The model of monozygotic twins has been repeatedly studied to control the genetic and age-specific effects on HIV disease. Focusing on this natural model, the expression of CD27/CD45RA differentiation markers and the distribution of the Vbeta TCR repertoire was analyzed on CD4+ and CD8+ T cells. In our HIV-discordant monozygotic twins, a significant reduction of naive T cells and a parallel accumulation of effector/memory T cells was induced by HIV infection, as well as a skewing of T cell repertoire evidenced by VbetaTCR analysis. The block of HIV replication by highly active antiretroviral therapy (HAART) restored most of the T cell maturation and selection process, with some exception among CTL differentiation and repertoire. Altogether, the model of HIV-discordant monozygotic twins is a valuable tool showing that HAART is not able to completely restore the CTL profile.