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

CD8+ T lymphocytes from HIV+ individuals can potently suppress HIV-1 replication in a noncytolytic manner. This suppression appears to be multifactorial and the molecules contributing have not been fully elucidated. As an approach to this question we used herpesvirus saimiri (HVS) to transform CD8+ T lymphocytes from an HIV+ asymptomatic donor to a continuously growing, activation-independent, IL-2-dependent phenotype. The transformed cell population, termed CD8(HVS), had an activated phenotype, contained HVS sequences, did not shed infectious HVS virus, and was polyclonal. The CD8(HVS) cells, despite the absence of detectable CTL activity, potently suppressed HIV-1 production by both autologous and heterologous CD4+ cells from infected donors. The CD8(HVS) cells in coculture also suppressed virus production from PBMCs acutely infected with syncytium-inducing (SI) strains or NSI primary isolates of HIV-1. The supernatants from the CD8(HVS) cells and their concentrates derived from these supernatants were suppressive to NSI primary isolates of HIV-1 but not to SI strains. Fractionation of these concentrates showed that the suppressive activity was associated with low molecular mass (6500- to 19,300-Da) protein species. Western blotting and ELISA indicated that the CC chemokines MIP-1alpha, MIP-1beta, and RANTES were present in these fractions. Antibody-blocking studies with antibodies to the CC chemokines indicated that a significant portion of the soluble HIV-suppressive activity was due to these molecules. However, these experiments also suggested the inhibitory activity of the CD8(HVS) cells in coculture is not due exclusively to the CC chemokines. The HVS-transformed cells provide a useful tool for the study of noncytolytic CD8+ T lymphocyte-mediated suppression of HIV-1.
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PMID:Herpesvirus saimiri transformation of HIV type 1 suppressive CD8+ lymphocytes from an HIV type 1-infected asymptomatic individual. 956 55

The in vivo response of the immune system after HIV infection in regard to cytokine production and C-C chemokine synthesis is not well known. Here we have analysed cytokine and chemokine mRNA production in lymph nodes with follicular hyperplasia (FHLN) of HIV-infected patients by in situ hybridization using anti-sense mRNA probes. The synthesis of mRNAs for interferon-gamma (IFN-gamma), IL-12p35, IL-12p40, IL-4, and for the C-C chemokines RANTES, MIP-1alpha, and MIP-1beta was compared with that of lymph nodes from non-infected individuals to define HIV-specific events. Only few cells expressing IFN-gamma, RANTES, MIP-1alpha, and MIP-1beta mRNAs were detectable in the T-dependent area of lymph nodes from HIV-negatives. In contrast, in FHLN from HIV+ patients a high number of IFN-gamma, RANTES, MIP-1alpha, and MIP-1beta mRNA-containing cells were detectable. Remarkably, only single individual IL-12p35 mRNA-producing cells were present in the T-dependent area from both HIV+ and HIV lymph nodes. Furthermore, the low number of IL-12p40 mRNA-expressing cells did not differ between HIV+ and HIV- lymph nodes. This indicates that IFN-gamma is expressed independently of IL-12, possibly by a direct T cell-mediated reaction. IL-4 mRNA-producing cells were hardly detectable in infected and control lymph nodes. The same findings were made in a limited number of samples from patients with advanced disease. Thus, these results demonstrate that a high IFN-gamma production is accompanied by a strong expression of MIP-1alpha, MIP-1beta, and RANTES in the lymph node after HIV infection. This favours the idea that a Th1-type immune response correlates with a preferential production of C-C chemokines in FHLN of HIV+ patients.
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PMID:Expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES genes in lymph nodes from HIV+ individuals: correlation with a Th1-type cytokine response. 956 95

