It is unclear why immunological control of HIV replication is incomplete in most infected individuals. We examined here the CD8+ T cell response to HIV-infected CD4+ T cells in rare patients with immunological control of HIV. Although high frequencies of HIV-specific CD8+ T cells were present in nonprogressors and progressors, only those of nonprogressors maintained a high proliferative capacity. This proliferation was coupled to increases in perforin expression. These results indicated that nonprogressors were differentiated by increased proliferative capacity of HIV-specific CD8+ T cells linked to enhanced effector function. In addition, the relative absence of these functions in progressors may represent a mechanism by which HIV avoids immunological control.
SummaryMig is a chemokine of the CXC subfamily that was discovered by differential screening of a cDNA library prepared from lymphokine-activated macrophages. The mig gene is inducible in macrophages and in other cells in response to interferon (IFN)-% We have transfected Chinese hamster ovary (CHO) cells with cDNA encoding human Mig and we have derived CHO cell lines from which we have purified recombinant human Mig (rHuMig). rHuMig induced the transient elevation of [Ca2+]i in human tumor-infiltrating T lymphocytes (TIL) and in cultured, activated human peripheral blood-derived lymphocytes. No responses were seen in human neutrophils, monocytes, or Epstein-Barr virus-transformed B lymphoblastoid cell lines. rHuMig was chemotactic for TIL by a modified Boyden chamber assay but rHuMig was not chemotactic for neutrophils or monocytes. The CHO cell lines, IFN-~/-treated human peripheral-blood monocytes, and IFN-~/-treated cells of the human monocytic cell line THP-1 all secreted multiple and identical HuMig species as revealed by SDS-PAGE. Using the CHO-derived rHuMig, we have shown that the species' heterogeneity is due to proteolytic cleavage at basic carboxy-terminal residues, and that the proteolysis occurs before and not after rHuMig secretion by the CHO cells. The major species of secreted rHuMig ranged from 78 to 103 amino acids in length, the latter corresponding to the full-length secreted protein predicted from the HuMig cDNA. Carboxy-terminal-truncated forms ofrHuMig were of lower specific activity compared to full-length rHuMig in the calcium flux assay, and the truncated species did not block the activity of the full-length species. It is likely that HuMig plays a role in T cell trafficking and perhaps in other aspects of the physiology of activated T cells.
Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) enter target cells by forming a complex between the viral envelope protein and two cell-surface membrane receptors: CD4 and a 7-span transmembrane chemokine receptor. Isolates of HIV that differ in cellular tropism use different subsets of chemokine receptors as entry cofactors: macrophage-tropic HIVs primarily use CCR5, whereas T-cell-tropic and dual-tropic isolates use CXCR4 receptors. HIV-mediated signal transduction through CCR5 is not required for efficient fusion and entry of HIV in vitro. Here we show that recombinant envelope proteins from macrophage-tropic HIV and SIV induce a signal through CCR5 on CD4+ T cells and that envelope-mediated signal transduction through CCR5 induces chemotaxis of T cells. This chemotactic response may contribute to the pathogenesis of HIV in vivo by chemo-attracting activated CD4+ cells to sites of viral replication. HIV-mediated signalling through CCR5 may also enhance viral replication in vivo by increasing the activation state of target cells. Alternatively, envelope-mediated CCR5 signal transduction may influence viral-associated cytopathicity or apoptosis.
The HIV-1 Tat protein is a potent chemoattractant for monocytes. We observed that Tat shows conserved amino acids corresponding to critical sequences of the chemokines, a family of molecules known for their potent ability to attract monocytes. Synthetic Tat
Mycobacterium tuberculosis is a virulent intracellular pathogen that survives in macrophages even in the presence of an intact adaptive immune response. Type I interferons (IFN) have been shown to exacerbate tuberculosis in mice and to be associated with disease progression in infected humans. Nevertheless, the mechanisms by which type I IFN regulate the host response to M. tuberculosis infection are poorly understood. In this study, we show that M. tuberculosis induces an IFN-related gene expression signature in infected primary human macrophages, which is dependent on host type I IFN signaling as well as the mycobacterial virulence factor, Region of Difference 1. We further demonstrate that type I IFN selectively limits the production of IL-1β, a critical mediator of immunity to M. tuberculosis. This regulation occurs at the level of IL1B mRNA expression, rather than caspase-1 activation or autocrine IL-1 amplification and appears to be preferentially utilized by virulent mycobacteria since avirulent M. bovis bacillus Calmette-Guerin (BCG) fails to trigger significant expression of type I IFN or release of mature IL-1β protein. The latter property is associated with decreased caspase-1-dependent IL-1β maturation in the BCG-infected macrophages. Interestingly, human monocytes in contrast to macrophages produce comparable levels of IL-1β in response to either M. tuberculosis or BCG. Together, these findings demonstrate that virulent and avirulent mycobacteria employ distinct pathways for regulating IL-1β production in human macrophages and reveal that in the case of M. tuberculosis infection the induction of type I IFN is a major mechanism utilized for this purpose.
