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Both T-cell activation during early HIV-1 infection and soluble markers of immune activation during chronic infection are predictive of HIV disease progression. Although the acute phase of HIV infection is associated with increased pro-inflammatory cytokine production, the relationship between cytokine concentrations and HIV pathogenesis is unknown.To identify cytokine biomarkers measurable in plasma during acute HIV-1 infection that predict HIV disease progression.Study including 40 South African women who became infected with HIV-1 and were followed longitudinally from the time of infection.The concentrations of 30 cytokines in plasma from women with acute HIV-1 infection were measured and associations between cytokine levels and both viral load set point 12 months postinfection and time taken for CD4 cell counts to fall below 350 cells/μl were determined using multivariate and Cox proportional hazards regression.We found that the concentrations of five plasma cytokines, IL-12p40, IL-12p70, IFN-γ, IL-7 and IL-15 in women with acute infection predicted 66% of the variation in viral load set point 12 months postinfection. IL-12p40, IL-12p70 and IFN-γ were significantly associated with lower viral load, whereas IL-7 and IL-15 were associated with higher viral load. Plasma concentrations of IL-12p40 and granulocyte–macrophage colony-stimulating factor during acute infection were associated with maintenance of CD4 cell counts above 350 cells/μl, whereas IL-1α, eotaxin and IL-7 were associated with more rapid CD4 loss.A small panel of plasma cytokines during acute HIV-1 infection was predictive of long-term HIV disease prognosis in this group of South African women.