PMID- 22654656
OWN - NLM
STAT- MEDLINE
DCOM- 20120904
LR  - 20211021
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Print)
IS  - 1553-734X (Linking)
VI  - 8
IP  - 5
DP  - 2012
TI  - Estimating the fitness cost of escape from HLA presentation in HIV-1 protease and 
      reverse transcriptase.
PG  - e1002525
LID - 10.1371/journal.pcbi.1002525 [doi]
LID - e1002525
AB  - Human immunodeficiency virus (HIV-1) is, like most pathogens, under selective 
      pressure to escape the immune system of its host. In particular, HIV-1 can avoid 
      recognition by cytotoxic T lymphocytes (CTLs) by altering the binding affinity of 
      viral peptides to human leukocyte antigen (HLA) molecules, the role of which is 
      to present those peptides to the immune system. It is generally assumed that HLA 
      escape mutations carry a replicative fitness cost, but these costs have not been 
      quantified. In this study, we assess the replicative cost of mutations which are 
      likely to escape presentation by HLA molecules in the region of HIV-1 protease 
      and reverse transcriptase. Specifically, we combine computational approaches for 
      prediction of in vitro replicative fitness and peptide binding affinity to HLA 
      molecules. We find that mutations which impair binding to HLA-A molecules tend to 
      have lower in vitro replicative fitness than mutations which do not impair 
      binding to HLA-A molecules, suggesting that HLA-A escape mutations carry higher 
      fitness costs than non-escape mutations. We argue that the association between 
      fitness and HLA-A binding impairment is probably due to an intrinsic cost of 
      escape from HLA-A molecules, and these costs are particularly strong for HLA-A 
      alleles associated with efficient virus control. Counter-intuitively, we do not 
      observe a significant effect in the case of HLA-B, but, as discussed, this does 
      not argue against the relevance of HLA-B in virus control. Overall, this article 
      points to the intriguing possibility that HLA-A molecules preferentially target 
      more conserved regions of HIV-1, emphasizing the importance of HLA-A genes in the 
      evolution of HIV-1 and RNA viruses in general.
FAU - Mostowy, Rafal
AU  - Mostowy R
AD  - Institute for Integrative Biology, ETH Zurich, Zurich, Switzerland. 
      rafal.mostowy@gmail.com
FAU - Kouyos, Roger D
AU  - Kouyos RD
FAU - Hoof, Ilka
AU  - Hoof I
FAU - Hinkley, Trevor
AU  - Hinkley T
FAU - Haddad, Mojgan
AU  - Haddad M
FAU - Whitcomb, Jeannette M
AU  - Whitcomb JM
FAU - Petropoulos, Christos J
AU  - Petropoulos CJ
FAU - Kesmir, Can
AU  - Kesmir C
FAU - Bonhoeffer, Sebastian
AU  - Bonhoeffer S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120524
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
RN  - 0 (HLA Antigens)
RN  - EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1)
RN  - EC 2.7.7.49 (HIV Reverse Transcriptase)
RN  - EC 3.4.23.- (HIV Protease)
RN  - EC 3.4.23.- (p16 protease, Human immunodeficiency virus 1)
SB  - IM
MH  - Adaptation, Physiological/*genetics
MH  - Computer Simulation
MH  - Genetic Fitness/*genetics
MH  - HIV Protease
MH  - HIV Reverse Transcriptase/*genetics
MH  - HIV-1/*genetics
MH  - HLA Antigens/*genetics
MH  - *Models, Genetic
MH  - Mutation/genetics
MH  - Virus Replication/*genetics
PMC - PMC3359966
COIS- MH, JMW, and CJP are employed by Monogram Biosciences Inc. The remaining authors 
      declare that no competing interests exist.
EDAT- 2012/06/02 06:00
MHDA- 2012/09/05 06:00
PMCR- 2012/05/01
CRDT- 2012/06/02 06:00
PHST- 2011/11/04 00:00 [received]
PHST- 2012/04/03 00:00 [accepted]
PHST- 2012/06/02 06:00 [entrez]
PHST- 2012/06/02 06:00 [pubmed]
PHST- 2012/09/05 06:00 [medline]
PHST- 2012/05/01 00:00 [pmc-release]
AID - PCOMPBIOL-D-11-01649 [pii]
AID - 10.1371/journal.pcbi.1002525 [doi]
PST - ppublish
SO  - PLoS Comput Biol. 2012;8(5):e1002525. doi: 10.1371/journal.pcbi.1002525. Epub 
      2012 May 24.