(1/2306) Similarities and differences in RANTES- and (AOP)-RANTES-triggered signals: implications for chemotaxis.
Chemokines are a family of proinflammatory cytokines that attract and activate specific types of leukocytes. Chemokines mediate their effects via interaction with seven transmembrane G protein-coupled receptors (GPCR). Using CCR5-transfected HEK-293 cells, we show that both the CCR5 ligand, RANTES, as well as its derivative, aminooxypentane (AOP)- RANTES, trigger immediate responses such as Ca2+ influx, receptor dimerization, tyrosine phosphorylation, and Galphai as well as JAK/STAT association to the receptor. In contrast to RANTES, (AOP)-RANTES is unable to trigger late responses, as measured by the association of focal adhesion kinase (FAK) to the chemokine receptor complex, impaired cell polarization required for migration, or chemotaxis. The results are discussed in the context of the dissociation of the late signals, provoked by the chemokines required for cell migration, from early signals. (+info)
(2/2306) Interactions between Tat and TAR and human immunodeficiency virus replication are facilitated by human cyclin T1 but not cyclins T2a or T2b.
The transcriptional transactivator (Tat) from the human immunodeficiency virus (HIV) does not function efficiently in Chinese hamster ovary (CHO) cells. Only somatic cell hybrids between CHO and human cells and CHO cells containing human chromosome 12 (CHO12) support high levels of Tat transactivation. This restriction was mapped to interactions between Tat and TAR. Recently, human cyclin T1 was found to increase the binding of Tat to TAR and levels of Tat transactivation in rodent cells. By combining individually with CDK9, cyclin T1 or related cyclins T2a and T2b form distinct positive transcription elongation factor b (P-TEFb) complexes. In this report, we found that of these three cyclins, only cyclin T1 is encoded on human chromosome 12 and is responsible for its effects in CHO cells. Moreover, only human cyclin T1, not mouse cyclin T1 or human cyclins T2a or T2b, supported interactions between Tat and TAR in vitro. Finally, after introducing appropriate receptors and human cyclin T1 into CHO cells, they became permissive for infection by and replication of HIV. (+info)
(3/2306) Induction of autoantibodies to mouse CCR5 with recombinant papillomavirus particles.
The vertebrate immune system has evolved to respond vigorously to microbial infection but to ignore self-antigens. Evidence has emerged that B cell responses to viruses are initiated by immune recognition of ordered arrays of antigen on the viral surface. To test whether autoantibodies against a self-antigen can be induced by placing it in a context that mimics the ordered surface of a viral particle, a peptide representing an extracellular loop of the mouse chemokine receptor CCR5 was incorporated into an immunodominant site of the bovine papillomavirus virus L1 coat protein, which self-assembles into virus-like particles. Mice inoculated with chimeric L1-CCR5 particles generated autoantibodies that bound to native mouse CCR5, inhibited binding of its ligand RANTES, and blocked HIV-1 infection of an indicator cell line expressing a human-mouse CCR5 chimera. These results suggest a general method for inducing autoantibodies against self-antigens, with diverse potential basic research and clinical applications. (+info)
(4/2306) No evidence for an effect of the CCR5 delta32/+ and CCR2b 64I/+ mutations on human immunodeficiency virus (HIV)-1 disease progression among HIV-1-infected injecting drug users.
The relationship between CCR5 and CCR2b genotypes and human immunodeficiency virus (HIV)-1 disease progression was studied among the 108 seroconverters of the Amsterdam cohort of injecting drug users (IDUs). In contrast to earlier studies among homosexual men, no effect on disease progression of the CCR5 Delta32/+ and the CCR2b 64I/+ genotypes was found, when progression to AIDS, death, or a CD4 cell count <200/microL was compared by a Cox proportional hazards model. Furthermore, CD4 cell decline (by a regression model for repeated measurements) and virus load in the first 3 years after seroconversion did not differ between the CCR5 and CCR2b wild type and heterozygous genotypes. A nested matched case-control study also revealed no significant effect of the CCR5 and CCR2b mutations. Immunologic differences between IDUs and homosexual men may account for the observed lack of effect. Alternatively, difference in transmission route or characteristics of the HIV-1 variants that circulate in IDUs could also explain this phenomenon. (+info)
(5/2306) Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage.
