The dominant source of CD4(+) and CD8(+) T-cell activation in HIV infection is antigenic stimulation

To distinguish between antigenic stimulation and CD4(+) T-cell homeostasis as the cause of T-cell hyperactivation in HIV infection, we studied T-cell activation in 47 patients before and during highly active antiretroviral th erapy (HAART). We show that expression of human leukocyte antigen (HLA)-DR, CD38, and Ki67 on T cells decreased during HAART but remained elevated ove r normal values until week 48 of therapy. We confirm previous reports that T-cell activation correlates positively with plasma HN RNA levels (suggesti ng antigenic stimulation), and negatively with CD4 count (suggesting CD4(+) T-cell homeostasis). However, these correlations may be spurious, because misleading, due to the well-established negative correlation between CD4 co unt and plasma HIV RNA levels. To resolve this conflict, we computed partia l correlation coefficients. Correcting for CD4 counts, we show that plasma HIV RNA levels contributed to T-cell hyperactivation. Correcting for plasma HIV RNA levels, we show that CD4(+) T-cell depletion contributed to T-cell activation. Correcting for both, activation of CD4(+) and CD8(+) T cells r emained positively correlated. Because this suggests that CD4(+) and CD8(+) T-cell activation is caused by a common additional factor, we conclude tha t antigenic stimulation by HIV or other (opportunistic) infections is the m ost parsimonious explanation for T-cell activation in HIV infection. Persis tence of HIV antigens may explain why T-cell activation fails to revert to levels found in healthy individuals after 48 weeks of therapy.