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Immunity & Ageing
Published in: Immunity & Ageing 1/2019

Open Access 01-12-2019 | Human Immunodeficiency Virus | Research

Lymphocyte homeostasis is maintained in perinatally HIV-infected patients after three decades of life

Authors: S. Paghera, E. Quiros-Roldan, A. Sottini, M. Properzi, F. Castelli, L. Imberti

Published in: Immunity & Ageing | Issue 1/2019

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Abstract

Background

While immunosenescence, defined as reduced production of new lymphocytes, restriction of T-cell receptor repertoire and telomeres shortening, has been extensively evaluated in HIV-infected children and adults, no data about these parameters are available in perinatally-infected patients with very long-lasting HIV infection.

Methods

We compared thymic and bone marrow output, telomere length (measured by Real-Time PCR) and T-cell receptor repertoire (determined by spectratyping) of 21 perinatally HIV-infected subjects (with a median of 27 years of infection) with those of 19 age-matched non-perinatally HIV-infected patients and 40 healthy controls. All patients received a combined antiretroviral therapy.

Results

While thymic and bone marrow output were not different among the analyzed groups, telomere length in peripheral blood cells and T-cell receptor diversity were significantly lower in HIV-perinatally and non-perinatally infected individuals compared to healthy controls.

Conclusions

In HIV-infected subjects, a normal thymic output together with a reduced telomere length and a restricted T-cell receptor repertoire could be explained by the shift of newly produced cells into memory subsets. This phenomenon may allow to control viral infection and maintain peripheral homeostasis.
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Literature
1.
2.
Castro H, Judd A, Gibb DM, Butler K, Lodwick RK, van Sighem A, et al. Risk of triple-class virological failure in children with HIV: a retrospective cohort study. Lancet. 2011;377:1580–7.PubMedCrossRef
3.
Lowenthal ED, Bakeera-Kitaka S, Marukutira T, Chapman J, Goldrath K, Ferrand RA. Perinatally acquired HIV infection in adolescents from sub-Saharan Africa: a review of emerging challenges. Lancet Infect Dis. 2014;14:627–39.PubMedPubMedCentralCrossRef
4.
Judd A, Foster C, Thompson LC, Sturgeon K, Le Prevost M, Jungmann E, et al. Sexual health of young people with perinatal HIV and HIV negative young people in England. PLoS One. 2018;12:e0205597.CrossRef
5.
Cagigi A, Cotugno N, Giaquinto C, Nicolosi L, Bernardi S, Rossi P, et al. Immune reconstitution and vaccination outcome in HIV-1 infected children: present knowledge and future directions. Hum Vaccin Immunother. 2012;8:1784–94.PubMedPubMedCentralCrossRef
6.
Moir S, Ho J, Malaspina A, Wang W, DiPoto AC, O'Shea MA, et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J Exp Med. 2008;205:1797–805.PubMedPubMedCentralCrossRef
7.
Sokoya T, Steel HC, Nieuwoudt M, Rossouw TM. HIV as a cause of immune activation and immunosenescence. Mediat Inflamm. 2017;2017:6825493.CrossRef
8.
Chiappini E, Bianconi M, Dalzini A, Petrara MR, Galli L, Giaquinto C, et al. Accelerated aging in perinatally HIV-infected children: clinical manifestations and pathogenetic mechanisms. Aging. 2018;10:3610–25.PubMedPubMedCentralCrossRef
9.
Hazenberg MD, Otto SA, Cohen Stuart JW, Verschuren MC, Borleffs JC, Boucher CA, et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naïve T cell population in HIV-1 infection. Nat Med. 2000;6:1036–42.PubMedCrossRef
10.
Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396:690–5.PubMedCrossRef
11.
De Rossi A, Walker AS, De Forni D, Klein N, Gibb DM. Relationship between changes in thymic emigrants and cell-associated HIV-1 DNA in HIV-1-infected children initiating antiretroviral therapy. Antivir Ther. 2005;10:63–71.PubMed
12.
Blanche S, Scott-Algara D, Le Chenadec J, Didier C, Montange T, Avettand-Fenoel V, et al. Naïve T lymphocytes and recent thymic emigrants are associated with HIV-1 disease history in french adolescents and young adults infected in the perinatal period: the ANRSEP38-IMMIP study. Clin Infect Dis. 2014;58:573–87.PubMedCrossRef