The first approved COVID‐19 vaccines include Pfizer/BioNTech BNT162B2, Moderna mRNA‐1273 and AstraZeneca recombinant adenoviral ChAdOx1‐S. Soon after approval, severe allergic reactions to the mRNA‐based vaccines that resolved after treatment were reported. Regulatory agencies from the European Union, Unites States and the United Kingdom agree that vaccinations are contraindicated only when there is an allergy to one of the vaccine components or if there was a severe allergic reaction to the first dose. This position paper of the European Academy of Allergy and Clinical Immunology (EAACI) agrees with these recommendations and clarifies that there is no contraindication to administer these vaccines to allergic patients who do not have a history of an allergic reaction to any of the vaccine components. Importantly, as is the case for any medication, anaphylaxis may occur after vaccination in the absence of a history of allergic disease. Therefore, we provide a simplified algorithm of prevention, diagnosis and treatment of severe allergic reactions and a list of recommended medications and equipment for vaccine centres. We also describe potentially allergenic/immunogenic components of the approved vaccines and propose a workup to identify the responsible allergen. Close collaboration between academia, regulatory agencies and vaccine producers will facilitate approaches for patients at risks, such as incremental dosing of the second injection or desensitisation. Finally, we identify unmet research needs and propose a concerted international roadmap towards precision diagnosis and management to minimise the risk of allergic reactions to COVID‐19 vaccines and to facilitate their broader and safer use.
Wild-type human respiratory syncytial virus (HRSV) is a poor inducer of alpha/beta interferons (IFN-␣/).However, recombinant HRSV lacking the NS1 and NS2 genes (⌬NS1/2) induced high levels of IFN-␣ and - in human pulmonary epithelial cells (A549) as well as in macrophages derived from primary human peripheral blood monocytes. Results with NS1 and NS2 single-and double-gene-deletion viruses indicated that the two proteins function independently as well as coordinately to achieve the full inhibitory effect, with NS1 having a greater independent role. The relative contributions of the individual NS proteins were the converse of that recently described for bovine RSV (J. F. Valarcher, J. Furze, S. Wyld, R. Cook, K. K. Conzelmann, and G. Taylor, J. Virol. 77:8426-8439, 2003). This pattern of inhibition by HRSV NS1 and NS2 also extended to the newly described antiviral cytokines IFN-1, -2 and -3.Human respiratory syncytial virus (HRSV) is the most common cause of viral bronchiolitis and pneumonia in infants and children worldwide, and a vaccine is needed (9, 10). HRSV belongs to the genus Pneumovirus of the family Paramyxoviridae and has single-stranded, negative-sense RNA as its genome (10). One of the differences between the members of the genus Pneumovirus and other members of Paramyxoviridae is that Pneumovirus species express two putative nonstructural proteins, NS1 and NS2, from separate mRNAs encoded by the first two genes in the viral gene order. Recombinant HRSVs in which the NS1 and/or NS2 genes have been deleted singly or in combination (⌬NS1, ⌬NS2, and ⌬NS1/2 viruses) exhibit reduced replication in cultured cells that are competent to produce alpha interferon (IFN-␣) and IFN-, as well as in mice, monkeys, and chimpanzees, but replicate more like wild-type (wt) HRSV in Vero cells that lack the IFN-␣/ genes (15, 16, 21-23, 25, 28). Clinical trials of recombinant HRSV (rHRSV) vaccine candidates lacking NS1 or NS2 are under way or in preparation. Bovine RSV (BRSV) is an animal counterpart of HRSV that exhibits a strong host range specificity in vivo and differs from HRSV by up to 71% with regard to the amino acid sequences of the various individual proteins (5). Studies with BRSV provided evidence that its NS1 and NS2 proteins can function independently as well as cooperatively to reduce the effectiveness of the IFN ␣/-mediated antiviral state (3,19). How this occurs is unclear, although it does not appear to involve an inhibition of either intracellular signaling or the expression of IFN-stimulated genes (4, 27).In the present study, we describe inhibition of the induction of IFN-␣ and - by the NS1 and NS2 proteins of HRSV. In addition, we investigated the effect of HRSV infection and of deleting NS1 and/or NS2 on the expression of the newly described antiviral cytokines IFN-1, -2 and -3 (alternatively designated interleukin 29 (IL-29), -28A, and -28B, respectively) (17, 20). These cytokines differ genetically and structurally from INF-␣/ but share the following characteristics. They appear to be broa...
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