Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism.

Abstract

Human cytomegalovirus (HCMV) is a potential cofactor in HIV-1 infection. To investigate the mechanism whereby HCMV promotes HIV-1 replication, a PBMC coculture assay which measures HIV-1 p24 antigen release was used as an index ofviral replication. HCMV-stimulated PBMC were capable of inducing HIV-1 replication in cocultures with acutely infected PBMC; however, this occurred only when the PBMC were from HCMV-seropositive donors (598±207 versus 27±10 pg/ml p24 antigen with PBMC from HCMV-seronegative donors on day 6 of coculture). Upon stimulation with HCMV, PBMC obtained exclusively from HCMV-seropositive donors released tumor necrosis factor (TNF)-a (270±79 pg/ml at 18 h of culture). Monoclonal antibodies to TNF-a blocked the activity of HCMV-stimulated PBMC in cocultures both with acutely HIV-1-infected PBMC and with the chronically infected promonocytic line U1. Also, treatment of HCMV-stimulated PBMC with pentoxifylline, an inhibitor of TNF-a mRNA, markedly reduced HIV-1 replication in cocultures both with acutely and chronically infected cells. These results indicate that TNF-a is a key mediator of HIV-1 replication induced by HCMV-stimulated PBMC and support the concept that this cytokine plays an important role in the pathogenesis of HIV-1 infection. (J. Clin. Invest. 1992. 89:574-580.)

Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E2 in human monocytes.

“…The inhibition was reversed to approximately control levels when MO were grown in the presence of mAb to TNF-␣ (Table III). These findings are in agreement with others and support the concept that TNF-␣ is a key mediator in the pathogenesis of HCMV disease (18,35). TNF-␣ has been identified as an important factor in the pathogenesis of AIDS.…”

“…CMV enhanced HIV replication in T cells and in mononuclear phagocytic cells (15)(16)(17). CMV-stimulated PBMC from CMV seropositive patients and enhanced HIV replication when co-cultured with acutely infected PBMC (18). The enhancement of HIV replication was associated with the release of TNF-␣ from the CMV stimulated PBMC.…”

“…TNF-␣ has been identified as an important factor in the pathogenesis of AIDS. It was previously shown that CMV-activated PBMCs enhanced HIV replication via a TNF-␣-dependent pathway (18). Down-regulation of TNF-␣ gene expression or neutralization of its activity may thus be beneficial in down-regulating both viruses and their concomitant pathology (35).…”

Differences in cytokine secretion by intestinal mononuclear cells, peripheral blood monocytes and alveolar macrophages from HIV-infected patients

“…TNF-x production by these cells might be influenced by coinfection with other viruses or bacteria. It has been reported that human eytomegalovirus-stimulatcd PBMC could induce HlV-1 rephcation via a TNF-x-mediated mechanism [52]. and for alveolar macrophages.…”

Molecular Pathways in Virus-Induced Cytokine Production

“…A CMV infection is normally subclinical but can be fatal in immunocompromised individuals or if the infection is acquired in utero. The cytokine profile of the early phase of CMV infection is typically proinflammatory, with production of IL-1␤, IL-6, IL-12, TNF-␣, IFN-␣/␤, and IFN-␥ (38,183,192,235,266). One of the major components of the CMV virion is the glycoprotein gB, and studies have shown that a significant proportion of the virus-host interactions are mediated through gB (27,267).…”