Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression

Abstract

CD4+ cells of most individuals infected with HIV-1 harbor a C-terminally truncated and constitutively activated form of signal transducer and activator of transcription-5 (STAT5Δ). We report that the chronically HIV-infected U1 cell line expresses STAT5Δ but not full-length STAT5. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation of U1 cells promoted early activation of STAT5Δ and of extracellular signal regulated kinases (ERKs), followed by later activation of activator protein 1 (AP-1) and HIV expression. Inhibition of ERK/AP-1 by PD98,059 abolished, whereas either tyrphostin AG490 or a STAT5 small interfering RNA (siRNA) enhanced, virion production in GM-CSF–stimulated U1 cells. Chromatin immunoprecipitation demonstrated the induction of STAT5Δ binding to STAT consensus sequences in the HIV-1 promoter together with a decreased recruitment of RNA polymerase II after 1 hour of GM-CSF stimulation of U1 cells. Down-regulation of STAT5Δ by siRNA resulted in the up-regulation of both HIV-1 gag-pol RNA and p24 Gag antigen expression in CD8-depleted leukocytes of several HIV-positive individuals cultivated ex vivo in the presence of interleukin-2 but not of interleukin-7. Thus, the constitutively activated STAT5Δ present in the leukocytes of most HIV-positive individuals acts as a negative regulator of HIV expression.

TRIM22 Inhibits HIV-1 Transcription Independently of Its E3 Ubiquitin Ligase Activity, Tat, and NF-κB-Responsive Long Terminal Repeat Elements

“…These observations indicate that the HIV-1 LTR harbors specific sequences required for TRIM22 inhibitory effects. In this regard, TRIM22, as well as other TRIM family members, has not yet been credited with the capacity to directly interact with DNA (29,76,77), whereas several host transcription factors, including NF-B, NFAT-1, AP-1, Sp1, STAT5, and others (15,20,35,45,72), could be direct or indirect targets of TRIM22-mediated transcriptional inhibition of the HIV-1 LTR. In accordance also with the insensitivity of the CMV promoter, known to be mainly regulated by the NF-B activation cascade (30,42), in 293T cells and with the lack of net suppressive effects on TNF-␣-driven transcription of the HIV-1 LTR, we indeed observed that TRIM22 antiviral activities were independent of the tandem NF-B binding element within the core enhancer region of the viral promoter.…”

Late Expression of Granulysin by Microbicidal CD4+ T Cells Requires PI3K- and STAT5-Dependent Expression of IL-2Rβ That Is Defective in HIV-Infected Patients

“…Furthermore, the anticryptococcal activity of IL-2-stimulated CD4 ϩ T cells was not affected when activated in the presence of HIV-1 gp120 (data not shown) at concentrations previously demonstrated to inhibit T cell responses (60). Alternatively, it has been demonstrated that HIVinfected individuals bear a constitutively activated C-terminally truncated form of STAT5 (STAT5⌬) (61,62). Of particular importance to the data presented herein, these STAT5⌬ isoforms show resistance to proteasome-mediated degradation and enhanced ability to bind to DNA (63), and they have been suggested to act as dominant negative regulators of STAT5-dependent gene transcription (64), including potentially IL-2-induced expression of granulysin in CD4 ϩ T cells from HIV-infected individuals.…”

Dual Mechanism of Impairment of Interleukin-7 (IL-7) Responses in Human Immunodeficiency Virus Infection: Decreased IL-7 Binding and Abnormal Activation of the JAK/STAT5 Pathway

“…Negative regulators include SLIM proteins, which lead to ubiquitin-dependent degradation of activated STAT (80), and transcriptional regulators, such as PIAS, which prevent STATs from binding to DNA through sumoylation (75). Another possible mechanism for the desensitization of IL-7 responses may be linked to the accumulation of truncated forms of STAT5, which appear to be increased in HIV infection (15), and which were shown to act as dominant-negative mutants of full-length STAT5 (24). Further studies will be needed to pinpoint the distal step at which STAT5 function is impaired.…”