A Strategy for Prophylactic Vaccination Against HIV

Salk, Jonas; Bretscher, Peter A.; Salk, Peter L.; Clerici, Mario; Shearer, Gene M.

doi:10.1126/science.8098553

Cited by 188 publications

(67 citation statements)

References 55 publications

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“…Recently, the identification of cohorts of HIV-exposed individuals who remain free of infection over a long period of viral exposure (53) as well as the existence of a small subgroup of HIV-1-infected subjects who are long term nonprogressors were described (54). Together with recent reports on viral life cycle (55,56), the above evidence argues that HIV infection and disease progression may ultimately result from a complex interplay between viral and host cellular factors involved in the immunological response to the viral infection and in the clinical evolution of AIDS.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Induces the Expression of the Interleukin-6 (IL6) Gene by Binding to the IL6 Leader RNA and by Interacting with CAAT Enhancer-binding Protein β (NF-IL6) Transcription Factors

Ambrosino

Ruocco

Chen

et al. 1997

Journal of Biological Chemistry

107

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Human immunodeficiency virus type 1 (HIV-1) infection is associated with severe psoriasis, B cell lymphoma, and Kaposi's sarcoma. A deregulated production of interleukin-6 (IL6) has been implicated in the pathogenesis of these diseases. The molecular mechanisms underlying the abnormal IL6 secretion of HIV-1-infected cells may include transactivation of the IL6 gene by HIV-1. Here we report the molecular mechanisms of Tat activity on the expression of the IL6 gene. By using 5 deletion mutants of pIL6Pr-CAT and using IL6:HIV-1-LTR hybrid constructs where discrete regions of the IL6 promoter replaced the TAR sequence in HIV-1 LTR, we identified a short sequence of the 5-untranslated region of the IL6 mRNA that is required for Tat to trans-activate the IL6 promoter. This sequence acquires a stemloop structure and includes a UCU sequence that binds to Tat and is necessary for full trans-activation. In addition, we provide the evidence that Tat can function by enhancing the CAAT enhancer-binding protein (C/EBP) DNA binding activity and is able to complex with in vitro translated C/EBP␤, which is a major mediator of IL6 promoter function. By using the yeast two-hybrid system and immunoprecipitation, we observed that the interaction of Tat with C/EBP proteins also occurred in vivo. The data are consistent with the possibility that Tat may function on heterologous genes by interacting with RNA structures possibly present in a large number of cellular and viral genes. In addition, Tat may function by protein-protein interactions, leading to the generation of heterodimers with specific transcription factors.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Induces the Expression of the Interleukin-6 (IL6) Gene by Binding to the IL6 Leader RNA and by Interacting with CAAT Enhancer-binding Protein β (NF-IL6) Transcription Factors

Ambrosino

Ruocco

Chen

et al. 1997

Journal of Biological Chemistry

107

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“…However, recent evidence suggests that CD8 T cells may also divide functionally into two types, corresponding to Thl and Th2 CD4 cells (4,48).…”

Section: Discussionmentioning

confidence: 99%

Divergent T-cell cytokine patterns in inflammatory arthritis.

Simon

Seipelt

Sieper

1994

Proc. Natl. Acad. Sci. U.S.A.

338

160

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A major immunoregulatory mechanism in inflammatory infections and allergic dies Is the control of the balance of cytokines secreted by Thl/Th2 subsets of T helper (Th) cells. This might also be true in autoimmune diseas; a Th2 pattern that prevents an effective immune response in infections with intracellular bacteria may favor immunosuppression in autoimmune disease. The pattern of cytokine expression was compared in the synovial tissue from patients with a typical autoimmune disease, rheumatoid arthritis, and with a disorder with similar synovial pathology but driven by persisting exogenous antigen, reactive arthritis. We screened 12 rheumatoid and 9 reactive arthritis synovial tissues by PCR and in situ hybridization for their expression of T-cell cytokines. The cytokine pattern differs significantly between the two diseases; rheumatoid arthritis samples express a Thllike pattern whereas in reactive arthritis interferon y expression is accompanied by that of interleukin 4. Studying the expression of cytokines by in situ hybridization confimed the results found by PCR; they also show an extremely low frequency of cytokine-transcribing cells. In a double-staining experiment, it was demonstrated that interleukin 4 is made by CD4 cells. These experiments favor the possibility of therapeutic intervention in inflammatory rheumatic diseases by means of inhibitory cytokines.The control of the balance of cytokines secreted by differing T-cell subsets is emerging as a major immunoregulatory mechanism (1, 2). The division ofT helper (Th) cells into Thl [secreting interferon y (IFN-y) and interleukin (IL) 2] and Th2 (secreting IL-4 and IL-5) found in the mouse (3) holds good for humans (2), provided that attention is focused on IL-4 (4). Cytokines of the Thl spectrum are generally elevated in successful responses to a variety of intracellular pathogens (5), and Th2 cytokines are elevated in allergic diseases and in helminth infections (6, 7). The balance appears to be maintained not only by the cytokines considered originally to be of Thl/Th2 type but also by other inhibitory cytokines such as transforming growth factor (3 and I1-10, which are not confined to one ofthe original subsets and can additionally be secreted by non-T cells (8,9). In this context the pattern of T-cell cytokines in reactive and rheumatoid arthritis is of particular interest. Not only is rheumatoid arthritis among the commonest of the candidate autoimmune diseases, it also offers easy access to the site of inflammation. Reactive and rheumatoid arthritis are sister diseases, in the sense that both are characterized by inflammation of joints and the development of similar synovial pathology. Reactive arthritis is triggered by intracellular bacteria that persist in the joint (10,11), whereas for rheumatoid arthritis, the triggering events are unknown but thought not to involve persistent infection. Comparison ofthe two diseases should be informative.The importance of T cells in initiating and maintaining inflammation in the rheumatic diseases...