To define predictors of survival time in late human immunodeficiency virus type 1 (HIV-1) disease, long- and short-duration survivors were studied after their CD4+ T cells fell to =50/mm3. Immune activation of CD4+ and CD8+ T cells, as measured by elevated cell surface expression of CD38 antigen, was strongly associated with shorter subsequent survival (P=.002). The naive CD45RA+CD62L+ T cell reserve was low in all subjects and did not predict survival (P=.34 for CD4+ and.08 for CD8+ cells). Higher virus burden correlated with CD8+ but not CD4+ cell activation and, after correcting for multiple comparisons, was not associated with shorter survival (P=.02). All of the patients' viruses used CCR5, CXCR4, or both, and coreceptor usage did not predict survival (P=. 27). Through mechanisms apparently unrelated to higher virus burden, immune activation is a major determinant of survival in advanced HIV-1 disease. (+info)
(6/2306) Chemokine and chemokine receptor gene variants and risk of non-Hodgkin's lymphoma in human immunodeficiency virus-1-infected individuals.
Normal B-lymphocyte maturation and proliferation are regulated by chemotactic cytokines (chemokines), and genetic polymorphisms in chemokines and chemokine receptors modify progression of human immunodeficiency virus-1 (HIV-1) infection. Therefore, 746 HIV-1-infected persons were examined for associations of previously described stromal cell-derived factor 1 (SDF-1) chemokine and CCR5 and CCR2 chemokine receptor gene variants with the risk of B-cell non-Hodgkin's lymphoma (NHL). The SDF1-3'A chemokine variant, which is carried by 37% of whites and 11% of blacks, was associated with approximate doubling of the NHL risk in heterozygotes and roughly a fourfold increase in homozygotes. After a median follow-up of 11.7 years, NHL developed in 6 (19%) of 30 SDF1-3'A/3'A homozygotes and 22 (10%) of 202 SDF1-+/3'A heterozygotes, compared with 24 (5%) of 514 wild-type subjects. The acquired immunodeficiency syndrome (AIDS)-protective chemokine receptor variant CCR5-triangle up32 was highly protective against NHL, whereas the AIDS-protective variant CCR2-64I had no significant effect. Racial differences in SDF1-3'A frequency may contribute to the lower risk of HIV-1-associated NHL in blacks compared with whites. SDF-1 genotyping of HIV-1-infected patients may identify subgroups warranting enhanced monitoring and targeted interventions to reduce the risk of NHL. (+info)
(7/2306) RANTES, IFN-gamma, CCR1, and CCR5 mRNA expression in peripheral blood, lymph node, and bronchoalveolar lavage mononuclear cells during primary simian immunodeficiency virus infection of macaques.
Primary infection of macaques with pathogenic isolates of simian immunodeficiency virus (SIV) (as a model of HIV infection in humans) represents a unique opportunity to study early lentivirus/host interactions. We sought to determine whether there is a temporal relationship linking SIV replication and dissemination and the expression of the chemokine RANTES (regulated upon activation normal T cell expressed and secreted) and the SIV/HIV coreceptor CCR5 in different tissues during acute SIV infection of macaques. Four cynomolgus macaques were inoculated intravenously with a pathogenic primary isolate of SIVmac251. RT-PCR was used to monitor the expression of RANTES and CCR5 mRNA in fresh isolated mononuclear cells from blood, lymph node, and bronchoalveolar lavages. These expressions were compared to those of IFN-gamma as an indicator of the development of the immune response and to another receptor for RANTES, CCR1, which is not described as a coreceptor for SIV/HIV-1 entry. An enhancement of CCR1/CCR5 mRNA expression was noticed during primary SIVmac251 infection of macaques, mainly in tissue. In the three different compartments investigated, IFN-gamma and RANTES overexpression was noticed by the time of systemic viral replication containment. Our results put CCR5 and RANTES mRNA expression back in the context of inflammatory and immune responses to SIV primary infection. (+info)
(8/2306) IL-15 induces the expression of chemokines and their receptors in T lymphocytes.
IL-15 is a T cell growth factor that shares many biological activities with IL-2 and uses the same beta/gamma polypeptides of the IL-2R complex for signal transduction. Accumulating evidence implicates an important role for this cytokine in the inflammatory response of the host. Consistent with such a role, IL-15 has been shown to be a chemoattractant for T lymphocytes, NK cells, and neutrophils. Extending these observations, we now show that IL-15 is a potent inducer of CC-, CXC-, and C-type chemokines in T lymphocytes. In addition, we demonstrate that IL-15 induces CC chemokine receptors, but not CXC chemokine receptors, in a dose-dependent manner. Thus, our findings suggest that the proinflammatory effects of IL-15 at least in part may be due to the induction of chemokines and their receptors in T cells. Furthermore, we demonstrate that IL-15 promotes entry and replication of macrophage-tropic HIV in T lymphocytes and suggest a plausible mechanism by which IL-15, a cytokine that is elevated in HIV-infected individuals, may promote the transition of HIV displaying the M-tropic phenotype primarily associated with the initial transmission into the T cell-tropic phenotype that predominates as the disease progresses. (+info)