Dataset Information

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 IFN?-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 IFN? or infected with HIV-1 before activation by TLR ligands. Transcriptome profiling by microarray revealed a gene expression profile for IFN?-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 IFN? (r?=?.679, p?=?.003). Similar to IFN?, 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 IFN?-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.

SUBMITTER: Appelberg KS

PROVIDER: S-EPMC5512335 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Appelberg K Sofia KS Wallet Mark A MA Taylor Jared P JP Cash Melanie N MN Sleasman John W JW Goodenow Maureen M MM

AIDS research and human retroviruses 20170412 7

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 explo ...[more]

PMID: 28142265

Similar Datasets

Project description:In order to prevent and/or control infections it is necessary to understand their early-time dynamics. However this is precisely the phase of HIV about which the least is known. To investigate the initial stages of HIV infection within a host we have developed a multi-type, continuous-time branching process model. This model is a stochastic extension of the standard viral dynamics model, under the assumption that the number of cell targets for viral infection is constant, biologically reasonable since, during the earliest stages of HIV infection, very few cells are infected relative to their total population size. We use our model to investigate three important clinical characteristics of early HIV infection following intravenous challenge: risk of infection, time to infection clearance (assuming failed infection), and time to infection detection. Our focus is on the impact of errors in viral replication that result in non-infectious virus production on these characteristics. Only a small fraction of circulating virus in any chronically infected individual is capable of infecting susceptible cells: estimates range from 1/104 - 1/103. Characterization and quantification of the processes by which virus becomes defective remains incomplete. We consider two mechanisms that result in defective virus: (1) Copying errors, i.e., lethal errors in reverse transcription, which introduce mutations into the HIV-1 proviral genome, some of which may cripple the viral genome produced, and (2) Packaging errors, i.e., errors during viral packaging, at the end of the viral replication cycle, which cause defective virus by packaging new virions without, for example, viral RNA or key proteins required for infectivity. We show that assumptions on mechanisms of defective virus production can significantly impact early HIV infection model predictions. For example, the risk of infection is orders of magnitude higher if all defective virus is associated with packaging errors, but infection is predicted to be detectable sooner following HIV exposure if all defective virus is associated with copying errors. Thus, in order to make reliable predictions of risk, clearance time, and detection time, better characterization of viral replication is required.

Project description:A unique HIV-host equilibrium exists in untreated HIV-2-infected individuals. This equilibrium is characterized by low to undetectable levels of viremia throughout the disease course, despite the establishment of disseminated HIV-2 reservoirs at levels comparable to those observed in untreated HIV-1 infection. Although the clinical spectrum is similar in the two infections, HIV-2 infection is associated with a much lower rate of CD4 T-cell decline and has a limited impact on the mortality of infected adults. Here we investigated HIV-2 infection of the human thymus, the primary organ for T-cell production. Human thymic tissue and suspensions of total or purified CD4 single-positive thymocytes were infected with HIV-2 or HIV-1 primary isolates using either CCR5 or CXCR4 coreceptors. We found that HIV-2 infected both thymic organ cultures and thymocyte suspensions, as attested to by the total HIV DNA and cell-associated viral mRNA levels. Nevertheless, thymocytes featured reduced levels of intracellular Gag viral protein, irrespective of HIV-2 coreceptor tropism and cell differentiation stage, in agreement with the low viral load in culture supernatants. Our data show that HIV-2 is able to infect the human thymus, but the HIV-2 replication cycle in thymocytes is impaired, providing a new model to identify therapeutic targets for viral replication control.HIV-1 infects the thymus, leading to a decrease in CD4 T-cell production that contributes to the characteristic CD4 T-cell loss. HIV-2 infection is associated with a very low rate of progression to AIDS and is therefore considered a unique naturally occurring model of attenuated HIV disease. HIV-2-infected individuals feature low to undetectable plasma viral loads, in spite of the numbers of circulating infected T cells being similar to those found in patients infected with HIV-1. We assessed, for the first time, the direct impact of HIV-2 infection on the human thymus. We show that HIV-2 is able to infect the thymus but that the HIV-2 replication cycle in thymocytes is impaired. We propose that this system will be important to devise immunotherapies that target viral production, aiding the design of future therapeutic strategies for HIV control.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets