The HLA-B27 allele is over-represented among human immunodeficiency virus type 1-infected long-term non-progressors. In these patients, strong CTL responses targeting HLA-B27-restricted viral epitopes have been associated with long-term asymptomatic survival. Indeed, loss of control of viraemia in HLA-B27 patients has been associated with CTL escape at position 264 in the immunodominant KK10 epitope. This CTL escape mutation in the viral Gag protein has been associated with severe viral attenuation and may require the presence of compensatory mutations before emerging. Here, we studied sequence evolution within HLA-B27-restricted CTL epitopes in the viral Gag protein during the course of infection of seven HLA-B27-positive patients. Longitudinal gag sequences obtained at different time points around the time of AIDS diagnosis were obtained and analysed for the presence of mutations in epitopes restricted by HLA-B27, and for potential compensatory mutations. Sequence variations were observed in the HLA-B27-restricted CTL epitopes IK9 and DR11, and the immunodominant KK10 epitope. However, the presence of sequence variations in the HLA-B27-restricted CTL epitopes could not be associated with an increase in viraemia in the majority of the patients studied. Furthermore, we observed low genetic diversity in the gag region of the viral variants throughout the course of infection, which is indicative of low viral replication and corresponds to the low viral load observed in the HLA-B27-positive patients. These data indicated that control of viral replication can be maintained in HLA-B27-positive patients despite the emergence of viral mutations in HLA-B27-restricted epitopes.
AmmaranondP.,
ZaundersJ.,
SatchellC.,
van BockelD.,
CooperD.A.,
KelleherA.D.2005; A new variant cytotoxic T lymphocyte escape mutation in HLA-B27-positive individuals infected with HIV type 1. AIDS Res Hum Retroviruses 21:395–397 doi:10.1089/aid.2005.21.395 [PubMed][CrossRef]
BaileyJ.R.,
LassenK.G.,
YangH.C.,
QuinnT.C.,
RayS.C.,
BlanksonJ.N.,
SilicianoR.F.2006a; Neutralizing antibodies do not mediate suppression of human immunodeficiency virus type 1 in elite suppressors or selection of plasma virus variants in patients on highly active antiretroviral therapy. J Virol 80:4758–4770 doi:10.1128/JVI.80.10.4758-4770.2006 [PubMed][CrossRef]
CarringtonM.,
O'BrienS.J.2003; The influence of HLA genotype on AIDS. Annu Rev Med 54:535–551 doi:10.1146/annurev.med.54.101601.152346 [PubMed][CrossRef]
Centers for Disease Control1992; 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 41:(RR-17)1–19[PubMed]
CornelissenM.,
HooglandF.M.,
BackN.K.T.,
JurriaansS.,
ZorgdragerF.,
BakkerM.,
BrinkmanK.,
PrinsM.,
van der KuylA.C.2009; Multiple transmissions of a stable human leucocyte antigen-B27 cytotoxic T-cell-escape strain of HIV-1 in The Netherlands. AIDS 23:1495–1500 doi:10.1097/QAD.0b013e32832d9267 [PubMed][CrossRef]
DeeksS.G.,
WalkerB.D.2007; Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27:406–416 doi:10.1016/j.immuni.2007.08.010 [PubMed][CrossRef]
FeeneyM.E.,
TangY.,
RooseveltK.A.,
LeslieA.J.,
McIntoshK.,
KarthasN.,
WalkerB.D.,
GoulderP.J.2004; Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive long-term-nonprogressing child. J Virol 78:8927–8930 doi:10.1128/JVI.78.16.8927-8930.2004 [PubMed][CrossRef]
GoonetillekeN.,
LiuM.K.,
Salazar-GonzalezJ.F.,
FerrariG.,
GiorgiE.,
GanusovV.V.,
KeeleB.F.,
LearnG.H.,
TurnbullE.L.other authors2009; The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med 206:1253–1272 doi:10.1084/jem.20090365 [PubMed][CrossRef]
GoulderP.J.R.,
PhillipsR.E.,
ColbertR.A.,
McAdamS.,
OggG.,
NowakM.A.,
GiangrandeP.,
LuzziG.,
MorganaB.other authors1997; Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 3:212–217 doi:10.1038/nm0297-212 [PubMed][CrossRef]
KaslowR.A.,
CarringtonM.,
AppleR.,
ParkL.,
MuñozA.,
SaahA.J.,
GoedertJ.J.,
WinklerC.,
O'BrienS.J.other authors1996; Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 2:405–411 doi:10.1038/nm0496-405 [PubMed][CrossRef]
KimuraM.1980; A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol 16:111–120 doi:10.1007/BF01731581 [PubMed][CrossRef]
KorberB.2000; Computational analysis of HIV molecular sequences. In HIV Signature and Sequence Variation Analysis pp. 55–72 Edited by
RodrigoA. G.,
LearnG. H.
Dordrecht: Kluwer;
LambotteO.,
BoufassaF.,
MadecY.,
NguyenA.,
GoujardC.,
MeyerL.,
RouziouxC.,
VenetA.,
DelfraissyJ.F.other authors2005; HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin Infect Dis 41:1053–1056 doi:10.1086/433188 [PubMed][CrossRef]
Martinez-PicadoJ.,
PradoJ.G.,
FryE.E.,
PfafferottK.,
LeslieA.,
ChettyS.,
ThobakgaleC.,
HoneyborneI.,
CrawfordH.other authors2006; Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1. J Virol 80:3617–3623 doi:10.1128/JVI.80.7.3617-3623.2006 [PubMed][CrossRef]
O'ConnellK.A.,
BrennanT.P.,
BaileyJ.R.,
RayS.C.,
SilicianoR.F.,
BlanksonJ.N.2010a; Control of HIV-1 in elite suppressors despite ongoing replication and evolution in plasma virus. J Virol 84:7018–7028 doi:10.1128/JVI.00548-10 [PubMed][CrossRef]
O'ConnellK.A.,
PelzR.K.,
DinosoJ.B.,
DunlopE.,
Paik-TeschJ.,
WilliamsT.M.,
BlanksonJ.N.2010b; Prolonged control of an HIV type 1 escape variant following treatment interruption in an HLA-B*27-positive patient. AIDS Res Hum Retroviruses 26:1307–1311 doi:10.1089/aid.2010.0135 [PubMed][CrossRef]
SchneidewindA.,
BrockmanM.A.,
YangR.,
AdamR.I.,
LiB.,
Le GallS.,
RinaldoC.R.,
CraggsS.L.,
AllgaierR.L.other authors2007; Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. J Virol 81:12382–12393 doi:10.1128/JVI.01543-07 [PubMed][CrossRef]
TenzerS.,
PetersB.,
BulikS.,
SchoorO.,
LemmelC.,
SchatzM.M.,
KloetzelP.M.,
RammenseeH.G.,
SchildH.,
HolzhütterH.G.2005; Modeling the MHC class I pathway by combining predictions of proteasomal cleavage, TAP transport and MHC class I binding. Cell Mol Life Sci 62:1025–1037 doi:10.1007/s00018-005-4528-2 [PubMed][CrossRef]
The International HIV Controllers Study2010; The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330:1551–1557 doi:10.1126/science.1195271 [PubMed][CrossRef]
Van't WoutA.B.,
BlaakH.,
RanL.J.,
BrouwerM.,
KuikenC.,
SchuitemakerH.1998; Evolution of syncytium-inducing and non-syncytium-inducing biological virus clones in relation to replication kinetics during the course of human immunodeficiency virus type 1 infection. J Virol 72:5099–5107[PubMed]