Background:  CMV is highly immunogenic for T cells, but the determinants of the restoration of a CD8 T cell-mediated protective immunity against CMV, with regard to antigenic repertoire, diversity, magnitude, and differentiation, after recovery from acute CMV events remains to be defined to better understand immune correlates of protection against persistent viruses.

Methods:  Thirty-eight CMV⁺ subjects (11 healthy HIV^–, 27 HIV⁺ with:  10 long-term non-progressors [LTNP], 14 recovering from HCMV-retinitis on HAART for < 2 or 5 years [8 short-term and 6 long-term recoverers], and 3 acute HCMV events) were studied. IFN-γ-producing CD8 T cells were analyzed by ELISpot and flow cytometry with 21 pools of 15-mer peptides spanning the pp65 and IE1 HCMV proteins.

Results:  The 24 HIV-infected subjects controlling CMV recognized a broader antigenic repertoire of pp65 and IE1 peptides (p = 0.01 and 0.05) with a broader CD8 T-cell diversity (2.5 pp65 and 2 IE1 pools/patient) than HIV^– (0.8 pp65 and 0.7 IE1 pool/patient; p = 0.01 and 0.01, respectively), except in acute HCMV events where both parameters were similar to HIV^– subjects. IE1 was the most frequent target in short-term recoverers while pp65 was dominant in long-term recoverers and LTNP compared with HIV^– (p = 0.01 and < 0.04). Numbers of HCMV-specific cells were similar in HIV^–, LTNP, and acute HCMV events, but higher after retinitis recovery, with maximal responses against IE1 in short-term recoverers and pp65 in long-term recoverers (4913 and 3544 SFC/10⁶ PBMC, respectively) (p = 0.02 and 0.04). Most HCMV-specific CD8 T cells displayed the late differentiated CD27^–28^– phenotype (above 72%) in all groups, with > 91% specific CD27^–28^– cells in acute HCMV events. In long-term recoverers, proportions of early specific T-cells (CD27⁺28⁺:  15 ± 9%) were similar as in HIV^– (15 ± 11%) and higher than in other HIV⁺ groups (LTNP, short-term recoverers, p = 0.03 and 0.02).

Conclusions:  The control of HCMV replication after acute CMV events in HIV-infected patients treated with HAART depends both:  upon a broad antigenic repertoire and diversity of HCMV-specific CD8 T cells, with preferential recognition of IE1 in the early recovery, switching to pp65 in the late recovery periods, rather than solely on the magnitude; and upon regeneration of early memory CD8 T cells with long term survival capacity directed against both pp65 and IE1. These data show that the repertoire, diversity, and differentiation contribute more strongly than the magnitude of virus-specific T cells alone in the control of persistent viruses such as HCMV.

Keywords: CMV; HAART; immunity