Novel cytotoxic T-lymphocyte escape mutation by a three-amino-acid insertion in the human immunodeficiency virus type 1 p6Pol and p6Gag late domain associated with drug resistance.
Cytolytic T lymphocytes (CTL) play a major role in controlling human immunodeficiency virus type 1 (HIV-1) infection. To evade immune pressure, HIV-1 is selected at targeted CTL epitopes, which may consequentially alter viral replication fitness. In our longitudinal investigations of the interplay between T-cell immunity and viral evolution following acute HIV-1 infection, we observed in a treatment-naïve patient the emergence of highly avid, gamma interferon-secreting, CD8(+) CTL recognizing an HLA-Cw*0102-restricted epitope, NSPTRREL (NL8). This epitope lies in the p6(Pol) protein, located in the transframe region of the Gag-Pol polyprotein. Over the course of infection, an unusual viral escape mutation arose within the p6(Pol) epitope through insertion of a 3-amino-acid repeat, NSPT(SPT)RREL, with a concomitant insertion in the p6(Gag) late domain, PTAPP(APP). Interestingly, this p6(Pol) insertion mutation is often selected in viruses with the emergence of antiretroviral drug resistance, while the p6(Gag) late-domain PTAPP motif binds Tsg101 to permit viral budding. These results are the first to demonstrate viral evasion of immune pressure by amino acid insertions. Moreover, this escape mutation represents a novel mechanism whereby HIV-1 can alter its sequence within both the Gag and Pol proteins with potential functional consequences for viral replication and budding.
Cao
Jianhong
J
Fred Hutchinson Cancer Research Center, D3-100, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
McNevin
John
J
McSweyn
Matthew
M
Liu
Yi
Y
Mullins
James I
JI
McElrath
M Juliana
MJ
D019380:Anti-HIV Agents / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008137:Longitudinal Studies; D016254:Mutagenesis, Insertional; D017434:Protein Structure, Tertiary; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology
D019380:Anti-HIV Agents; D018984:Epitopes, T-Lymphocyte; D054301:gag Gene Products, Human Immunodeficiency Virus; C083002:p6 gag protein, Human immunodeficiency virus 1; D054302:pol Gene Products, Human Immunodeficiency Virus