The CC chemokines MIP-1alpha, MIP-1beta, and RANTES suppress replication of certain HIV-1 strains in cultured PBMC and T cell lines by blocking interaction of gp120 with CC chemokine receptor 5 (CCR5). However, the same chemokines can enhance HIV-1 replication in cultured macrophages. The net effect of chemokines on HIV-1 infection in intact lymphoid tissue, the major reservoir of HIV-1 in vivo, is unknown and unpredictable since the tissue contains both T lymphocytes and macrophages. Here we show that exogenous MIP-1alpha, MIP-1beta, and RANTES markedly suppressed replication of CCR5-tropic HIV-1 strains in blocks of human lymphoid tissue infected ex vivo. Moreover, endogenous MIP-1alpha, MIP-1beta, and RANTES were upregulated in tissues infected ex vivo with CXC chemokine receptor 4-tropic but not CCR5-tropic HIV-1. Such an upregulation may contribute to the virus phenotype shift in the course of HIV disease in vivo.
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PMID:Blockade of CC chemokine receptor 5 (CCR5)-tropic human immunodeficiency virus-1 replication in human lymphoid tissue by CC chemokines. 957 51

We examined the human immunodeficiency virus type 1 infectability of CD4+ lymphocytes isolated from CCR5 wild-type individuals, individuals heterozygous for the delta32 allele of CCR5, and HIV-1-exposed but uninfected (EU) individuals who had CD4+ lymphocytes refractory to M-tropic viral replication. None of the EU individuals were found to be heterozygous for the delta32 allele. The CD4+ lymphocytes isolated from CCR5/delta32 and EU individuals were less infectable with an M-tropic viral isolate of HIV-1 than CCR5/CCR5 control individuals but were equally as infectable with a T-tropic viral isolate. The restriction to M-tropic viral isolate replication did not associate with any profound genotypic change in the CCR5 gene. CD4+ lymphocytes from CCR5/delta32 and CCR5/CCR5 EU individuals were more sensitive to the HIV-inhibitory effects of the recombinant beta-chemokines RANTES, MIP-1alpha, and MIP-1beta than were CD4+ lymphocytes from CCR5/CCR5 control individuals. CD4+ lymphocytes from EU individuals also showed increased sensitivity to recombinant beta-chemokines and low surface expression of CCR5. A phenotype of low CCR5 expression and high secretion of beta-chemokines is associated with reduced infectability of cells by M-tropic HIV-1. This phenotype may also be associated with protection against sexual transmission of HIV-1.
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PMID:Reduced HIV-1 infectability of CD4+ lymphocytes from exposed-uninfected individuals: association with low expression of CCR5 and high production of beta-chemokines. 958 79

The purified CD4+ lymphocytes of a group of highly exposed but HIV-1-uninfected individuals were determined to be less susceptible to infection with multiple non-syncytium-inducing (NSI) primary isolates of HIV-1 than were CD4+ lymphocytes from nonexposed control individuals. This relative resistance to HIV-1 infection did not extend to T cell line-adapted or syncytium-inducing (SI) primary viral isolates, was restricted by the envelope glycoprotein, and was associated with an increased production of the C-C chemokines RANTES, MIP-1alpha, and MIP-1beta. The block to replication in CD4+ lymphocytes from two exposed-uninfected subjects was at the point of entry, as was the block imposed by the recombinant C-C chemokines RANTES, MIP-1alpha, and MIP-1beta. Resistance to infection and the high production of beta chemokines were characteristic of every CD4+ lymphocyte clone from the exposed-uninfected subjects. We have now identified the mechanism underlying this in vitro and in vivo resistance to infection: These individuals have inherited a homozygous 32-bp nucleotide deletion (delta32) within the gene encoding the coreceptor for primary NSI isolates of HIV-1 (CCR5). This deletion encodes a severely truncated and unstable protein that is not expressed on the cell surface. This allele is common in the Caucasian population, with a frequency of 0.0808, but is not found in people of African or Asian ancestry. To determine its role in HIV-1 transmission and disease progression, we analyzed the CCR5 genotype of 1252 homosexual men enrolled in the Chicago component of the Multicenter AIDS Cohort Study (MACS). No infected participant was found to be homozygous for the delta32 allele whereas 3.6% of at-risk but uninfected Caucasian participants were homozygous, showing the highly protective role of this genotype against sexual acquisition of HIV-1. No evidence was found to suggest that heterozygotes were protected against HIV-1 infection, but a limited protective role against disease progression was noted. The delta32 allele of CCR5 is therefore an important host factor in HIV-1 transmission and pathogenesis.
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PMID:The HIV type 1 coreceptor CCR5 and its role in viral transmission and disease progression. 958 91

