patients with pleural TB. Expression of CCR5 mRNA was significantly induced by MTB in PBMC from patients with pulmonary TB. Further, expression of CCR5 was higher in PFMC compared to PBMC from patients with pleural TB. Also, CCR5 was fourfold higher on CD14(+) pleural mononuclear cells than on CD4(+) lymphocytes. Blocking new HIV-1 infection of mononuclear cells may be useful in control of HIV-1 during dual HIV-1/TB infection.
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PMID:Inhibition of human immunodeficiency virus-1 (HIV-1) by beta-chemokine analogues in mononuclear cells from HIV-1-infected patients with active tuberculosis. 1623 20

Tuberculosis is the most frequent coinfection in humans infected with HIV-1, but little is known about mechanisms that favors coinfection. The aim of this work is to understand tuberculosis and HIV infections. We determined the pattern of expression of CD11c, CD14, CD40, CCR5, and CXCR4 and quantified IL-1beta, IL-6, IL-8, TNF-alpha, and RANTES in tuberculosis patients and HIV patients. Monocytes from healthy PPD+ volunteers (HP(+)V) stimulated with intracellular proteins (IP), lipids, and polysaccharides (PLS) from Mycobacterium tuberculosis down regulate CD11c expression (p < 0.05). On the contrary, CD14 expression was elevated in tuberculosis patients (p < 0.05) and HIV-infected patients (p > 0.05). CD14 expression was elevated on monocytes from HP(+)V stimulated with PLS and lipids (p < 0.05). CD40 low expression was found in tuberculosis patients and on monocytes from HP(+)V stimulated with lipids, but it was elevated in HIV-infected patients (p < 0.05). CXCR4 and CCR5 expression was high in pulmonary tuberculosis patients and low in HIV-infected patients (p < 0.05). Finally, CCR5+ monocytes from HP(+)V after stimulation with PLS and CXCR4+ lymphocytes were elevated after stimulation with IP (p < 0.05). In general, high levels of IL-1beta, IL-6, and TNF-alpha were found in all groups, but low levels of RANTES were found in pulmonary tuberculosis patients. In conclusion, the pulmonary tuberculosis patients have a microenvironment that facilitates the HIV infection through three possible mechanisms: (1) increasing the coreceptor for HIV entrance, (2) increasing proinflammatory cytokines, and (3) down-regulating RANTES. At the same time, HIV patients have a microenvironment that facilitates entry of M. tuberculosis into macrophages through CD14.
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PMID:Mycobacterium tuberculosis upregulates coreceptors CCR5 and CXCR4 while HIV modulates CD14 favoring concurrent infection. 1643 45

Microglial cells are central to brain immunity and intervene in many human neurological diseases. The aim of this study was to develop a convenient cellular model for human microglial cells, suitable for HIV studies. Microglia derive from the hematogenous myelomonocytic lineage, possibly as a distinct subpopulation but in any case able to invade the CNS, proliferate, and differentiate into ameboid and then ramified microglia in the adult life. We thus attempted to derive microglia-like cells from human monocytes. When cultured with astrocyte-conditioned medium (ACM), monocytes acquired a ramified morphology, typical of microglia. They overexpressed substance P and the calcium binding protein Iba-1 and dimly expressed class II MHC, three characteristics of microglial cells. Moreover, they also expressed a potassium inward rectifier current, another microglia-specific feature. These monocyte-derived microglia-like cells (MDMi) were CD4(+)/CD14(+), evocative of an activated microglia phenotype. When treated with lipopolysaccharide (LPS), MDMi lost their overexpression of substance P, which returned to untreated monocyte-derived macrophage (MDM) level. Compared with MDM, MDMi expressed higher CD4 but lower CCR5 levels; they could be infected by HIV-1(BaL), but produced less virus progeny than MDM did. This model of human microglia may be an interesting alternative to primary microglia for large scale in vitro HIV studies and may help to better understand HIV-associated microgliosis and chronic inflammation in the brain.
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PMID:Characterization of human monocyte-derived microglia-like cells. 1680 99

