Forkhead box O (FOXO)1, FOXO3, interferon regulatory factor (IRF)4, X-linked inhibitor of apoptosis protein (xIAP), and E74-like factor (ELF)4 have been described as important regulators of T cell functions and differentiation. However, whether these molecules are associated with HIV-1 disease progression is still unknown. In this study, we showed that the levels of FOXO3, IRF4, and xIAP mRNA in rapid progressors (RPs) were significantly higher than in HIV-negative healthy controls (HCs). Moreover, FOXO3 expression was positively correlated with HIV-1 viral load and CD4+ T cell activation. Remarkably, increased CD4+ and CD8+ T cell activation was apparent in RPs compared with typical progressors and HCs. In addition, a profile of higher apoptosis, more CD8+ TEM cells, and fewer CD4+ and CD8+ Naive T cells were observed in early HIV infection patients with low CD4+ T cell counts. Furthermore, in vitro, IRF4 and xIAP expression was enhanced in peripheral blood mononuclear cells from healthy people following T cell receptor stimulation. T cell activation was decreased by treatment with siRNA inhibiting FOXO3, IRF4, and xIAP. Our results show that significantly increased levels of FOXO3, IRF4, and xIAP mRNA in Chinese HIV-1-infected patients were related to T cell immune activation, implicating them as potential targets for developing new therapeutic avenues to slow down HIV-1 disease progression.
Get full access to this article
View all access options for this article.
References
1.
LiHM, PengRR, LiJ, et al.: HIV incidence among men who have sex with men in China: A meta-analysis of published studies. PLoS One, 2011; 6:e23431.
2.
XiaoY, SunJ, LiC, et al.: Prevalence and correlates of HIV and syphilis infections among men who have sex with men in seven provinces in China with historically low HIV prevalence. J Acquir Immune Defic Syndr, 2010; 53Suppl 1:S66–S73.
3.
XuJJ, ZhangM, BrownK, et al.: Syphilis and HIV seroconversion among a 12-month prospective cohort of men who have sex with men in Shenyang, China. Sex Transm Dis, 2010; 37:432–439.
4.
FisherM, PaoD, BrownAE, et al.: Determinants of HIV-1 transmission in men who have sex with men: A combined clinical, epidemiological and phylogenetic approach. AIDS, 2010; 24:1739–1747.
5.
GuoH, WeiJF, YangH, HuanX, TsuiSK, ZhangC: Rapidly increasing prevalence of HIV and syphilis and HIV-1 subtype characterization among men who have sex with men in Jiangsu, China. Sex Transm Dis, 2009; 36:120–125.
6.
HuangX, LodiS, FoxZ, et al.: Rate of CD4 decline and HIV-RNA change following HIV seroconversion in men who have sex with men: A comparison between the Beijing PRIMO and CASCADE cohorts. J Acquir Immune Defic Syndr, 2013; 62:441–446.
7.
XuJ, HanX, ReillyKH, ShangH: New features of the HIV epidemic among men who have sex with men in China. Emerg Microbes Infect, 2013; 2:e45.
8.
GrasL, GeskusRB, JurriaansS, et al.: Has the rate of CD4 cell count decline before initiation of antiretroviral therapy changed over the course of the Dutch HIV epidemic among MSM?. PLoS One, 2013; 8:e64437.
9.
YanH, YangH, LiJ, et al.: Emerging disparity in HIV/AIDS disease progression and mortality for men who have sex with men, Jiangsu Province, China. AIDS Behav, 2014; 18Suppl 1:S5–S10.
10.
PaulME, ShearerWT, KozinetzCA, LewisDE: Comparison of CD8(+) T-cell subsets in HIV-infected rapid progressor children versus non-rapid progressor children. J Allergy Clin Immunol, 2001; 108:258–264.
11.
ResinoS, CorreaR, BellonJM, Munoz-FernandezMA: Preserved immune system in long-term asymptomatic vertically HIV-1 infected children. Clin Exp Immunol, 2003; 132:105–112.
12.
ThobakgaleCF, StreeckH, MkhwanaziN, et al.: Short communication: CD8(+) T cell polyfunctionality profiles in progressive and nonprogressive pediatric HIV type 1 infection. AIDS Res Hum Retroviruses, 2011; 27:1005–1012.
13.
GengW, FanX, DiaoY, et al.: Rapid disease progression in HIV-1-infected men who have sex with men is negatively correlated with peripheral plasmacytoid dendritic cell counts at the early stage of primary infection. J Clin Immunol, 2011; 31:882–890.
14.
ZhangZN, XuJJ, FuYJ, et al.: Transcriptomic analysis of peripheral blood mononuclear cells in rapid progressors in early HIV infection identifies a signature closely correlated with disease progression. Clin Chem, 2013; 59:1175–1186.
15.
