Early increase of CD4⁺ CD45RA⁺ and CD4⁺ CD95⁻ cells with conserved repertoire induced by anti-retroviral therapy in HIV-infected patients

Administration of anti-retroviral drugs induces a decrease of viral load associated with increase of CD4⁺ cell count in most HIV-infected patients. To investigate the early changes in CD4⁺ cell phenotype induced by anti-retroviral therapy, six patients with CD4⁺ cell count > 100/mm³ and never treated with anti-HIV therapy were enrolled and blood samples collected several times within 14 days from the initiation of therapy with Zidovudine plus Didanosine. CD4⁺ cell count and HIV viraemia were investigated at each time point, as well as the expression of CD45RA, CD45RO and CD95/Fas molecules on CD4⁺ cells, and the T cell receptor (TCR) Vβ repertoire of CD4⁺ cells. All patients showed a rapid and dramatic decrease in viral load with a corresponding increase of CD4⁺ cell count. The main remodelling of CD4⁺ cell subpopulations took place in the first 14 days of therapy, and consisted of: (i) increased CD4⁺ CD45RA⁺/CD4⁺  CD45RO⁺ ratio; (ii) decrease of CD95/Fas expression. The rise in absolute number of CD4⁺ CD45RA⁺ cells was paralleled by an increase of CD4⁺ CD95/Fas⁻ cells and accounted for most of the early increment of CD4⁺ cell count. The TCR Vβ repertoire of CD4⁺ cells was conserved after anti-HIV therapy, with the exception of two patients with expanded CD4⁺ Vβ12⁺ cells, which also tested CD45RA⁺ and CD95/Fas⁻. These experiments show that newcomer CD4⁺ lymphocytes are CD45RA⁺ CD95/Fas⁻ cells, suggesting that blocking HIV replication causes an early and antigen-independent proliferation of possibly ‘naive’ cells unprimed for CD95/Fas-mediated apoptosis. These cells expressed a conserved and widespread TCR repertoire, suggesting that their capability for antigenic recognition is intact.