Repertoire, diversity, and differentiation of specific CD8 T cells are associated with immune protection against human cytomegalovirus disease.
To determine the correlates of immune recovery from active human CMV (HCMV) disease, we compared the antigenic repertoire, diversity, magnitude, and differentiation of HCMV-specific CD8+ T cells in HIV-HCMV coinfected subjects with no, cured, or active HCMV disease and in healthy HIV-negative HCMV-positive controls. ELISPOT-IFN-gamma assays using peptide pools spanning the pp65 and immediate early 1 (IE1) HCMV proteins showed that HCMV-specific CD8+ T cells had a significantly broader antigenic repertoire and greater diversity in HIV-positive patients controlling HCMV replication than in those with active HCMV disease, but the magnitude of the CD8 T cell response did not differ between the different groups. HCMV-specific T cells mainly were focused against IE1 during the short-term recovery from retinitis, and switched toward pp65 during long-term recovery. HCMV-specific T cells displaying an "early" (CD8+CD27+CD28+) and "intermediate" (CD8+CD27-CD28+) differentiation phenotype were increased significantly during long-term recovery compared with other HIV-positive patients and were nearly undetectable during active HCMV disease. HCMV-specific T cells with a "late" (CD8+CD27-28-) differentiation phenotype predominated in all cases. Therefore, restoration of immune protection against HCMV after active HCMV disease in immunodeficient individuals is associated with enlarged repertoire and diversity, and with early differentiation of virus-specific CD8+ T cells, thus defining immune correlates of protection against diseases caused by persistent viruses.
Sacre
Karim
K
Laboratoire d'Immunologie Cellulaire et Tissulaire, INSERM U543, Hôpital Pitié-Salpétrière, Université Pierre et Marie Curie, 75013 Paris, France.
Carcelain
Guislaine
G
Cassoux
Nathalie
N
Fillet
Anne-Marie
AM
Costagliola
Dominique
D
Vittecoq
Daniel
D
Salmon
Dominique
D
Amoura
Zahir
Z
Katlama
Christine
C
Autran
Brigitte
B
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D000328:Adult; D000956:Antigens, Viral / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005602:France; D020276:HIV Long-Term Survivors; D006801:Humans; D017874:Immediate-Early Proteins / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000276:immunology; D012173:Retinitis / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology
D000956:Antigens, Viral; D018106:CD28 Antigens; D016827:CD8 Antigens; D017874:Immediate-Early Proteins; D010750:Phosphoproteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D007371:Interferon-gamma