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

Abstract

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.

FIG. 1.

Expression of gp120 remains constant despite changes in viral load. HIV gp120 was measured longitudinally in subjects with greater than 1 ng/ml at baseline and compared to the viral load at each time point. Gray boxes indicated periods when a subject was on antiretroviral therapy.

FIG. 2.

Proinflammatory and immunoregulatory cytokines are higher in subjects with detectable gp120. Plasma cytokines were measured by ELISA at baseline and a follow-up time point 6 months later. Subjects with detectable gp120 were compared to subjects without detectable gp120 who were matched by viral load and CD4 count. Each subject is represented by a unique symbol that is consistent throughout all graphs. HIV seronegative individuals were included as a control. The median concentration of TNF-α, IL-6, and IL-10 was higher in subjects with detectable gp120 compared to those without gp120 at baseline and follow-up. Additionally, the concentration of IFN-γ was higher at follow-up.

FIG. 3.

Proliferative responses to HIV may be affected by gp120. Proliferative responses to the HIV proteins, p24 and Nef were determined using a standard tritium incorporation assay. A stimulation index (SI) of greater than five (dashed line) was considered a positive response. Subjects with detectable plasma gp120 appeared less likely to respond to HIV antigens than subjects without detectable gp120; however, there was insufficient power to determine whether this difference was significant.