Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Individuals infected with HIV-1 have varying rates of progression to AIDS. Cellular immune responses, comprised of cytolytic and noncytolytic CD8(+) T cell effector functions, are considered important for controlling viremia and maintaining the clinically asymptomatic state. Although there is general agreement regarding CD8(+) T lymphocyte cytotoxic functions, considerable controversy exists over the nature of the noncytolytic antiviral activity of CD8(+) cells. The discovery that RANTES (regulated on activation, normal T cell expressed and secreted), MIP-1alpha, and MIP-1beta (macrophage inflammatory protein 1 alpha and beta) could inhibit HIV-1 replication by blocking viral entry processes led to the notion that these molecules are responsible for the CD8(+) cell suppressive activity. However, T tropic HIV isolates requiring the CXCR4 coreceptor for entry are insensitive to the antiviral effects of these beta-chemokines. Using a CXCR4-dependent virus, we determined that the mechanism of CD8(+) T cell-mediated activity did act after viral entry into the host cell. We also define the kinetics of the HIV life cycle in primary activated human CD4(+)-enriched T cells by using an HIV-1 reporter virus system pseudotyped with the CXCR4-dependent HIV-1 envelope gene of NL4-3. Analysis of these kinetic data indicates that CD8(+) T cell-mediated suppressive activity acts at a stage in the viral life cycle after entry and independently of the HIV envelope. Additionally, we show that the antiviral activity targets stages of the virus life cycle correlating with transcription and early proviral gene expression. These findings not only provide a range of possible targets for the CD8(+) T cell-mediated activity but also support the notion that this antiviral activity is multifactorial in nature.
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PMID:CD8+ T cell-mediated suppressive activity inhibits HIV-1 after virus entry with kinetics indicating effects on virus gene expression. 1072 7

Neutralizing cytokine antibodies are found in healthy and diseased individuals, including patients treated with recombinant cytokines. Identification of CCR-5 as co-receptor for HIV has focused interest on CC chemokines and their potential therapeutic use. Chemokine-binding components in plasma of HIV-infected patients were therefore assessed by radioimmunoassay and radioreceptor assay. IgG from 4/505 HIV patients and 9/2000 healthy controls (p>0.05) bound rMIP-1alpha and rMIP-1beta, but not rRANTES. No other plasma factors bound the chemokines. The antibodies inhibited receptor binding of both chemokines. There was no association between presence of antibodies and disease stage or HIV progression rate. Three of 11 patients treated with rIL-2 developed IgG antibodies suppressing cellular binding and growth promotion of rIL-2. Hence, circulating factors, including antibodies MIP-1alpha/MIP-1beta, are uncommon in healthy individuals and HIV patients, and are apparently without prognostic significance. In contrast to earlier reports, IL-2 antibodies were found only in HIV patients treated with rIL-2.
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PMID:Low prevalence of antibodies and other plasma factors binding to CC chemokines and IL-2 in HIV-positive patients. 1073 57

In order to better define the role of HIV-related chemokines in human erythropoiesis we studied: A) the expression of chemokine receptors, both on human CD34(+) cells which include erythroid progenitors and on more mature erythroid cells; B) the functionality of these receptors by calcium flux, chemotaxis assay and phosphorylation of mitogen-activated protein kinases (MAPK) p42/44 (ERK1/ERK2) and AKT, and finally C) the influence of chemokines on BFU-E formation. We found that HIV-related chemokine receptor CXCR4, but not CCR5, is detectable on human CD34(+) BFU-E cells. CXCR4 surface expression decreased during erythroid maturation, although CXCR4 mRNA was still present in cells isolated from differentiated erythroid colonies. SDF-1, a CXCR4 ligand, induced calcium flux and phosphorylation of MAPK (p42/44) and AKT in CD34(+)KIT(+) bone marrow mononuclear cells which contain BFU-E, as well as chemotactic activity of both human CD34(+) BFU-E progenitors and erythroid cells isolated from day 2-6 BFU-E colonies. Responsiveness to SDF-1 decreased when the cells differentiated to the point of surface expression of the erythroid-specific marker Glycophorin-A. In contrast, the CCR5 ligands (macrophage inflammatory protein-1alpha [MIP-1alpha], MIP-1beta, and RANTES) did not activate calcium flux, MAPK and AKT phosphorylation or chemotaxis of CD34(+)KIT(+) cells or cells isolated from the BFU-E colonies. Interestingly, none of the chemokines tested in this study had any effect on BFU-E colony formation. In conclusion, only CXCR4 is functional, and its specific ligand SDF-1 may therefore play an important role in the homing and/or retention of early erythroid precursors in the bone marrow environment.
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PMID:The role of HIV-related chemokine receptors and chemokines in human erythropoiesis in vitro. 1074 85

