Phenotype and functional characteristics of HIV-specific cytotoxic CD8+ T cells in chronically infected patients: dual effects of highly active antiretroviral therapy.
BACKGROUND
Cytotoxic CD8+ T cells (CTLs) are critical for the control of viral infections. Although these cells can be recognized in most HIV-infected individuals, they fail to successfully control HIV replication. Distinct functional defects seem to limit their efficacy in HIV infection, although they have been not fully elucidated.


METHODS
Blood lymphocytes collected from 61 HLA-A0201+, untreated, chronically HIV-infected individuals were examined for the presence of CTLs against epitopes from HIV Gag and Pol proteins, using tetrameric complexes. Several functional aspects of these cells were further analyzed (immunophenotype; ability to produce interferon-gamma (IFN-gamma) in response to the specific peptide; proliferative capacity; and cytolytic activity). Lymphoproliferative responses of these cells confronting different stimulus were also evaluated. A longitudinal analysis was carried out in a subgroup who underwent antiretroviral therapy and were followed for 6 months.


RESULTS
CD8+ T cells staining with the tetramer complexes (Tet+) were detected in 44% of patients, with TetGag+ cells being more frequently detected and at higher levels than TetPol+ cells. Most Tet+ cells expressed a memory phenotype, showed an impaired ability to produce IFN-gamma when stimulated with the cognate peptide, and showed a very low expansion when cultured in the presence of the peptide. There was a negative correlation between the proportion of Tet+ cells producing IFN-gamma and plasma HIV-RNA. Although Tet+ cells diminished in most individuals after beginning antiretroviral therapy, some patients showed de novo appearance of Tet+ cells.


CONCLUSIONS
Most Tet+ cells in chronic HIV-infected individuals express a memory phenotype and show an impaired production of IFN-gamma and a lower proliferative response to specific HIV antigens. Interestingly, some individuals under successful antiretroviral therapy may show de novo appearance of specific CTLs. The implications of these findings are relevant for a better understanding of virus-host interactions.
Hospital Carlos III Sinesio Delgado 10 28029 Madrid, Spain. jbenito1@hotmail.com
José M
JM
Benito
Mariola
M
López
Sara
S
Lozano
Pilar
P
Martinez
Marcelo
M
Kuroda
Juan
J
González-Lahoz
Vincent
V
Soriano
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D002455:Cell Division / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015683:Gene Products, gag / Q000276:immunology; D015684:Gene Products, pol / Q000276:immunology; D006678:HIV / Q000276:immunology* / Q000502:physiology; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008137:Longitudinal Studies; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015684:Gene Products, pol; D015789:HLA-A2 Antigen; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma