Dynamics of viral variants in HIV-1 Nef and specific cytotoxic T lymphocytes in vivo.
The vigorous CTL response directed against HIV is considered to be important in reducing HIV viral load, although it is unable to stop ongoing viral replication, which generates new antigenic variants. We analyzed the impact of sequential changes in five epitopes of HIV-1 Nef on CTL recognition in four stable patients. A high rate of variation was found, and in all these patients we could detect CTL specific for 32 out of 36 autologous viral variants occurring in 5 HLA-A2- or HLA-B7-restricted Nef epitopes at two time points. Two distinct patterns for dynamics of CTL responses to viral variation were observed: 1) temporary amplification of viral variants followed by expansion of variant-specific CTL, ultimately leading to the disappearance of 12 out of the 14 initial epitope variants within two years. A second set of viral variants that had replaced the initial ones could also stimulate specific CTL precursors in the context of the same or an alternative HLA molecule; and 2) persistence of 2 viral variants in relatively conserved epitopes despite specific CTL recognition. Therefore, a remarkable flexibility of the immune system allows constant adaptation of CTL to multiple HIV variants and thus elimination of HIV variant-producing cells in slow progressors.
Laboratory of Cellular and Tissue Immunology, Hospital Pitié-Salpétriére, Paris, France. ghaas@ccr.jussieu.fr
G
G
Haas
U
U
Plikat
P
P
Debré
M
M
Lucchiari
C
C
Katlama
Y
Y
Dudoit
O
O
Bonduelle
M
M
Bauer
H G
HG
Ihlenfeldt
G
G
Jung
B
B
Maier
A
A
Meyerhans
B
B
Autran
D000595:Amino Acid Sequence; D000940:Antigenic Variation / Q000235:genetics*; D003602:Cytotoxicity, Immunologic; D004279:DNA, Viral / Q000235:genetics; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005500:Follow-Up Studies; D015693:Gene Products, nef / Q000276:immunology*; D015754:Genes, nef; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology; D006801:Humans; D011533:Proviruses / Q000235:genetics; D012641:Selection, Genetic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus
D004279:DNA, Viral; D000939:Epitopes; D015693:Gene Products, nef; D015234:HLA-A Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus