Epitope escape from HIV-1-targeted CD8+ cytotoxic T lymphocyte (CTL) responses occurs rapidly after acute infection and contributes to the eventual failure of effective immune control of HIV-1 infection. Because the early CTL response is key in determining HIV-1 disease outcome, studying the process of epitope escape is crucial for understanding what leads to failure of immune control in acute HIV-1 infection and will provide important implications for HIV-1 vaccine design. HIV-1-specific CD8+ T lymphocyte responses against viral epitopes were mapped in six acutely infected individuals, and the magnitudes of these responses were measured longitudinally during acute infection. The evolution of autologous circulating viral epitopes was determined in four of these subjects. In-depth testing of CD8+ T lymphocyte responses against index and all autologous-detected variant epitopes was performed in one subject. Among the four individuals examined, 10 of a total of 35 CD8+ T cell responses within Gag, Pol, and Nef showed evidence of epitope escape. CTL responses with viral epitope variant evolution were shown in one subject, and this evolution occurred with and without measurable CTL responses against epitope variants. These results demonstrate a dynamic period of viral epitope evolution in early HIV-1 infection due to CD8+ CTL response pressure.
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References
1.
AliA, JamiesonBD, and YangOO. Half-genome human immunodeficiency virus type 1 constructs for rapid production of reporter viruses. J Virol Methods, 2003; 110:137–142.
2.
AliA, and YangOO. A novel small reporter gene and HIV-1 fitness assay. J Virol Methods, 2006; 133:41–47.
3.
AllenTM.Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature, 2000; 407:386–390.
4.
AllenTM, YuXG, KalifeET, et al.De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T-lymphocyte escape in chronic human immunodeficiency virus type 1 infection. J Virol, 2005; 79:12952–12960.
5.
BalamuruganA, NgHL, and YangOO. Rapid T cell receptor delineation reveals clonal expansion limitation of the magnitude of the HIV-1-specific CD8+ T cell response. J Immunol, 2010; 185:5935–5942.
6.
BorrowP, LewickiH, HahnBH, ShawGM, and OldstoneMB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol, 1994; 68:6103–6110.
7.
BorrowP, LewickiH, WeiX, et al.Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med, 1997; 3:205–211.
8.
BuseyneF, FevrierM, GarciaS, GougeonML, and RiviereY. Dual function of a human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte clone: inhibition of HIV replication by noncytolytic mechanisms and lysis of HIV-infected CD4+ cells. Virology, 1996; 225:248–253.
9.
CoffinJM.HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science, 1995; 267:483–489.
10.
DayCL, KaufmannDE, KiepielaP, et al.PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature, 2006; 443:350–354.
11.
De La CruzJ, VollbrechtT, FrohnenP, et al.Ineffectual Targeting of HIV-1 Nef by cytotoxic T lymphocytes in acute infection results in no functional impairment or viremia reduction. J Virol, 2014; 88:7881–7892.
12.
GoonetillekeN, LiuMK, Salazar-GonzalezJF, et al.The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med, 2009; 206:1253–1272.
13.
HennMR, BoutwellCL, CharleboisP, et al.Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. PLoS Pathog, 2012; 8:e1002529.
14.
IbarrondoFJ, AntonPA, FuerstM, et al.Parallel human immunodeficiency virus type 1-specific CD8+ T-lymphocyte responses in blood and mucosa during chronic infection. J Virol, 2005; 79:4289–4297.
15.
JinX, BauerDE, TuttletonSE, et al.Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med, 1999; 189:991–998.
16.
JonesNA, WeiX, FlowerDR, et al.Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response. J Exp Med, 2004; 200:1243–1256.
17.
KalamsSA, BuchbinderSP, RosenbergES, et al.Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. J Virol, 1999; 73:6715–6720.
18.
KemballCC, PackCD, GuayHM, et al.The antiviral CD8+ T cell response is differentially dependent on CD4+ T cell help over the course of persistent infection. J Immunol, 2007; 179:1113–1121.
19.
KiepielaP, NgumbelaK, ThobakgaleC, et al.CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med, 2007; 13:46–53.
20.
KlenermanP, and ZinkernagelRM. Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature, 1998; 394:482–485.
21.
KoupRA, SafritJT, CaoY, et al.Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol, 1994; 68:4650–4655.
22.
LiuMK, HawkinsN, RitchieAJ, et al.Vertical T cell immunodominance and epitope entropy determine HIV-1 escape. J Clin Invest, 2013; 123:380–393.
23.
LiuY, McNevinJ, CaoJ, et al.Selection on the human immunodeficiency virus type 1 proteome following primary infection. J Virol, 2006; 80:9519–9529.
24.
Martinez-PicadoJ, PradoJG, FryEE, et al.Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1. J Virol, 2006; 80:3617–3623.
25.
MatloubianM, ConcepcionRJ, and AhmedR. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol, 1994; 68:8056–8063.
26.
McMichaelAJ, and PhillipsRE. Escape of human immunodeficiency virus from immune control. Ann Rev Immunol, 1997; 15:271–296.
27.
MellorsJW, RinaldoCRJr., GuptaP, WhiteRM, ToddJA, and KingsleyLA.Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science, 1996; 272:1167–1170.
28.
NdhlovuZM, KamyaP, MewalalN, et al.Magnitude and kinetics of CD8+ T cell activation during Hyperacute HIV infection impact viral set point. Immunity, 2015; 43:591–604.
29.
ParkerKC, BednarekMA, and ColiganJE. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol, 1994; 152:163–175.
30.
PhillipsRE, Rowland-JonesS, NixonDF, et al.Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature, 1991; 354:453–459.
31.
RammenseeH, BachmannJ, EmmerichNP, BachorOA, and StevanovicS. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics, 1999; 50:213–219.
32.
RosenbergES.Vigorous HIV-1-Specific CD4+ T cell responses associated with control of viremia. Science, 1997; 278:1447–1450.
33.
SchmitzJE, KurodaMJ, SantraS, et al.Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science, 1999; 283:857–860.
34.
SchwartzO, MarechalV, Le GallS, LemonnierF, and HeardJM. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat Med, 1996; 2:338–342.
35.
StreeckH, JolinJS, QiY, et al.Human immunodeficiency virus type 1-specific CD8+ T-cell responses during primary infection are major determinants of the viral set point and loss of CD4+ T cells. J Virol, 2009; 83:7641–7648.
36.
StreeckH, and NixonDF. T cell immunity in acute HIV-1 infection. J Infect Dis, 2010; 202Suppl 2:S302–S308.
37.
SunY, PermarSR, BuzbyAP, and LetvinNL. Memory CD4+ T-lymphocyte loss and dysfunction during primary simian immunodeficiency virus infection. J Virol, 2007; 81:8009–8015.
38.
van DeutekomHW, WijnkerG, and de BoerRJ. The rate of immune escape vanishes when multiple immune responses control an HIV infection. J Immunol, 2013; 191:3277–3286.
39.
WongJT, and ColvinRB. Bi-specific monoclonal antibodies: selective binding and complement fixation to cells that express two different surface antigens. J Immunol, 1987; 139:1369–1374.
40.
YangOO, ChurchJ, KitchenCM, et al.Genetic and stochastic influences on the interaction of human immunodeficiency virus type 1 and cytotoxic T lymphocytes in identical twins. J Virol, 2005; 79:15368–15375.
41.
YangOO, KalamsSA, TrochaA, et al.Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol, 1997; 71:3120–3128.
42.
YangOO, SarkisPT, AliA, et al.Determinant of HIV-1 mutational escape from cytotoxic T lymphocytes. J Exp Med, 2003; 197:1365–1375.
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