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“…The mechanism whereby human immunodeficiency virus produces this inhibition of IL-12 production is unknown but has been suggested to be important for the progressive development of immunodeficiency (3,6,14,36,42,44). Because IL-12 is sufficient to induce development of the Th1 phenotype, knowledge of its regulation is important for understanding cell-mediated immune responses (21).…”

Section: ϫ135mentioning

confidence: 99%

Regulation of Interleukin 12 p40 Expression through an NF-κB Half-Site

Murphy

Cleveland

Kulesza

et al. 1995

Molecular and Cellular Biology

472

401

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Interleukin 12 (IL-12) is an inducible cytokine composed of 35-and 40-kDa subunits that is critical for promoting T helper type 1 development and cell-mediated immunity against pathogens. The 40-kDa subunit, expressed by activated macrophages and B cells, is induced by several pathogens in vivo and in vitro and is augmented or inhibited by gamma interferon (IFN-␥) or IL-10, respectively. Control of IL-12 p40 expression is therefore important for understanding resistance and susceptibility to a variety of pathogens, including Leishmania major and perhaps human immunodeficiency virus. In this report, we provide the first characterization of IL-12 p40 gene regulation in macrophages. We localize inducible activity of the promoter to the sequence ؊122 GGGGAATTTTA؊132 not previously recognized to bind Rel family transcription factors. We demonstrate binding of this sequence to NF-B (p50/p65 and p50/c-Rel) complexes in macrophages activated by several p40-inducing pathogens and provide functional data to support a role for NF-B family members in IL-12 p40 activation. Finally, we find that IFN-␥ treatment of cells enhances this binding interaction, thus potentially providing a mechanism for IFN-␥ augmentation of IL-12 production by macrophages.Interleukin 12 (IL-12) production by macrophages is critical in induction of T helper type 1 (Th1) cells during initial immune responses to pathogens (5,15,21,32,45). Th1 cells produce gamma interferon (IFN-␥) and IL-2, which promote macrophage activation and cytolytic T-cell maturation, thus generating effective cell-mediated responses to intracellular pathogens (33, 37). The macrophage is the principal source of IL-12 production in responses to certain intracellular pathogens, such as Listeria monocytogenes (20,21,48). Recently, Chehimi and colleagues described diminished IL-12 production by macrophages in human immunodeficiency virus-infected individuals (2) and proposed that this may contribute to reduced cell-mediated immunity seen in AIDS (6, 7). Thus, understanding IL-12 production by macrophages, and its inhibition in settings of disease, could contribute to immune response-based therapies or vaccine designs.IL-12 is an inducible, heterodimeric, disulfide-linked cytokine composed of 35-and 40-kDa subunits encoded by separate genes (5,19,24,43,49). Expression of the 35-kDa subunit is constitutive and ubiquitous. In contrast, the 40-kDa subunit is expressed only by macrophages and B cells; it is strongly induced by several bacterial stimuli and is considered the regulatory component for IL-12 expression (11). Further, we and others have found that some cytokines, notably IFN-␥ and IL-10, can exert their effects on T-cell responses by augmenting or inhibiting macrophage production of 21,26). To date, the transcriptional regulation of p40 gene induction by bacteria and by cytokines is uncharacterized.In this report, we demonstrate several important features of IL-12 p40 gene regulation in macrophages. First, we localize the inducible promoter activity for the p40 gene to a nov...

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A Strategy for Prophylactic Vaccination Against HIV

Cited by 188 publications

References 55 publications

HIV-1 Tat Induces the Expression of the Interleukin-6 (IL6) Gene by Binding to the IL6 Leader RNA and by Interacting with CAAT Enhancer-binding Protein β (NF-IL6) Transcription Factors

HIV-1 Tat Induces the Expression of the Interleukin-6 (IL6) Gene by Binding to the IL6 Leader RNA and by Interacting with CAAT Enhancer-binding Protein β (NF-IL6) Transcription Factors

Divergent T-cell cytokine patterns in inflammatory arthritis.

Regulation of Interleukin 12 p40 Expression through an NF-κB Half-Site

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