A Soluble Factor(s) Secreted from CD8⁺T Lymphocytes Inhibits Human Immunodeficiency Virus Type 1 Replication through STAT1 Activation

Abstract

CD8؉ T lymphocytes can suppress 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. However, the mechanism by which CAF inhibits LTR activation is not understood. Here, we show that conditioned media from several herpesvirus saimari-transformed CD8؉ T lymphocytes inhibit, in a time-and dose-dependent manner, the replication of HIV-1 pseudotype viruses that express the envelope glycoproteins of vesicular stomatitis virus (HIV-1 VSV ). The same conditioned media also inhibit phorbol myristate acetateinduced activation of the HIV-1 LTR and activate the signal transducer and activator of transcription 1 (STAT1) protein. We have obtained direct evidence that STAT1 is necessary for CAF-mediated inhibition of LTR activation and HIV-1 replication. Thus, the inhibitory effect of CAF on HIV-1 VSV replication was abolished in STAT1-deficient cells. Moreover, CAF inhibition of LTR activation was diminished both in STAT1-deficient cells and in cells expressing a STAT1 dominant negative mutant but was restored when STAT1 was reintroduced into the STAT1-deficient cells. We also observed that CAF induced the expression of interferon regulatory factor 1 (IRF-1), and that IRF-1 gene induction was STAT-1 dependent. Taken together, our results suggest that CAF activates STAT1, leading to IRF-1 induction and inhibition of gene expression regulated by the HIV-1 LTR. This study therefore helps clarify one molecular mechanism of host defense against HIV-1.

A Soluble Factor Secreted by an HIV-1-Resistant Cell Line Blocks Transcription through Inactivating the DNA-Binding Capacity of the NF-κB p65/p50 Dimer

“…Although their identities are not yet known, the mechanism of their antiviral activities points to the inhibition of transcription of viral genes (4,10). The findings presented in this study indicate that HRF blocks HIV-1 transcription through direct action on the nuclear NF-B p50/p65 dimer, preventing it from forming transcriptionally active DNA/protein complex.…”

“…R ecent years brought much attention to novel mechanisms of defense against HIV-1 by both CD8 and CD4 T cells (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Although much of this interest was dedicated to studying the antiviral responses of CD8 T lymphocytes, it has been well known that some infected individuals mount vigorous HIV-1-specific CD4 T cells responses, resulting in the elaboration of IFN-␥ and antiviral ␤-chemokines (12).…”

“…Interference with the expression of H1B reversed the acquired resistance phenotype, suggesting that it contributes to HRF activity and providing verification that the acquisition of the resistant phenotype induced global changes leading to novel mechanisms imposing a block of virus transcription. One such mechanism was described recently for an antiviral factor secreted by CD8 T cells, CD8 antiviral factor (CAF), acting as an inducer of STAT-1, that was postulated to inhibit viral transcription (4).…”

SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag

“…To elucidate the specific step in HIV-1 production that is enhanced by SOCS1, we next performed gene reporter assays using either luciferase expression constructs under the control of wildtype HIV-LTR (pLTR-luc), or a full-length provirus vector (pNL4-3-luc) (15). Interestingly, SOCS1 overexpression was found not to affect the transcription of these reporter constructs (data not shown), indicating that SOCS1 enhances HIV-1 replication via posttranscriptional mechanisms during virus production.…”

Breast Milk α-Defensins Are Associated with HIV Type 1 RNA And CC Chemokines in Breast Milk But Not Vertical HIV Type 1 Transmission

“…15,21,22 Increasing evidence supports a role for α-defensins in inhibiting HIV-1 infection, [23][24][25][26][27][28] and several different mechanisms have been proposed, including direct activity on HIV-1 virions, inhibition of viral replication following HIV-1 entry into cells, and upregulation of CC chemokines. [25][26][27] A recent study among 23 HIV-1-infected infants suggested that increased α-defensins in breast milk collected at 1 week postpartum were associated with reduced risk of infant HIV-1 acquisition after adjusting for breast milk HIV-1 RNA. 22 To further examine associations between α-defensins and vertical HIV-1 transmission, we measured α-defensins in breast milk specimens collected from HIV-1-infected women and defined correlates of elevated α-defensins and the relationship between defensins and infant HIV-1 acquisition during 1 year of follow-up.…”