Determinants and kinetics of chronic immune activation in HIV-1 infection
Infection with the human immunodeficiency virus (HIV-1) results in profound dysfunction and eventual destruction of the immune system if left untreated. HIV infection also brings about generalized immune activation, which increases with disease progression. However, this does not contain the virus, but instead enhances HIV replication and dissemination, and contributes to the depletion of CD4+ T-lymphocytes. Consequently, the control of HIV-induced immune activation is emerging as an essential component of chronic disease management.
I examined the determinants and kinetics of immune activation in asymptomatic HIV-infected individuals successfully treated with highly active antiretroviral therapy for over five years. T-lymphocyte activation was assessed by quantifying: (i) cell surface expression of the activation markers CD38 and HLA-DR; (ii) intracellular production of the cytokines interleukin-2 and interferon-gamma (IFN-γ); and (iii) ELISPOT IFN-γ responses to HIV antigens. I determined that T-cell activation slowly decreased with time and was dependent on HIV viral load. B-lymphocyte activation was assessed by monitoring serum concentrations of IgG antibody. Most patients had hypergammaglobulinemia, excess serum IgG, at the outset which persisted over five years of therapy despite undetectable serum HIV, indicating that B-cell activation was not driven solely by viral load. I determined that hypergammaglobulinemia was isolated to the IgG1 subclass and that most of the IgG was not specific for HIV antigens, as HIV-specific antibody titers decreased over five years without a parallel reduction in total IgG. I then sought novel causes of sustained hypergammaglobulinemia and first found an increased frequency of B-cells infected with Epstein-Barr Virus (EBV, a pathogen that targets B-lymphocytes and stimulates antibody production) that was associated with higher HIV viral loads, but not with serum IgG concentration. Next, I examined levels of B-cell activating factor of the TNF family (BAFF), a potent B-cell activator produced by myeloid cells. I found increased serum BAFF in hypergammaglobulinemic patients, suggestive of an association between BAFF and excess serum IgG. As HIV infection of macrophages in vitro did not stimulate BAFF production, the source of excess BAFF is likely to be elsewhere.