Human immunodeficiency viruses induce rare attenuated diseases due either to HIV-1 in the exceptional long-term nonprogressors (LTNPs) or to HIV-2 in West Africa. To better understand characteristics of these two disease types we performed a multiplex comparative analysis of cell activation, exhaustion, and expression of coreceptors and restriction factors in CD4 T cells susceptible to harbor those viruses. We analyzed by flow cytometry the expression of HLA-DR, PD1, CCR5, CXCR6, SAMHD1, Blimp-1, and TRIM5α on CD4 T cell subsets from 10 HIV-1+ LTNPs and 14 HIV-2+ (12 nonprogressors and 2 progressors) of the ANRS CO-15 and CO-5 cohorts, respectively, and 12 HIV− healthy donors (HD). The V3 loop of the HIV-1 envelope from 6 HIV-1+ LTNPs was sequenced to determine the CXCR6-binding capacity. Proportions of HLA-DR+ and PD1+ cells were higher in memory CD4 T subsets from HIV-1 LTNPs compared with HIV-2 and HD. Similar findings were observed for CCR5+ cells although limited to central-memory CD4 T cell (TCM) and follicular helper T cell subsets, whereas all major subsets from HIV-1 LTNPs contained less CXCR6+ cells compared with HIV-2. All six V3 loop sequences from HIV-1 LTNPs contained a proline at position 326. Proportions of SAMHD1+ cells were higher in all resting CD4 T subsets from HIV-1 LTNPs compared with the other groups, whereas Blimp-1+ and Trim5α+ cells did not differ. The CD4 T cell subsets from HIV-1 LTNPs differ from those of HIV-2-infected subjects by higher levels of activation, exhaustion, and SAMHD1 expression that can reflect the distinct patterns of host/virus relationships.
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References
1.
MagierowskaM, TheodorouI, DebréP, et al.: Combined genotypes of CCR5, CCR2, SDF1, and HLA genes can predict the long-term nonprogressor status in human immunodeficiency virus-1-infected individuals. Blood, 1999; 93:936–941.
2.
CarringtonM: HLA and HIV-1: Heterozygote advantage and B*35-Cw*04 disadvantage. Science, 1999; 283:1748–1752.
3.
DescoursB, Avettand-FenoelV, BlancC, et al.: Immune responses driven by protective human leukocyte antigen alleles from long-term nonprogressors are associated with low HIV reservoir in central memory CD4 T cells. Clin Infect Dis, 2012; 54:1495–1503.
4.
PaiardiniM, PandreaI, ApetreiC, SilvestriG: Lessons learned from the natural hosts of HIV-related viruses. Annu Rev Med, 2009; 60:485–495.
5.
DescoursB, CribierA, Chable-BessiaC, et al.: SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4+ T-cells. Retrovirology, 2012; 9:87.
6.
SamriA, CharpentierC, DialloMS, et al.: Limited HIV-2 reservoirs in central-memory CD4 T-cells associated to CXCR6 co-receptor expression in attenuated HIV-2 infection. PLoS Pathog, 2019; 15:e1007758.
7.
WetzelKS, YiY, YadavA, et al.: Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses. PLoS Pathog, 2018; 14:e1007003.
8.
HreckaK, HaoC, GierszewskaM, et al.: Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature, 2011; 474:658–661.
9.
LaguetteN, SobhianB, CasartelliN, et al.: SAMHD1 is the dendritic– and myeloid–cell–specific HIV–1 restriction factor counteracted by Vpx. Nature, 2011; 474:654–657.
10.
RuffinN, BrezarV, AyindeD, et al.: Low SAMHD1 expression following T-cell activation and proliferation renders CD4+ T cells susceptible to HIV-1. AIDS, 2015; 29:519–530.
11.
CimminoL, MartinsGA, LiaoJ, et al.: Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression. J Immunol, 2008; 181:2338–2347.
12.
IwasakiY, FujioK, OkamuraT, et al.: Egr-2 transcription factor is required for Blimp-1-mediated IL-10 production in IL-27-stimulated CD4+ T cells. Eur J Immunol, 2013; 43:1063–1073.
13.
KellerAD, ManiatisT: Identification and characterization of a novel repressor of beta-interferon gene expression. Genes Dev, 1991; 5:868–879.
14.
MartinsGA, CimminoL, LiaoJ, MagnusdottirE, CalameK: Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival. J Exp Med, 2008; 205:1959–1965.
15.
MichaelsKK, NatarajanM, EulerZ, AlterG, VigliantiG, HendersonAJ: Blimp-1, an intrinsic factor that represses HIV-1 proviral transcription in memory CD4+ T cells. J Immunol, 2015; 194:3267–3274.
16.
de MassonA, KirilovskyA, ZoorobR, et al.: Blimp-1 overexpression is associated with low HIV-1 reservoir and transcription levels in central memory CD4+ T cells from elite controllers. AIDS, 2014; 28:1567.
17.
MartinsG, CalameK: Regulation and functions of Blimp-1 in T and B lymphocytes. Annu Rev Immunol, 2008; 26:133–169.
18.
CrottyS, JohnstonRJ, SchoenbergerSP: Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol, 2010; 11:114–120.
19.
CheKF, ShankarEM, MuthuS, et al.: p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 pathway signaling regulates expression of inhibitory molecules in T cells activated by HIV-1-exposed dendritic cells. Mol Med, 2012; 18:1169–1182.
20.
SeddikiN, PhetsouphanhC, SwaminathanS, et al.: The microRNA-9/B-lymphocyte-induced maturation protein-1/IL-2 axis is differentially regulated in progressive HIV infection. Eur J Immunol, 2013; 43:510–520.
21.
ShankarEM, CheKF, MessmerD, LifsonJD, LarssonM: Expression of a broad array of negative costimulatory molecules and Blimp-1 in T cells following priming by HIV-1 pulsed dendritic cells. Mol Med, 2011; 17:229–240.
22.
HatziioannouT, Perez-CaballeroD, YangA, CowanS, BieniaszPD: Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α. Proc Natl Acad Sci U S A, 2004; 101:10774–10779.
23.
StremlauM, OwensCM, PerronMJ, KiesslingM, AutissierP, SodroskiJ: The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys. Nature, 2004; 427:848–853.
24.
StremlauM, PerronM, WelikalaS, SodroskiJ: Species-specific variation in the B30.2(SPRY) domain of TRIM5α determines the potency of human immunodeficiency virus restriction. J Virol, 2005; 79:3139–3145.
25.
TowersG, BockM, MartinS, TakeuchiY, StoyeJP, DanosO: A conserved mechanism of retrovirus restriction in mammals. Proc Natl Acad Sci U S A, 2000; 97:12295–12299.
26.
TakeuchiJS, PercheB, MigraineJ, et al.: High level of susceptibility to human TRIM5α conferred by HIV-2 capsid sequences. Retrovirology, 2013; 10:50.
27.
WilliamsKC, BurdoTH: HIV and SIV infection—the role of cellular restriction and immune responses in viral replication and pathogenesis. APMIS, 2009; 117:400–412.
28.
BlanksonJ: Control of HIV-1 replication in elite suppressors. Discov Med, 2010; 9:261–266.
29.
VieillardV, Fausther-BovendoH, SamriA, DebréP: Specific phenotypic and functional features of natural killer cells from HIV-infected long-term nonprogressors and HIV controllers. J Acquir Immune Def Syndr, 2010; 53:564–573.
30.
ThiébautR, MatheronS, TaiebA, et al.: Long-term nonprogressors and elite controllers in the ANRS CO5 HIV-2 cohort. AIDS, 2011; 25:865–867.
31.
LucarO, Sadjo DialloM, BayardC, et al.: B7-H6-mediated downregulation of NKp30 in natural killer cells contributes to HIV-2 immune escape. AIDS, 2019; 33:23–32.
32.
AkibaH, TakedaK, KojimaY, et al.: The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J Immunol, 2005; 175:2340–2348.
33.
YuD, RaoS, TsaiLM, et al.: The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity, 2009; 31:457–468.
34.
ChevalierN, JarrossayD, HoE, et al.: CXCR5 Expressing human central memory CD4 T cells and their relevance for humoral immune responses. J Immunol, 2011; 186:5556–5568.
35.
MoserB: CXCR5, the defining marker for follicular B helper T (TFH) cells. Front Immunol, 2015; 6:296.
36.
BraibantM, AgutH, RouziouxC, CostagliolaD, AutranB, BarinF: Characteristics of the env genes of HIV type 1 quasispecies in long-term nonprogressors with broadly neutralizing antibodies. J Acquir Immune Defic Syndr, 2008; 47:274–284.
37.
AlbertJ, FenyöEM: Simple, sensitive, and specific detection of human immunodeficiency virus type 1 in clinical specimens by polymerase chain reaction with nested primers. J Clin Microbiol, 1990; 28:1560–1564.
38.
HallTA: BioEdit: A user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp, 1999; 41:95–98.
39.
ThompsonJD, HigginsDG, GibsonTJ: CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res, 1994; 22:4673–4680.
40.
CandottiD, CostagliolaD, JobertyC, et al.: Status of long-term asymptomatic HIV-1 infection correlates with viral load but not with virus replication properties and cell tropism. French ALT Study Group. J Med Virol, 1999; 58:256–263.
41.
KlattNR, VintonCL, LynchRM, et al.: SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination. Blood, 2011; 118:5803–5812.
42.
HongJJ, AmanchaPK, RogersK, AnsariAA, VillingerF: Spatial alterations between CD4(+) T follicular helper, B, and CD8(+) T cells during simian immunodeficiency virus infection: T/B cell homeostasis, activation, and potential mechanism for viral escape. J Immunol, 2012; 188:3247–3256.
43.
XuY, WeatherallC, BaileyM, et al.: Simian immunodeficiency virus infects follicular helper CD4 T cells in lymphoid tissues during pathogenic infection of pigtail macaques. J Virol, 2013; 87:3760–3773.
44.
ZaundersJ, DantaM, BaileyM, et al.: CD4+ T follicular helper and IgA+ B cell numbers in gut biopsies from HIV-infected subjects on antiretroviral therapy are similar to HIV-uninfected individuals. Front Immunol, 2016; 7:438.
45.
Hey-NguyenWJ, XuY, PearsonCF, et al.: Quantification of residual germinal center activity and HIV-1 DNA and RNA levels using fine needle biopsies of lymph nodes during antiretroviral therapy. AIDS Res Hum Retroviruses, 2017; 33:648–657.
46.
HaniL, ChaillonA, NereM-L, et al.: Proliferative memory SAMHD1low CD4+ T cells harbour high levels of HIV-1 with compartmentalized viral populations. PLoS Pathog, 2019; 15:e1007868.
47.
RyooJ, ChoiJ, OhC, et al.: The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med, 2014; 20:936–941.
48.
KaczmarekK, MoralesA, HendersonAJ: T cell transcription factors and their impact on HIV expression. Virology (Auckl), 2013; 4:41–47.
49.
KalliesA, HawkinsED, BelzGT, et al.: Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat Immunol, 2006; 7:466–474.
50.
KalliesA, HasboldJ, TarlintonDM, et al.: Plasma cell ontogeny defined by quantitative changes in Blimp-1 expression. J Exp Med, 2004; 200:967–977.
51.
ZhangH-L, LiuF-L, JinY-B, et al.: The effects of TRIM5α polymorphism on HIV-2ROD and SIVmac239 replication in PBMCs from Chinese rhesus macaques and Vietnamese-origin cynomolgus macaques. Virology, 2016; 487:222–229.
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