HIV particles that use the chemokine receptor CXCR4 as a coreceptor for entry into cells (X4-HIV) inefficiently transmit infection across mucosal surfaces [1], despite their presence in seminal fluid and mucosal secretions from infected individuals [2] [3] [4]. In addition, although intestinal lymphocytes are susceptible to infection with either X4-HIV particles or particles that use the chemokine receptor CCR5 for viral entry (R5-HIV) during ex vivo culture [5], only systemic inoculation of R5-chimeric simian-HIV (S-HIV) results in a rapid loss of CD4(+) intestinal lymphocytes in macaques [6]. The mechanisms underlying the inefficient capacity of X4-HIV to transmit infection across mucosal surfaces and to infect intestinal lymphocytes in vivo have remained elusive. The CCR5 ligands RANTES, MIP-1alpha and MIP-1beta suppress infection by R5-HIV-1 particles via induction of CCR5 internalization, and individuals whose peripheral blood lymphocytes produce high levels of these chemokines are relatively resistant to infection [7] [8] [9]. Here, we show that the CXCR4 ligand stromal derived factor-1 (SDF-1) is constitutively expressed by mucosal epithelial cells at sites of HIV transmission and propagation. Furthermore, CXCR4 is selectively downmodulated on intestinal lymphocytes within the setting of prominent SDF-1 expression. We postulate that mucosally derived SDF-1 continuously downmodulates CXCR4 on resident HIV target cells, thereby reducing the transmission and propagation of X4-HIV at mucosal sites. Moreover, such a mechanism could contribute to the delayed emergence of X4 isolates, which predominantly occurs during the later stages of the HIV infection.
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PMID:Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation. 1074 78

It is now recognized that, in addition to drug-mediated therapies against human immunodeficiency virus type 1 (HIV-1), the immune system can exert antiviral effects via CD8(+) T-cell-generated anti-HIV factors. This study demonstrates that (i) supernatants from peripheral blood mononuclear cells (PBMC) stimulated with influenza A virus inhibit replication of CCR5- and CXCR4-tropic HIV-1 isolates prior to reverse transcription; (ii) the HIV-suppressive supernatants can be generated by CD4- or CD8-depleted PBMC; (iii) this anti-HIV activity is partially due to alpha interferon (IFN-alpha), but not to IFN-gamma, IFN-beta, the beta-chemokines MIP-1alpha, MIP-1beta, and RANTES, or interleukin-16; (iv) the anti-HIV activity is generated equally well by PBMC cultured with either infectious or UV-inactivated influenza A virus; and (v) the antiviral activity can be generated by influenza A-stimulated PBMC from HIV-infected individuals. These findings represent a novel mechanism for inhibition of HIV-1 replication that differs from the previously described CD8 anti-HIV factors (MIP-1alpha, MIP-1beta, RANTES, and CD8 antiviral factor).
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PMID:Inhibition of human immunodeficiency virus type 1 replication prior to reverse transcription by influenza virus stimulation. 1077 86

We have tracked the in vivo migration and have identified in vivo correlates of cytotoxic T-lymphocyte (CTL) activity in HIV-seropositive subjects infused with autologous gene-marked CD8(+) HIV-specific CTL. The number of circulating gene-marked CTL ranged from 1.6 to 3.5% shortly after infusion to less than 0.5% 2 weeks later. Gene-marked CTL were present in the lymph node at 4.5- to 11-fold excess and colocalized within parafollicular regions of the lymph node adjacent to cells expressing HIV tat fusion transcripts, a correlate of virus replication. The CTL clones expressed the CCR5 receptor and localized among HIV-infected cells expressing the ligands MIP-1alpha and MIP-1beta, CC-chemokines produced at sites of virus replication. Aggregates of apoptotic cells and cells expressing granzyme-B localized within these same sites. In contrast, lymph node sections from untreated HIV-seropositive subjects, all with significant viral burden (> 50,000 HIV RNA copies/mL plasma), showed no CC-chemokine expression and exhibited only sporadic and randomly distributed cells expressing granzymes and/or apoptotic cells. These studies show that the infused CTL specifically migrate to sites of HIV replication and retain their antigen-specific cytolytic potential. Moreover, these studies provide a methodology that will facilitate studies of both the magnitude and functional phenotype of Ag-specific CD8(+) T cells in vivo.
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PMID:HIV-specific cytotoxic T lymphocytes traffic to lymph nodes and localize at sites of HIV replication and cell death. 2083 Aug 24