We examined the effect of immune stimulation by a human immunodeficiency virus type 1 (HIV-1) immunogen (Remune) compared to a non-HIV vaccine (influenza) on HIV-1-specific immune responses in HIV-1-seropositive subjects. HIV-1 p24 antigen-stimulated lymphocyte proliferation was not augmented after immunization with the influenza vaccine. In contrast, subjects increased their lymphocyte proliferative responses to p24 antigen after one immunization with HIV-1 immunogen (Remune) (gp120-depleted inactivated HIV-1 in incomplete Freund's adjuvant). Furthermore, p24 antigen-stimulated beta-chemokine production (RANTES, MIP-1alpha, MIP-1beta) was also augmented after immunization with the HIV-1 immunogen but not influenza vaccine. Taken together, these results suggest that in this cohort, HIV-specific immune responses to p24 antigen can be augmented after immunization with an HIV-1 immunogen. The ability to upregulate immune responses to the more conserved core proteins may have important implications in the development of immunotherapeutic interventions for HIV-1 infection.
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PMID:In vitro p24 antigen-stimulated lymphocyte proliferation and beta-chemokine production in human immunodeficiency virus type 1 (HIV-1)-seropositive subjects after immunization with an inactivated gp120-depleted HIV-1 immunogen (Remune). 960 82

The chemokines RANTES, MIP-1alpha, and MIP-1beta have been identified as HIV-1-suppressive factors produced by CD8+ T cells. We examined the possibility that HIV-1-specific, chemokine-releasing T cells could be expanded from the lymph nodes of patients with advanced infection. Lymphocytes, separated from lymph nodes of patients with peripheral blood CD4 counts less than 500/microl obtained at diagnostic biopsies, were activated with anti-CD3 monoclonal antibody, and cultured in vitro for up to 12 days with IL-2. The phenotype, proliferative response, chemokine production, and anti-HIV-1 activity of the expanded cells was examined. Cells expanded 2.4- to 49-fold from patients with as few as 15 CD4+ cells/microl in their peripheral blood. Expanded cells were a mixture of CD8+CD45RO+ and CD4+CD45RO+ T cells. The CD8+ cells were also CD30+CDw60+CD11b-. When challenged with autologous B cell targets expressing HIV-1 Env protein, unseparated expanded cells, and purified CD8+ and CD4+ T cell subsets, proliferated and secreted MIP-1alpha and RANTES. Expanded cells were negative for HIV-1 by PCR and by culture. Culture supernatants inhibited the replication of HIV-1 in CD4+ cells in vitro. These studies indicate that HIV-1 can stimulate chemokine release by CD8+ and CD4+ cells expanded from infected lymph nodes, even from individuals with advanced infection. The numbers of chemokine-releasing T cells produced in these short-term cultures may be sufficient to be applied therapeutically as an autologous cellular therapy for HIV-1.
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PMID:HIV type 1-reactive chemokine-producing CD8+ and CD4+ cells expanded from infected lymph nodes. 961 75

Increase Th2 cytokine production may contribute to some clinical manifestations of HIV infection, and studies have suggested that IL-13 rather than IL-4 is involved in these conditions. We directly tested this hypothesis by administrating IL-13 to SIV-infected macaques. SIV-infected rhesus macaques received a daily subcutaneous injection for 21 days of either IL-13 (10 microg/kg/day) or a placebo. The four macaques treated with IL-13 experienced body weight loss (9.95 +/- 0.71%) related to intestinal tract damage: they all suffered from a complete atrophy of duodenal villi. This was presumably due to premature epithelial cell death: proliferating Ki67+ cells in glandular crypts were as numerous as in control animals, but many epithelial cells developed apoptosis. The duodenal mucosa was infiltrated with cells expressing CD56 and PEN5, two markers of NK cells, and there was a deregulation of local cytokine and chemokine production characterized by a decrease in IL-10 gene expression (25% of controls) and an increase in gene expression for IFN-gamma (4-fold control), MIP-1alpha (8-fold control), and MIP-1beta (13-fold control). Thus, IL-13 can induce digestive epithelial cell injury in vivo in primates infected with a retrovirus. Therefore, its role should be considered in digestive manifestations of HIV infection as well as in other disorders associated with intestinal epithelial atrophy.
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PMID:Administration of interleukin 13 to simian immunodeficiency virus-infected macaques: induction of intestinal epithelial atrophy. 964 77

Macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normal T cell expressed and secreted), which are the natural ligands of the CC-chemokine receptor CCR5, inhibit replication of MT-2- negative strains of HIV-1 by interfering with the ability of these strains to utilize CCR5 as a coreceptor for entry in CD4(+) cells. The present study investigates the capacity of natural killer (NK) cells isolated from HIV-infected individuals to produce CC-chemokines and to suppress HIV replication in autologous, endogenously infected cells as well as to block entry of MT-2-negative HIV into the CD4(+) T cell line PM-1. NK cells freshly isolated from HIV-infected individuals had a high number of mRNA copies for MIP-1alpha and RANTES. NK cells produced significant amounts of RANTES, MIP-1alpha, and MIP-1beta constitutively, in response to stimulation with IL-2 alone and when they were performing their characteristic lytic activity (K562 killing). After CD16 cross-linking and stimulation with IL-2 or IL-15 NK cells produced CC-chemokines to levels comparable to those produced by anti-CD3-stimulated CD8(+) T cells. Furthermore, CD16 cross-linked NK cells suppressed (49-97%) viral replication in cocultures of autologous CD8/NK-depleted PBMC to a degree similar to that of PHA or anti-CD3-stimulated CD8(+) T cells. In 50% of patients tested, NK-mediated HIV suppression could be abrogated by neutralizing antibodies to MIP-1alpha, MIP-1beta and RANTES; in contrast, CD8(+) T cell-mediated suppression was not significantly overcome upon neutralization of CC-chemokines. Supernatants derived from cultures of CD16 cross-linked NK cells stimulated with IL-2 or IL-15 dramatically inhibited entry of a MT-2-negative strain of HIV, BaL, in the CD4(+)CCR5(+) PM-1 T cell line. These data suggest that activated NK cells may be an important source of CC-chemokines in vivo and may suppress HIV replication by CC-chemokine-mediated mechanisms in addition to classic NK-mediated lytic mechanisms.
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PMID:Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro. 964 76

Signal transductions by the dual-function CXCR4 and CCR5 chemokine receptors/HIV type 1 (HIV-1) coreceptors were electrophysiologically monitored in Xenopus laevis oocytes that also coexpressed the viral receptor CD4 and a G protein-coupled inward-rectifying K+ channel (Kir 3.1). Large Kir 3.1-dependent currents generated in response to the corresponding chemokines (SDF-1alpha for CXCR4 and MIP-1alpha; MIP-1beta and RANTES for CCR5) were blocked by pertussis toxin, suggesting involvement of inhibitory guanine nucleotide-binding proteins. Prolonged exposures to chemokines caused substantial but incomplete desensitization of responses with time constants of 5-7 min and recovery time constants of 12-19 min. CXCR4 and CCR5 exhibited heterologous desensitization in this oocyte system, suggesting possible inhibition of a common downstream step in their signaling pathways. In contrast to chemokines, perfusion with monomeric or oligomeric preparations of the glycoprotein of Mr 120, 000 (gp120) derived from several isolates of HIV-1 did not activate signaling by CXCR4 or CCR5 regardless of CD4 coexpression. However, adsorption of the gp120 from a T-cell-tropic virus resulted in CD4-dependent antagonism of CXCR4 response to SDF-1alpha, whereas gp120 from macrophage-tropic viruses caused CD4-dependent antagonism of CCR5 response to MIP-1alpha. These antagonisms could be partially overcome by high concentrations of chemokines and were specific for coreceptors of the corresponding HIV-1 isolates, suggesting that they resulted from direct interactions of gp120-CD4 complexes with coreceptors and that they did not involve the desensitization pathway. These results indicate that monomeric or oligomeric gp120s specifically antagonize CXCR4 and CCR5 signaling in response to chemokines, but they do not exclude the possibility that gp120s might also function as weak agonists in some cells. The gp120-mediated disruption of CXCR4 and CCR5 signaling may contribute to AIDS pathogenesis.
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PMID:gp120 envelope glycoproteins of human immunodeficiency viruses competitively antagonize signaling by coreceptors CXCR4 and CCR5. 965 30

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