CAF-Mediated Human Immunodeficiency Virus (HIV) Type 1 Transcriptional Inhibition Is Distinct from α-Defensin-1 HIV Inhibition

Chang, Theresa L.; François, Fleur; Mosoian, Arevik; Klotman, Mary E.

doi:10.1128/jvi.77.12.6777-6784.2003

Cited by 109 publications

(103 citation statements)

References 52 publications

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“…Numerous papers revisited and expanded upon the original paper describing anti-HIV-1 activity of ␣-defensins (41). The anti-HIV-1 activity of ␣-defensins is reported to be dual, the peptides acting directly as virucidal compounds and indirectly as modulators of transcription (42,43). Interestingly, potential in vivo roles for ␣-defensins in the protection against HIV-1 infection were recently reported.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Flamand

Tremblay

Borgeat

2007

The Journal of Immunology

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Leukotriene B4 (LTB4) is a bioactive lipid derived from the metabolism of arachidonic acid. Mainly produced by polymorphonuclear leukocytes (PMN) and macrophages, LTB4 triggers several functional responses important in host defense, including the secretion of lysosomal enzymes, the activation of NADPH oxidase activity, NO formation, and phagocytosis. We report that LTB4, but not structural analogs thereof, stimulates primed human PMN to release molecules having potent antimicrobial activities. Exposure of bacteria (Escherichia coli and Staphylococcus aureus) or viruses (herpes simplex virus type 1 and HIV type 1) to supernatants of LTB4-activated PMN lead to ≥90% reduction in infectivity. ELISA and mass spectroscopy analysis of proteins released from LTB4-activated PMN have identified several antimicrobial proteins, including α-defensins, cathepsin G, elastase, lysozyme C, and LL-37, that are likely to participate in the killing of microorganisms. In addition to these in vitro observations, i.v. injections of LTB4 (50 μg/kg) to monkeys led to an increase in α-defensin plasmatic levels and enhanced ex vivo antimicrobial activities of plasma. These results demonstrate the ability of LTB4 to cause the release of potent antimicrobial agents from PMN in vitro as well as in vivo and add further support to the important role of LTB4 in host defense.

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Section: Discussionmentioning

confidence: 99%

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Flamand

Tremblay

Borgeat

2007

The Journal of Immunology

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“…In addition, they have been shown not to be responsible for the Stat1-mediated inhibition of the viral promoter transcriptional activation. 89 Protease activity can also play a role as protease inhibitors such as leupeptin restore HIV-1 infectivity in CD8+ T cells. 90 Other factors, such as ribonucleases may also have antiviral activity.…”

Section: Prospectsmentioning

confidence: 99%

Gene therapy progress and prospects: Novel gene therapy approaches for AIDS

Wolkowicz

Nolan

2005

Gene Ther

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“…The first mechanism is supported by evidence that ␣-defensins inhibit the HIV infectious cycle after virus entry into target cells. 23,24 This effect appears to be mediated The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734.…”

Section: Introductionmentioning

confidence: 99%

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

Furci¹,

Sironi²,

Tolazzi³

et al. 2006

Blood

102

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␣-defensins are antibiotic peptides that act as natural inhibitors of HIV-1 infection. However, the mechanisms of such inhibition are still unclear. Here we demonstrate that ␣-defensins block the earliest steps in the viral infectious cycle, as documented using an HIV-1 envelopemediated cell-fusion assay. A broad-spectrum inhibitory activity was observed on primary and laboratory-adapted HIV-1 isolates irrespective of their coreceptor specificity and genetic subtype. A primary mechanism of such inhibition was identified as the ability of ␣-defensins to bind specifically both to the primary HIV-1 cellular receptor, CD4, and to the viral envelope glycoprotein, gp120. Moreover, treatment of CD4 ؉ T cells with ␣-defensins caused a dramatic downmodulation of CD4 expression. By monoclonal antibody competition, the regions of interaction with ␣-defensins were mapped to the D1 domain of CD4 and to a surface contiguous to the CD4-and coreceptorbinding sites of gp120. Consistent with these findings, ␣-defensins inhibited the binding of gp120 to CD4. These data demonstrate that ␣-defensins specifically block the initial phase of the HIV infectious cycle and modulate the expression of CD4, a critical receptor in the physiology of T-cell activation. IntroductionEvidence suggests that a concerted action of innate and adaptive immune responses is essential for the effective containment and, ultimately, the clearance of invading microorganisms. 1 The innate immune system is phylogenetically more archaic and constitutes the first line of antimicrobial defense, characterized by a rapid response time; however, it is limited in its target specificity. By contrast, the adaptive immune system has evolved refined molecular devices for the recognition of a wide variety of specific epitopes, but a lag time is required for its functional activation. Once activated, most of the cells involved in both innate and cognate immune responses secrete soluble factors, including cytokines, chemokines, antibiotic peptides, and others, which can directly antagonize infectious microorganisms and/or contribute to the recruitment and activation of other immune cells, thereby amplifying the cascade of defense mechanisms and bolstering their effectiveness. 2,3 In HIV infection, various host-derived soluble factors with antiviral activity have been described, which act by both specific and nonspecific mechanisms. These include chemokines such as RANTES, MIP-1␣, and MIP-1␤ 4 ; cytokines such as the interferons, IL-10, IL-13, IL-16, transforming growth factor-␤, and others 5 ; as well as, more recently, defensins. [6][7][8][9] Defensins are natural antibiotic peptides that play an important role in innate immune responses by acting as broad-spectrum antibacterial, antifungal, and antiviral effector molecules 10 as well as by enhancing certain adaptive immune responses. 11 ␣-defensins 1 to 3 are 3-to 4-kDa cationic peptides (29 to 30 amino acids [aa]) characterized by a conserved 6-cysteine motif, with 3 disulfide bonds that impose a characteristic ␤-sheet ...

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CAF-Mediated Human Immunodeficiency Virus (HIV) Type 1 Transcriptional Inhibition Is Distinct from α-Defensin-1 HIV Inhibition

Abstract: CD8؉ T lymphocytes can inhibit human immunodeficiency virus type 1 (HIV-1) replication by secreting a soluble factor(s) known as CD8 ؉ T-lymphocyte antiviral factor (CAF). One site of CAF action is inhibition of HIV-1 RNA transcription, particularly at the step of long terminal repeat (

Cited by 109 publications

References 52 publications

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Gene therapy progress and prospects: Novel gene therapy approaches for AIDS

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

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