Several cytokines and chemokines including chemokine (C-C motif) ligand-2 (CCL2) are induced in HIV-1 infection. However, the impact of HIV-1 viremia on CCL2 regulation is largely unknown. We utilized a DNA oligonucleotide microarray covering 110 inflammatory genes. Five genes were induced by at least 2-fold in PBMCs of HIV-1 viremic (>100,000 RNA copies ml(-1)) as compared with aviremic (<50 RNA copies ml(-1)) individuals. These genes were CCL2, CXC chemokine ligand-10, IFN-gamma, GTP-cyclohydrolase-1 and C-C chemokine receptor-1. In addition to microarray data verification by real-time PCR, analysis of independent patient samples revealed a similar expression pattern. CCL2 was the most strongly regulated gene at mRNA level and its serum concentration was significantly elevated in viremic compared with aviremic and HIV-1 seronegative controls, indicating a positive correlation between viremia and CCL2. Flow cytometric studies demonstrated a higher percentage of CCL2-expressing CD14(+) monocytes in viremic compared with aviremic individuals. These results suggest a highly restricted modulation of host inflammatory gene response by HIV. Genes up-regulated in the viremic state, in particular CCL2, presumably serve as potential enhancing factors in HIV-1 replication, represented by high viral load in HIV-1 viremic patients. Inhibition of increased CCL2 production could provide a new therapeutic intervention in HIV-1 infection.
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PMID:Host chemokine (C-C motif) ligand-2 (CCL2) is differentially regulated in HIV type 1 (HIV-1)-infected individuals. 1691 90

Mycobacterium avium is an opportunistic pathogen that commonly infects individuals colonized with HIV-1, although it is less frequent in the post-HAART era. These microorganisms invade macrophages after interacting with TLR2 and/or CD14 co-receptors, but signaling pathways promoting survival in macrophages are not well defined. Although IFN-gamma plays an important role in protective immunity against bacterial infections, IFN-gamma responses are compromised in AIDS patients and evidence suggests that exogenous IFN-gamma is inadequate to clear the mycobacteria. To determine the mechanism by which M. avium survives intracellularly, even in the presence of IFN-gamma, we studied the effect of mycobacteria infection in macrophages during early IFN-gamma signaling events. M. avium infected cells exhibited a reduced response to IFN-gamma, with suppressed phosphorylation of STAT-1 compared with uninfected cells. Interaction of M. avium with macrophage receptors increased gene expression of the suppressors of cytokine signaling (SOCS) to diminish IFN responsiveness. Specifically, we observed an increase in mRNA for both SOCS-3 and SOCS-1, which correlates with elevated levels of SOCS protein and positive immunostaining in M. avium/HIV-1 co-infected tissues. We also linked the p38 MAPK signaling pathway to mycobacterial-induced SOCS gene transcription. The induction of SOCS may be part of the strategy that allows the invader to render the macrophages unresponsive to IFN-gamma, which otherwise promotes clearance of the infection. Our data provide new insights into the manipulation of the host response by this opportunistic pathogen and the potential for modulating SOCS to influence the outcome of M. avium infection in immunocompromised hosts.
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PMID:Mycobacterium avium-induced SOCS contributes to resistance to IFN-gamma-mediated mycobactericidal activity in human macrophages. 1694 87

