Tumor necrosis factor α is associated with viral control and early disease progression in patients with HIV type 1 infection.

Inflammation in early human immunodeficiency virus type 1 (HIV-1) disease progression is not well characterized. Ninety patients with untreated primary HIV-1 infection were studied to determine associations of inflammatory proteins with early disease progression. High plasma tumor necrosis factor α (TNF-α) levels (≥8.5 pg/mL) were significantly associated with an increased viral load set point and shorter times to reaching a CD4(+) T-cell count of <500 cells/mm(3) and initiating antiretroviral therapy. The increased risk of reaching a CD4(+) T-cell count of <500 cells/mm(3) in the group with high TNF-α levels was driven by viral load but was independent of concurrent CD4(+) T-cell count. Thus, TNF-α appears to be an important mediator of inflammation in patients with poor viral control and early HIV-1 disease progression.

A monoclonal antibody against lymphocyte function-associated antigen-1 decreases HIV-1 replication by inducing the secretion of an antiviral soluble factor.

BACKGROUND: Lymphocyte Function-Associated Antigen-1 (LFA-1) likely plays a role in the pathogenesis of against HIV-1 and is known to facilitate cell-to-cell transmission of the virus. A monoclonal antibody specific for LFA-1 (Cytolin®) was evaluated as a potential therapeutic in pilot studies performed in the mid-1990s. These uncontrolled human studies suggested that administration of this anti-LFA-1 antibody to HIV-1 infected individuals could provide a modest benefit by decreasing circulating HIV-1 RNA and increasing CD4+ T cell counts. At the time, it was proposed that when bound to cytolytic T cells, the antibody inhibited lysis of activated CD4+ T cells. Given the renewed interest in monoclonal antibody therapy for HIV-1 infected individuals, we investigated possible mechanisms of action of this antibody in vitro. METHODS: To assess whether this anti-LFA-1 antibody binds to HIV-1, a virus capture assay was performed. Binding of the antibody to cells was assessed using flow cytometry. Inhibition of HIV-1 replication was determined in culture by measuring the amount of p24 produced by ELISA. After co-culture of the antibody with peripheral blood mononuclear cells, supernatants were assayed for cytokines and chemokines using various immunoassays. RESULTS: Our experiments demonstrate that anti-LFA-1 antibody binds to CCR5 and CXCR4 utilizing strains of HIV-1. It also binds to CD8+ T cells and dendritic cells. When bound to virus prior to infection, there is no decrease in HIV-1 replication, suggesting it does not directly inhibit viral replication via virus binding. When bound to cells, it does not inhibit lysis of CD4+ T cells, as was originally hypothesized. Binding to cells does appear to induce the production of a soluble factor that inhibits HIV-1 replication. We determined that this soluble factor was not any of the cytokines or chemokines with known anti-HIV-1 activity. Further, the antibody does not appear to induce any common immune modulating cytokines or chemokines. CONCLUSIONS: These results suggest that one possible mechanism of action of this anti-LFA-1 antibody is to inhibit HIV-1 replication via the production of a soluble antiviral factor that is induced upon binding to cells.

Detection of HIV gp120 in plasma during early HIV infection is associated with increased proinflammatory and immunoregulatory cytokines.

Events that occur during acute HIV infection likely contribute to the immune dysfunction common in HIV-infected individuals. During this early stage, there is high-level viral replication, loss in CD4(+) T cell number and function, and an up-regulation of proinflammatory and immunoregulatory cytokines. The mechanisms responsible for this are not completely understood. We hypothesize that the HIV envelope glycoprotein, gp120, contributes to immune dysfunction during early HIV infection. Using a cohort of subjects enrolled during acute and early HIV infection, we determined the amount of gp120, TNF-α, IL-6, IL-10, IFN-α, and IFN-γ in plasma at baseline and 6 months. At matched time points, we also measured CD4(+) T cell proliferation, T cell activation, and apoptosis. Plasma from 109 subjects was screened for gp120. Thirty-six subjects (33%) had detectable gp120 (0.5-15.6 ng/ml). Subjects with greater than 1 ng/ml of gp120 at baseline had similar levels at all time points tested, even when viral replication was undetectable due to therapy. Subjects with detectable gp120 had higher levels of plasma IL-6, IL-10, and TNF-α. There was no difference in the level of T cell activation, proliferation, or apoptosis in subjects with gp120 compared to those without. We conclude that persistent expression of gp120 occurs in a subset of individuals. Furthermore, the presence of gp120 is associated with higher levels of plasma IL-6, IL-10, and TNF-α, which may contribute to immune dysfunction during early HIV infection.