CD28-Negative CD4+ and CD8+ T Cells in Antiretroviral Therapy–Naive HIV-Infected Adults Enrolled in Adult Clinical Trials Group Studies

Human immunodeficiency virus (HIV) infection and aging are both implicated in the impairment of immunity [1], with T cells the component of immunity most affected. Chronic activation of T cells as a consequence of infections, inflammatory diseases, or increasing age may lead to a progressive loss of T-cell function and proliferative capacity. This process, commonly referred to as T-cell replicative senescence, is often characterized by loss of the costimulatory molecule CD28 on the surface of T cells, a molecule essential for effective T-cell activation and upregulation of cytokine expression [2]. The link between CD28 expression, aging, and HIV infection was first suggested more than a decade ago [3]. Loss of CD28 expression on T cells of HIV-infected individuals and changes in this expression after antiretroviral treatment (ART) initiation have not, however, been extensively studied. Previous studies indicate that reduced expression of CD28 is associated with HIV progression in both untreated [4] and treated [5, 6] adults. There is emerging evidence that treatment decreases the frequency of CD28− T cells. For example, in a cross-sectional study comparing 14 treated to 14 age- and CD4 count–matched treatment-naive adults, the former had higher levels of expression [7]. A longitudinal study of HIV-infected individuals with pre- and 6-month posttreatment samples found an increase in CD28 expression on CD8+ T cells after treatment [5]. Another study of 20 HIV-infected individuals observed a progressive increase in CD28 expression for both CD4+ and CD8+ T cells through 3 years of treatment [6]. These studies were small and hence not able to fully assess the factors associated with changes in the frequency of these cells. Another important question is whether expression normalizes during long-term effective ART. Valdez et al [6] observed a trend toward higher CD4+ and CD8+ senescence for aviremic, treated HIV-infected adults than for HIV-uninfected adults, and Desai et al [8] found that effectively treated adults had significantly higher CD8+ senescence than uninfected adults. A recent study of women aged ≥40 years found that virally suppressed HIV-infected women had higher CD8+ senescence than did age- and race-matched uninfected controls [9]. Within several Adult Clinical Trials Group (ACTG) studies and the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort, advanced flow cytometry was performed in almost 1300 individuals pre- or post-ART. With this large sample size, we had the opportunity to expand our knowledge of CD28 expression in HIV-infected adults. Our objectives in this study were to (1) describe pre-ART expression among treatment-naive HIV-infected individuals; (2) describe the changes in CD28 expression after virally suppressive treatment; and (3) compare posttreatment expression to that observed among HIV-uninfected individuals. As a secondary objective we also examined correlations between CD28 expression and T-cell activation, and explored whether pre-ART expression was associated with activation pre- and posttreatment.