Cytokines and beta-chemokines play an important role in the complex interaction between HIV-1 and the immune system. We studied platelet-free plasma (PFP) levels and ex vivo production of cytokines and beta-chemokines at different HIV disease stages and the influence of potent protease inhibitor therapy on their production in late-stage patients. Mitogen-induced production of MIP-1alpha, MIP-1beta, and RANTES by PBMCs was higher in HIV-infected patients than in HIV-seronegative controls. Patients with late-stage HIV infection (CD4+ cells <50/microl) showed a higher production of MIP-1alpha and RANTES and lower plasma levels of IL-2 compared with HIV-positive patients at the intermediate stage (CD4+ cells >150/microl). Pretreatment RANTES production correlated negatively with CD4+ and CD8+ cell counts; also, MIP-1alpha production was inversely correlated with CD4+ cell counts. Among patients with a CD4+ cell count <50/microl, RANTES production before protease inhibitor treatment was inversely correlated with viral load. Late-stage patients with IL-2 production higher than 50 pg/ml before treatment showed a more impressive increase in CD4+ cell counts after protease inhibitor therapy. The production of MIP-1alpha, MIP-1beta, RANTES, and IFN-gamma was markedly reduced at 8 weeks and partially restored at 24 weeks after beginning protease inhibitor therapy. PFP levels of RANTES showed a concurrent decrease. Patients with more advanced HIV infection show a higher production of inflammatory cytokines, which is reduced by protease inhibitor therapy. Residual late-stage IL-2 producers may represent a subset of patients with a higher potential for immunologic reconstitution.
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PMID:Circulating levels and ex vivo production of beta-chemokines, interferon gamma, and interleukin 2 in advanced human immunodeficiency virus type 1 infection: the effect of protease inhibitor therapy. 1087 9

Although CD4+ T-cell activation has long been shown to promote infection and replication of simian immunodeficiency virus (SIV) and HIV, recent studies have documented that not all activated CD4+ T cells from human and nonhuman primates are susceptible to infection with HIV/SIV, respectively. Activation of CD4+ T cells with anti-CD3 + anti-CD28 conjugated beads led to induction of a state of anti-viral resistance to infection with strains of viruses that primarily use CCR5 as a coreceptor. The studies reported herein were designed to address the mechanism by which anti-CD3 + anti-CD28-induced stimulation in turn induced antiviral resistance. Results of these studies show that the anti-viral resistance induced by activation of CD4+ T cells with anti-CD3 + anti-CD28 is primarily conferred by the synthesis of tumor necrosis factor-alpha (TNF-alpha), and highlight a unique regulatory role for TNF-alpha in regulating synthesis of MIP-1alpha, MIP-1beta, and regulated-on-activation normal T-expressed and secreted cells, which contributes to this state of antiviral resistance to R5-tropic strains of HIV/SIV. However, while TNF-alpha has a protective role in antiviral resistance of activated CD4+ T cells to R5-tropic viruses, it enhances CXCR4 expression of CD4+ T cells and mediates increased susceptibility to infection with X4-tropic strains of HIV and recombinant SIVs. The results of the studies reported herein also suggest that it is not the Th1 v/s Th2 cytokine profile but the mode of CD4+ T-cell activation that dictates the synthesis of distinct cytokines which regulate the expression of chemokines and chemokine receptors which in turn regulate and confer susceptibility/resistance to R5 v/s X4-tropic HIV and SIV.
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PMID:A novel role for tumor necrosis factor-alpha in regulating susceptibility of activated CD4+ T cells from human and nonhuman primates for distinct coreceptor using lentiviruses. 1087 90

We used a novel differential display (DD) technique to identify host factors involved in virus replication, pathogenesis, and host response in HIV-1-infected T cells. Thirteen cDNA fragments differentially expressed in HIV-1NL4-3-infected MT-4 cells prior to the occurrence of specific apoptotic cell death were sequenced and identified. Two of seven elevated genes were identical to HIV-1 sequences and the other five were MIP-1alpha, ACTE-III, CD11c, arginase I, and CCR5. The six downregulated genes included prothymosin-a, Jaw-1, proteasome subunit XAPC7, splicing factor 9G8, GA17 protein, and an unknown mRNA. Northern blot and RT-PCR analyses confirmed the altered gene expressions in MT-4 cells as well as in another T cell line, MOLT-4. We also revealed that the amount of MIP-1alpha in culture supernatant of HIV-1-infected cells was increased by more than 15-fold relative to control cells, and the expression of its receptor CCR5 was cooperatively upregulated on the surface of these cells. Furthermore, the upregulation of CD11c after HIV-1 infection was slightly inhibited by blocking the MIP-1alpha-mediated signal transduction. These results indicate that genes altered on HIV-1 infection may be mutually organized and play an important role in HIV-1-induced pathogenesis.
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PMID:Identification and characterization of differentially expressed mRNAs in HIV type 1-infected human T cells. 1089 Mar 61

The C-C chemokines MIP-1alpha, MIP-1beta and RANTES are specific and powerful inhibitors of HIV infectivity. They appear to work by blocking the interaction of the virus with the receptor (CCR5). The latter is utilized as a coreceptor for cell penetration by macrophage-tropic (R5) HIV strains responsible for the majority of HIV transmissions. A natural high capability to release such chemokines has been proposed as a protection factor against HIV infection in exposed uninfected individuals. We report that oral administration of N-acetyl-cysteine (NAC) to healthy volunteers increases the capability of their peripheral blood mononuclear cells (PBMC) to release such anti HIV chemokines upon stimulation. The data reported may explain at least in part the mechanism of action of NAC as an anti HIV therapeutic agent: By potentiating chemokine production NAC may decrease susceptibility to infection.
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PMID:Oral N-acetyl-cysteome increases the production of anti HIV chemokines in peripheral blood mononuclear cells. 1090 Dec 82


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