Newly Exerted T Cell Pressures on Mutated Epitopes following Transmission Help Maintain Consensus HIV-1 Sequences.
CD8+ T cells are important for HIV-1 virus control, but are also a major contributing factor that drives HIV-1 virus sequence evolution. Although HIV-1 cytotoxic T cell (CTL) escape mutations are a common aspect during HIV-1 infection, less is known about the importance of T cell pressure in reversing HIV-1 virus back to a consensus sequences. In this study we aimed to assess the frequency with which reversion of transmitted mutations in T cell epitopes were associated with T cell responses to the mutation. This study included 14 HIV-1 transmission pairs consisting of a 'source' (virus-donor) and a 'recipient' (newly infected individual). Non-consensus B sequence amino acids (mutations) in T cell epitopes in HIV-1 gag regions p17, p24, p2 and p7 were identified in each pair and transmission of mutations to the recipient was verified with population viral sequencing. Longitudinal analyses of the recipient's viral sequence were used to identify whether reversion of mutations back to the consensus B sequence occurred. Autologous 12-mer peptides overlapping by 11 were synthesized, representing the sequence region surrounding each reversion and longitudinal analysis of T cell responses to source-derived mutated and reverted epitopes were assessed. We demonstrated that mutations in the source were frequently transmitted to the new host and on an average 17 percent of mutated epitopes reverted to consensus sequence in the recipient. T cell responses to these mutated epitopes were detected in 7 of the 14 recipients in whom reversion occurred. Overall, these findings indicate that transmitted non-consensus B epitopes are frequently immunogenic in HLA-mismatched recipients and new T cell pressures to T cell escape mutations following transmission play a significant role in maintaining consensus HIV-1 sequences.
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, California.
Emily M
EM
Eriksson
Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, California.
Teri
T
Liegler
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, California.
Chris E
CE
Keh
Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
Annika C
AC
Karlsson
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, California.
Sara J
SJ
Holditch
Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, California.
Christopher D
CD
Pilcher
Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, California.
Lisa
L
Loeb
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, California.
Douglas F
DF
Nixon
Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, California.
Frederick M
FM
Hecht
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016384:Consensus Sequence; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D019143:Evolution, Molecular; D015658:HIV Infections / Q000276:immunology / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D009154:Mutation; D012367:RNA, Viral / Q000032:analysis; D017423:Sequence Analysis, RNA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D018984:Epitopes, T-Lymphocyte; D012367:RNA, Viral; D054301:gag Gene Products, Human Immunodeficiency Virus