Immunologic and virologic evolution during periods of intermittent and persistent low-level viremia

Background: HIV replication, HIV-specific T-cell responses and T-cell activation each contributes to disease outcome during untreated HIV infection. The interaction of these factors is not well understood, particularly in the setting of antiretroviral therapy. Methods: This is a longitudinal study of antiretroviral-treated patients with plasma HIV RNA levels < 1000 copies/ml. Patients were divided into three groups: suppressed viremia, intermittent viremia ('blips') and persistent low-level viremia. HIV-specific immunity was measured using interferon-gamma ELISPOT. T-cell activation was defined by CD38 and HLA-DR co-expression. Drug resistance was quantified using a phenotypic susceptibility assay. Results: The breadth and the magnitude of the HIV-specific CD8 T-cell response was greater in patients with either intermittent or persistent viremia compared to patients with suppressed viremia. In contrast, T-cell activation was significantly elevated only in those patients with persistent viremia. Patients with persistent low-level viremia had moderate levels of phenotypic antiretroviral drug resistance that increased over time. Virologic failure (confirmed increase in viral load > 1000 HIV RNA copies/ml) was primarily observed in the persistently viremic group. Conclusions: Antiretroviral-treated individuals with intermittent viremia appear to mount an effective HIV-specific T-cell response while not experiencing increases in the level of immune activation. This may limit viral evolution and emergence of drug resistance. In contrast, antiretroviral-treated individuals with persistent low-level viremia exhibit significant increases in overall immune activation and a substantial risk of subsequent treatment failure. It is likely that higher viremia and stronger immune activation act synergistically to accelerate the development of systemic drug resistance. (C) 2004 Lippincott Williams Wilkins.