Human immunodeficiency virus type 1 (HIV-1) transmission by the parenteral route is similar to mucosal transmission in the predominance of virus using the CCR5 coreceptor (R5 virus), but it is unclear whether blood dendritic cells (DCs), monocytes, or T cells are the cells initially infected. We used ex vivo HIV-1 infection of sorted blood mononuclear cells to model the in vivo infection of blood leukocytes. Using quantitative real-time PCR to detect full-length HIV-1 DNA, both sorted CD11c(+) myeloid and CD11c(-) plasmacytoid DCs were more frequently infected than other blood mononuclear cells, including CD16(+) or CD14(+) monocytes or resting CD4(+) T cells. There was a strong correlation between CCR5 coreceptor use and preferential DC infection across a range of HIV-1 isolates. After infection of unsorted blood mononuclear cells, HIV-1 was initially detected in the CD11c(+) DCs and later in other leukocytes, including clustering DCs and activated T cells. DC infection with R5 virus was productive, as shown by efficient transmission to CD4(+) T cells in coculture. Blood DCs infected with HIV-1 in vitro and cultured alone expressed only low levels of multiply spliced HIV-1 RNA unless cocultured with CD4(+) T cells. Early selective infection of immature blood DCs by R5 virus and upregulation of viral expression during DC-T-cell interaction and transmission provide a potential pathway for R5 selection following parenteral transmission.
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PMID:Preferential infection of dendritic cells during human immunodeficiency virus type 1 infection of blood leukocytes. 1716 3

Two major interferon (IFN)-mediated antiviral defense enzymes are double-stranded (ds)RNA-dependent 2',5'-oligoadenylate (2-5A) synthetase (2-5OAS) and p68 kinase (PKR). When activated by dsRNA, 2-5OAS synthesizes 2-5A, which binds to and activates RNase L. Activated RNase L hydrolyzes single-stranded viral RNA, thereby inhibiting viral protein synthesis. HIV-1 inhibits the IFN-mediated intracellular antiviral pathways. We have reported the synthesis and characterization of a nuclease-resistant 2-5A agonist (2-5A(N6B)) that overcomes the HIV-1 induced blockades by restoring the 2-5OAS/RNase L antiviral pathway (Homan JW, et al., J Acquir Immune Defic Syndr 2002;30:9-20). The objective of this study was to test the effect of 2-5A(N6B) on chronically infected CD4(+) T lymphocytes and CD14(+) monocytes derived from HIV-1-seropositive individuals. Wild-type HIV-1 replication was effectively inhibited by 2-5A(N6B) in CD4(+) T lymphocytes and CD14(+) monocytes purified from HIV-1 seropositive individuals (n = 18) compared to untreated cells. We also assessed the cytotoxicity of 2-5A(N6B) and report that 2-5A(N6B) exerts its anti-HIV-1 activity with no evidence of cytotoxicity (IC(90) > 100,000 nM). Furthermore, 2-5A(N6B) did not alter the cellular RNA profile, affect CCR5 or CXCR4 coreceptor expression, or activate caspase-dependent apoptosis. Evidence is also provided to show that 2-5A(N6B), and naturally occurring 2-5A(4), act as ligands to activate human Toll-like receptor 4. These results indicate that the 2-5A agonist 2-5A(N6B) has the potential to enhance host cell innate and acquired immune defense mechanisms against HIV-1 infection.
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PMID:Inhibition of HIV type 1 replication in CD4+ and CD14+ cells purified from HIV type 1-infected individuals by the 2-5A agonist immunomodulator, 2-5A(N6B). 1726 42

Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G), a human cytidine deaminase, is a potent inhibitor of HIV replication. To explore a possible role of this protein in modulating in vivo susceptibility to HIV infection, we analyzed APOBEC3G expression in HIV-exposed seronegative individuals, HIV-seropositive patients, and healthy control subjects. The results showed that the expression of APOBEC3G is significantly increased in peripheral blood mononuclear cells (PBMCs)--mainly CD14(+) cells--and in cervical tissues of HIV-exposed seronegative individuals. Higher APOBEC3G expression correlated with a reduced susceptibility of PBMCs to in vitro infection with the HIV-1(Ba-L) R5 strain. APOBEC3G could be important in modulating in vivo susceptibility to sexually transmitted HIV infection.
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PMID:Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G: a possible role in the resistance to HIV of HIV-exposed seronegative individuals. 1733 Jul 85


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