Marked epitope- and allele-specific differences in rates of mutation in human immunodeficiency type 1 (HIV-1) Gag, Pol, and Nef cytotoxic T-lymphocyte epitopes in acute/early HIV-1 infection.
During acute human immunodeficiency virus type 1 (HIV-1) infection, early host cellular immune responses drive viral evolution. The rates and extent of these mutations, however, remain incompletely characterized. In a cohort of 98 individuals newly infected with HIV-1 subtype B, we longitudinally characterized the rates and extent of HLA-mediated escape and reversion in Gag, Pol, and Nef using a rational definition of HLA-attributable mutation based on the analysis of a large independent subtype B data set. We demonstrate rapid and dramatic HIV evolution in response to immune pressures that in general reflect established cytotoxic T-lymphocyte (CTL) response hierarchies in early infection. On a population level, HLA-driven evolution was observed in approximately 80% of published CTL epitopes. Five of the 10 most rapidly evolving epitopes were restricted by protective HLA alleles (HLA-B*13/B*51/B*57/B*5801; P = 0.01), supporting the importance of a strong early CTL response in HIV control. Consistent with known fitness costs of escape, B*57-associated mutations in Gag were among the most rapidly reverting positions upon transmission to non-B*57-expressing individuals, whereas many other HLA-associated polymorphisms displayed slow or negligible reversion. Overall, an estimated minimum of 30% of observed substitutions in Gag/Pol and 60% in Nef were attributable to HLA-associated escape and reversion events. Results underscore the dominant role of immune pressures in driving early within-host HIV evolution. Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response.
Brumme
Zabrina L
ZL
Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. zbrumme@partners.org
Brumme
Chanson J
CJ
Carlson
Jonathan
J
Streeck
Hendrik
H
John
Mina
M
Eichbaum
Quentin
Q
Block
Brian L
BL
Baker
Brett
B
Kadie
Carl
C
Markowitz
Martin
M
Jessen
Heiko
H
Kelleher
Anthony D
AD
Rosenberg
Eric
E
Kaldor
John
J
Yuki
Yuko
Y
Carrington
Mary
M
Allen
Todd M
TM
Mallal
Simon
S
Altfeld
Marcus
M
Heckerman
David
D
Walker
Bruce D
BD
D000208:Acute Disease; D000483:Alleles; D000595:Amino Acid Sequence; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D019143:Evolution, Molecular; D015750:Genes, gag / Q000235:genetics; D015754:Genes, nef / Q000235:genetics; D015751:Genes, pol / Q000235:genetics; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000378:metabolism; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D054298:Human Immunodeficiency Virus Proteins