title: CAF-mediated human immunodeficiency virus (HIV) type 1 transcriptional inhibition is distinct from alpha-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 (LTR)-driven gene expression. The inhibitory effect of CAF on HIV-1 LTR activation is mediated through STAT1 activation. A recent study reports that alpha-defensins 1 to 3 account for CAF activity against HIV-1. Here, we address whether alpha-defensins, particularly alpha-defensin-1, contribute to CAF-mediated inhibition of HIV-1 transcription. Both recombinant alpha-defensin-1 and CAF derived from herpesvirus saimiri (HVS)-transformed CD8(+) cells inhibited HIV-1 infection and gene expression. For both factors, the inhibition of HIV-1 infection did not occur at the level of viral entry. Pretreatment of cells with alpha-defensin-1 followed by a washing out prior to infection blocked infection by HIV-1, indicating that direct inactivation of virions was not required for its inhibitory effect. In contrast to CAF, alpha-defensin-1 did not inhibit phorbol myristate acetate- or Tat-mediated HIV-1 LTR activation in a transient transfection system, nor did it activate STAT1 tyrosine phosphorylation. Furthermore, alpha-defensins 1 to 3 were below the level of detection in a panel of HVS-transformed CD8(+) cells with potent HIV-1 inhibitory activity and a neutralizing antibody against alpha-defensins 1 to 3 did not reverse the inhibitory effect of CAF on HIV-1 gene expression in infected cells and on HIV-1 LTR activation in transfected cells. Taken together, our results suggest that alpha-defensin-1 inhibits HIV-1 infection following viral entry but that alpha-defensins 1 to 3 are not responsible for the HIV-1 transcriptional inhibition by CAF.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Theresa Li-Yun
authors.initials: TL
authors.lastname: Chang
authors.forename: Fleur
authors.initials: F
authors.lastname: François
authors.forename: Arevik
authors.initials: A
authors.lastname: Mosoian
authors.forename: Mary E
authors.initials: ME
authors.lastname: Klotman
mesh_terms: D000998:Antiviral Agents / Q000502:physiology*; D001685:Biological Factors / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002461:Cell Line, Transformed; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000821:virology; D014158:Transcription, Genetic / Q000187:drug effects*; D023084:alpha-Defensins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000998:Antiviral Agents; D001685:Biological Factors; D023084:alpha-Defensins; C406413:human neutrophil peptide 1