Features of children perinatally infected with HIV-1 surviving longer than 5 years. Italian Register for HIV infection in children. Lancet, 1994; 343:191–195.
16.
NielsenK, McSherryG, PetruA, et al.: A descriptive survey of pediatric human immunodeficiency virus-infected long-term survivors. Pediatrics, 1997; 99:E4.
17.
YaoS, BuzoBF, PhamD, et al.: Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation. Immunity, 2013; 39:833–845.
18.
GentleIE, MoelterI, LechlerN, et al.: Inhibitors of apoptosis proteins (IAPs) are required for effective T-cell expansion/survival during antiviral immunity in mice. Blood, 2014; 123:659–668.
19.
YouF, WangP, YangL, et al.: ELF4 is critical for induction of type I interferon and the host antiviral response. Nat Immunol, 2013; 14:1237–1246.
20.
YamadaT, ParkCS, MamonkinM, LacorazzaHD: Transcription factor ELF4 controls the proliferation and homing of CD8+ T cells via the Kruppel-like factors KLF4 and KLF2. Nat Immunol, 2009; 10:618–626.
21.
KimMV, OuyangW, LiaoW, ZhangMQ, LiMO: The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection. Immunity, 2013; 39:286–297.
22.
StaronMM, GraySM, MarshallHD, et al.: The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity, 2014; 41:802–814.
23.
van GrevenyngheJ, ProcopioFA, HeZ, et al.: Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection. Nat Med, 2008; 14:266–274.
24.
SullivanJA, KimEH, PlischEH, SureshM: FOXO3 regulates the CD8 T cell response to a chronic viral infection. J Virol, 2012; 86:9025–9034.
25.
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.
26.
HanX, XuJ, ChuZ, et al.: Screening acute HIV infections among Chinese men who have sex with men from voluntary counseling & testing centers. PLoS One, 2011; 6:e28792.
27.
FiebigEW, WrightDJ, RawalBD, et al.: Dynamics of HIV viremia and antibody seroconversion in plasma donors: Implications for diagnosis and staging of primary HIV infection. AIDS, 2003; 17:1871–1879.
28.
HeS, ZhangZ, FuY, et al.: Thymic function is most severely impaired in chronic HIV-1 infection, but individuals with faster disease progression during early HIV-1 infection expressed lower levels of RTEs. J Acquir Immune Defic Syndr, 2015; 70:472–478.
29.
MonteiroM, EvaristoC, LegrandA, NicolettiA, RochaB: Cartography of gene expression in CD8 single cells: Novel CCR7- subsets suggest differentiation independent of CD45RA expression. Blood, 2007; 109:2863–2870.
30.
TincatiC, SavoldiA, CannizzoES, et al.: T-cell phenotype and function following a first cART regimen containing either a protease inhibitor or a non-nucleoside retrotranscriptase inhibitor in HIV-infected late presenters: Results from a retrospective, ex vivo study. Antivir Ther, 2016; 21:133–142.
31.
MburuS, MarnewickJL, AbayomiA, IppH: Modulation of LPS-induced CD4+ T-cell activation and apoptosis by antioxidants in untreated asymptomatic HIV infected participants: An in vitro study. Clin Dev Immunol, 2013; 2013:631063.
32.
ZaundersJJ, CunninghamPH, KelleherAD, et al.: Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV-1) infection: Partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia. J Infect Dis, 1999; 180:320–329.
33.
TogherS, LarangeA, SchoenbergerSP, FeauS: FoxO3 is a negative regulator of primary CD8+ T-cell expansion but not of memory formation. Immunol Cell Biol, 2015; 93:120–125.
34.
LiP, SpolskiR, LiaoW, et al.: BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature, 2012; 490:543–546.
35.
SchieferAI, VeselyP, HasslerMR, EggerG, KennerL: The role of AP-1 and epigenetics in ALCL. Front Biosci (Schol Ed), 2015; 7:226–235.
36.
HayashiK, AltmanA. Protein kinase C theta (PKCtheta): A key player in T cell life and death. Pharmacol Res, 2007; 55:537–544.
37.
BermejoM, Lopez-HuertasMR, HedgpethJ, et al.: Analysis of protein kinase C theta inhibitors for the control of HIV-1 replication in human CD4+ T cells reveals an effect on retrotranscription in addition to viral transcription. Biochem Pharmacol, 2015; 94:241–256.
38.
Lopez-HuertasMR, MateosE, Sanchez Del CojoM, et al.: The presence of HIV-1 Tat protein second exon delays fas protein-mediated apoptosis in CD4+ T lymphocytes: A potential mechanism for persistent viral production. J Biol Chem, 2013; 288:7626–7644.
39.
KarimR, MackWJ, StillerT, et al.: Association of HIV clinical disease progression with profiles of early immune activation: Results from a cluster analysis approach. AIDS, 2013; 27:1473–1481.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
