CD8 T cell response and evolutionary pressure to HIV-1 cryptic epitopes derived from antisense transcription.
Retroviruses pack multiple genes into relatively small genomes by encoding several genes in the same genomic region with overlapping reading frames. Both sense and antisense HIV-1 transcripts contain open reading frames for known functional proteins as well as numerous alternative reading frames (ARFs). At least some ARFs have the potential to encode proteins of unknown function, and their antigenic properties can be considered as cryptic epitopes (CEs). To examine the extent of active immune response to virally encoded CEs, we analyzed human leukocyte antigen class I-associated polymorphisms in HIV-1 gag, pol, and nef genes from a large cohort of South Africans with chronic infection. In all, 391 CEs and 168 conventional epitopes were predicted, with the majority (307; 79%) of CEs derived from antisense transcripts. In further evaluation of CD8 T cell responses to a subset of the predicted CEs in patients with primary or chronic infection, both sense- and antisense-encoded CEs were immunogenic at both stages of infection. In addition, CEs often mutated during the first year of infection, which was consistent with immune selection for escape variants. These findings indicate that the HIV-1 genome might encode and deploy a large potential repertoire of unconventional epitopes to enhance vaccine-induced antiviral immunity.
Bansal
Anju
A
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. ABansal@uab.edu
Carlson
Jonathan
J
Yan
Jiyu
J
Akinsiku
Olusimidele T
OT
Schaefer
Malinda
M
Sabbaj
Steffanie
S
Bet
Anne
A
Levy
David N
DN
Heath
Sonya
S
Tang
Jianming
J
Kaslow
Richard A
RA
Walker
Bruce D
BD
Ndung'u
Thumbi
T
Goulder
Philip J
PJ
Heckerman
David
D
Hunter
Eric
E
Goepfert
Paul A
PA
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002908:Chronic Disease; D015331:Cohort Studies; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019143:Evolution, Molecular; D005260:Female; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005805:Genes, MHC Class I / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D016372:RNA, Antisense / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013019:South Africa; D014158:Transcription, Genetic / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D016372:RNA, Antisense; D012367:RNA, Viral; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054302:pol Gene Products, Human Immunodeficiency Virus