Activation of CD8 T cells normalizes and correlates with the level of infectious provirus in tonsils during highly active antiretroviral therapy in early HIV-1 infection

Abstract

Objectives: To study the effects of antiretroviral therapy on T cell activation in blood and tonsils from HIV-1 infected individuals in relation to CD4 cell count, plasma viremia, and infectious HIV-1 provirus. Design: A 48-week study of viral load and T cell subsets in blood and tonsils from 12 HIV-1-positive individuals with a mean CD4 cell number of 400 3 106 cells/l treated with a combination of zidovudine, lamivudine, and indinavir. Methods: Tonsil biopsies and blood samples were collected at regular intervals. Lymphocytes were phenotyped and quantified by three-color flow cytometry; infectious provirus was quantified by a limiting dilution assay. HIV-1-negative individuals were included as controls. Results: The fraction of tonsillar CD8 T cells expressing CD69, CD38, or HLA-DR in the patients with suppressed virus replication declined to levels comparable with that in controls by 48 weeks and showed a strong positive correlation with tonsillar infectious provirus and plasma viremia. The level of CD4 T cell activation was within normal range in tonsils throughout the study. The fraction of HLA-DR+ cells within CD4 and CD8 T cells in blood declined rapidly in parallel with plasma viremia but remained slightly higher compared with that in uninfected individuals. Conclusion: Antiretroviral therapy normalizes tonsillar CD8 T cell activation in HIV-1-positive individuals in parallel with suppression of viral replication, indicating reduced CD8 cell turnover. Normal tonsillar CD4 T cell activation suggests limited CD4 cell turnover in early HIV infection. Activated CD8 T cells in lymphoid tissue is superior to that in blood as an immunological marker for the virological response to antiretroviral therapy.