Mechanisms for Macrophage-Mediated HIV-1 Induction

Abstract

Viral latency is a long-term pathogenic condition in patients infected with HIV-1. Low but sustained virus replication in chronically infected cells can be activated by stimulation with proinflammatory cytokines such as TNF-α, IL-1 β, or other host factors. However, the precise mechanism by which cellular activation induces latently infected cells to produce virions has remained unclear. In the present report, we present evidence that activation of HIV-1 replication in latently infected U1 or ACH2 cells by human macrophages is mediated by a rapid nuclear localization of NF-κB p50/p65 dimer with concomitant increased expression of proinflammatory cytokines. Multiplexed RT-PCR amplification of mRNA isolated from cocultures of macrophages and U1 and ACH2 cells showed significant induction of IL-1β, IL-6, IL-8, TNF-α, and TGF-β expression within 3 h of coincubation. Fixation of macrophages, U-1, or ACH2 cells with paraformaldehyde before coculture completely abrogated the induction of NF-κB subunits and HIV-1 replication, suggesting that cooperative interaction between the two cell types is an essential process for cellular activation. Pretreatment of macrophage-U1 or macrophage-ACH2 cocultures with neutralizing anti-TNF-α Ab down-regulated the replication of HIV-1. In addition, pretreatment of macrophage-U1 or macrophage-ACH2 cocultures with the NF-κB inhibitor (E)3-[(4-methylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7082) prevented the induction of cytokine expression, indicating a pivotal role of NF-κB-mediated signaling in the reactivation of HIV-1 in latently infected cells by macrophages. These results provide a mechanism by which macrophages induce HIV-1 replication in latently infected cells.

HIV-1 Reactivation Induced by the Periodontal Pathogens Fusobacterium nucleatum and Porphyromonas gingivalis Involves Toll-Like Receptor 4 and 9 Activation in Monocytes/Macrophages

“…Normally, the activation of TLRs in monocytes/macrophages by bacteria leads to the production of proinflammatory cytokines (e.g., TNF-␣, IL-1␤, and IL-6). Importantly, these proinflammatory cytokines have been suggested as an important mechanism of HIV-1 reactivation in latently infected cells (20,61). Hence, to test whether production of these cytokines in response to F. nucleatum and P. gingivalis was playing a role in HIV-1 promoter activation, we first determined the levels of TNF-␣, IL-1␤, and IL-6 produced by either THP89GFP cells or their parental THP-1 cells in response to different concentrations of bacterial extracts.…”

Primary Human Mammary Epithelial Cells Endocytose HIV-1 and Facilitate Viral Infection of CD4 + T Lymphocytes

“…6C) (mean concentrations of Ͼ10 pg/ml) revealed that MEC are highly secretory cells that release a variety of immune mediators with widely ranging concentrations. Several of these factors, including IL-8 and IL-6, have been shown to upregulate HIV-1 replication in vitro (7,12,20) and may contribute to the observed increase in virus replication in PBMCs exposed to MEC secretions.…”

“…Analysis of the apical secretions from the polarized cells by multiplex assays revealed the presence of a complex array of cytokines, chemokines, and growth factors. Breast milk is known to contain many chemokines and cytokines (24,41), some of which may influence HIV-1 infection and transmission (7,12,20). Epidemiologic studies have sought to find correlations between individual breast milk components and transmission of HIV-1 through breast-feeding or between HIV-infected and noninfected women (8,35,42,44).…”

Role of Cytokines and Chemokines in HIV Infection

“…It is thought that stimulation of viral replication in chronically infected cells is due to activation of NF-B. In addition to IL-1 and TNF-, contact with macrophages as well as a number of stressors can stimulate NF-B, including phorbol esters, radical oxygen intermediates, and UV irradiation (Devadas et al;. Clinical manifestations of AIDS include both immunologic and neurologic disorders.…”

“…Chronic infection and viral latency are typical of HIV-1 infection. Stimulation with IL-1 as well as TNF-can stimulate viral replication in chronically infected cells (Devadas et al;. Monocytes are also major reservoirs for HIV-1 in infected tissue and vectors for virus transmission to target cells, as well as sources of potent cytokines that can affect cell function and virus replication (Devadas et al;.…”