HIV-1 Infection Primes Macrophages Through STAT Signaling to Promote Enhanced Inflammation and Viral Replication

Abstract

Macrophages play important roles in HIV-1 pathogenesis as targets for viral replication and mediators of chronic inflammation. Similar to IFNγ-priming, HIV-1 primes macrophages, resulting in hyperresponsiveness to subsequent toll-like receptor (TLR) stimulation and increased inflammatory cytokine production. However, the specific molecular mechanism of HIV-1 priming and whether cells must be productively infected or if uninfected bystander cells also are primed by HIV-1 remains unclear. To explore these questions, human macrophages were primed by IFNγ or infected with HIV-1 before activation by TLR ligands. Transcriptome profiling by microarray revealed a gene expression profile for IFNγ-primed cells that was further modulated by the addition of lipopolysaccharide (LPS). HIV-1 infection elicited a gene expression profile that correlated strongly with the profile induced by IFNγ (r = .679, p = .003). Similar to IFNγ, HIV-1 enhanced TLR ligand-induced tumor necrosis factor (TNF) protein expression and release. Increased TNF production was limited to productively infected cells. Specific signal transducer and activator of transcription (STAT)1 and STAT3 inhibitors suppressed HIV-1-mediated enhancement of TLR-induced TNF expression as well as HIV-1 replication. These findings indicate that viral replication and inflammation are linked through a common IFNγ-like, STAT-dependent pathway and that HIV-1-induced STAT1 and STAT3 signaling are involved in both inflammation and HIV-1 replication. Systemic innate immune activation is a hallmark of active HIV-1 replication. Our study shows that inflammation may develop as a consequence of HIV-1 triggering STAT-IFN pathways to support viral replication.

CRISPR/Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV-1 infection in macrophages

“…). This finding agrees with previous work where we demonstrated the importance of STAT signaling for HIV‐1 replication in MDMs . These data demonstrate that HIV‐1 must strike a balance between some T1 IFN signaling, which is needed for producing transcription factors such as STAT1 and STAT3, and too much IFN signaling, which allows the cells to mount an effective antiviral response.…”

“…Previous work done by our group has shown that STAT1 and STAT3 are necessary for efficient HIV‐1 replication. Blocking phosphorylation of either of these 2 molecules resulted in significant reduction in viral replication . However, the current study shows that increasing the amount of phosphorylated STAT1 and STAT2 also results in a significant reduction in viral replication.…”

“…Macrophages play an important role in this process and can act as mediators of inflammation . We recently reported that HIV‐1 replication in macrophages requires activity of STAT1, a protein usually associated with antiviral responses . The role of STAT1 was in postintegration expression of HIV‐1 mRNA from the long terminal repeat (LTR) promoter.…”

Reversible Human Immunodeficiency Virus Type-1 Latency in Primary Human Monocyte-Derived Macrophages Induced by Sustained M1 Polarization

“…Both IFN-γ and TNF-α have been earlier described as potent inducers of HIV-1 transcription and expression acting via activation of STAT1 and of the canonical NF-kB pathway, respectively, in different cell models, including interleukin-2 (IL-2) activated PBMC 35 and myeloid cells 23 – 26 . Therefore, we have investigated whether the silent transcriptional and expression profiles observed in M1 2 MDM could be accounted for by an impaired activation of these two transcription factors.…”

“…This HIV-restrictive profile was characterized by several features, including downregulation of the CD4 molecule from the cell surface, upregulated secretion of CCR5-binding chemokines and induction of the expression of the putative restriction factor APOBEC3A 22 . In the present study, we have investigated the potential consequences of restimulating infected M1-MDM with IFN-γ and TNF-α, as these cytokines are credited with latency-reversal capacity driven by activation of STAT1 and NF-kB transcription factors, respectively 23 – 26 . Quite surprisingly, we observed that a second stimulation of infected M1-MDM with these pro-inflammatory cytokines several days after infection, a condition here defined as “M1 squared (M1 2 ) MDM”, further inhibited HIV-1 replication down to very low levels for several weeks.…”