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To examine changes in the distribution of CD4+CD45RA+ (naive) and CD4+CD45RO+ (memory) lymphocytes in various stages of HIV infection and the effect of these changes on disease progression.Expression of CD45RA+ and CD45RO+ on CD4+ lymphocytes was analysed by flow cytometry in a prospectively followed cohort of 300 HIV-infected individuals (median follow-up time, 2.90 years; range, 0.02–4.54 years) and in a group of 102 age- and sex-matched uninfected controls. Survival analysis was performed considering AIDS development and death as endpoints.The median CD4+ CD45RA+/CD45RO+ ratio was 1.3 (25–75% quartiles, 0.9–2.4) in controls; it was increased to 1.8 (1.1–2.5) in 40 HIV-infected individuals with CD4+ cell counts > 500 × 106/l (P < 0.05); it was similar at 1.4 (0.8–2.0) in 106 HIV-infected individuals with CD4+ cell counts of 200–500 × 106/l; and it was decreased to 0.9 (0.5–1.4) in 154 HIV-infected individuals with CD4+ cell counts < 200 × 106/l (P<10−6). When fitted in a Cox model adjusting for the total number of CD4+ cells and age a lower concentration of CD4+CD45RA+ cells was associated with an increased risk of dying. The concentration of CD4+CD45RO+ cells was not significantly associated with AIDS or death in age- and CD4+ cell count-adjusted Cox models.This study confirms a selective loss of memory CD4+ cells early in HIV infection followed by increased loss of naive CD4+ cells in later stages of the infection. The loss of naive CD4+ cells seems to be important in the pathogenesis of terminal HIV infection.