13.
Fabre-Mersseman V, Dutrieux J, Louise A, Rozlan S, Lamine A, Parker R, et al. CD4+ recent thymic emigrants are infected by HIV in vivo, implication for pathogenesis. AIDS. 2011;25:1153–62.PubMedCrossRef
14.
Connors M, Kovacs JA, Krevat S, Gea-Banacloche JC, Sneller MC, Flanigan M, et al. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med. 1997;3:533–40.PubMedCrossRef
15.
Gea-Banacloche JC, Martino L, Mican JM, Hallahan CW, Baseler M, Stevens R, et al. Longitudinal changes in CD4+ T cell antigen receptor diversity and naïve/memory cell phenotype during 9 to 26 months of antiretroviral therapy of HIV-infected patients. AIDS Res Hum Retrovir. 2000;16:1877–86.PubMedCrossRef
16.
Kharbanda M, McCloskey TW, Pahwa R, Sun M, Pahwa S. Alterations in T-cell receptor Vbeta repertoire of CD4 and CD8 T lymphocytes in human immunodeficiency virus-infected children. Clin Diagn Lab Immunol. 2003;10:53–8.PubMedPubMedCentral
17.
Baum PD, Young JJ, Schmidt D, Zhang Q, Hoh R, Busch M, et al. Blood T-cell receptor diversity decreases during the course of HIV infection, but the potential for a diverse repertoire persists. Blood. 2012;119:3469–77.PubMedPubMedCentralCrossRef
18.
Killian MS, Monteiro J, Matud J, Hultin LE, Hausner MA, Yang OO, et al. Persistent alterations in the T-cell repertoires of HIV- 1-infected and at-risk uninfected men. AIDS. 2004;18:161–70.PubMedCrossRef
19.
Lee JC, Boechat MI, Belzer M, Church JA, De Ville J, Nielsen K, et al. Thymic volume, T-cell populations, and parameters of thymopoiesis in adolescent and adult survivors of HIV infection acquired in infancy. AIDS. 2006;20:667–74.PubMedCrossRef
20.
Lewis J, Payne H, Walker AS, Otwombe K, Gibb DM, Babiker AG, et al. Thymic output and CD4 T-cell reconstitution in HIV-infected children on early and interrupted antiretroviral treatment: evidence from the children with HIV early antiretroviral therapy trial. Front Immunol. 2017;8:1162.PubMedPubMedCentralCrossRef
21.
Aguilera-Sandoval CR, Yang OO, Jojic N, Lovato P, Chen DY, Boechat MI, et al. Supranormal thymic output up to 2 decades after HIV-1 infection. AIDS. 2016;30:701–11.PubMedCrossRef
22.
Yin L, Kou ZC, Rodriguez C, Hou W, Goodenow MM, Sleasman JW. Antiretroviral therapy restores diversity in the T-cell receptor Vbeta repertoire of CD4 T-cell subpopulations among human immunodeficiency virus type 1-infected children and adolescents. Clin Vaccine Immunol. 2009;16:1293–301.PubMedPubMedCentralCrossRef
23.
Rb-Silva R, Nobrega C, Azevedo C, Athayde E, Canto-Gomes J, Ferreira I, et al. Thymic function as a predictor of immune recovery in chronically HIV-infected patients initiating antiretroviral therapy. Front Immunol. 2019;10:25.PubMedPubMedCentralCrossRef
24.
Gianesin K, Noguera-Julian A, Zanchetta M, Del Bianco P, Petrara MR, Freguja R, et al. Premature aging and immune senescence in HIV-infected children. AIDS. 2016;30:1363–73.PubMedCrossRef
25.
Leeansyah E, Cameron PU, Solomon A, Tennakoon S, Velayudham P, Gouillou M, et al. Inhibition of telomerase activity by human immunodeficiency virus (HIV) nucleos(t) ide reverse transcriptase inhibitors: a potential factor contributing to HIV-associated accelerated aging. J Infect Dis. 2013;207:1157–65.PubMedCrossRef
26.
Pathai S, Lawn SD, Gilbert CE, McGuinness D, McGlynn L, Weiss HA, et al. Accelerated biological ageing in HIV-infected individuals in South Africa: a case-control study. AIDS. 2013;27:2375–84.PubMedCrossRef
27.
Zanet DL, Thorne A, Singer J, Maan EJ, Sattha B, Le Campion A, et al. CIHR emerging team Grant on HIV therapy and aging: CARMA. Association between short leukocyte telomere length and HIV infection in a cohort study: no evidence of a relationship with antiretroviral therapy. Clin Infect Dis. 2014;58:1322–32.PubMedCrossRef
28.
Hukezalie KR, Thumati NR, Côté HC, Wong JM. In vitro and ex vivo inhibition of human telomerase by anti-HIV nucleoside reverse transcriptase inhibitors (NRTIs) but not by non-NRTIs. PLoS One. 2012;7:e47505.PubMedPubMedCentralCrossRef
29.
Cagigi A, Rinaldi S, Di Martino A, Manno EC, Zangari P, Aquilani A, et al. Premature immune senescence during HIV-1 vertical infection relates with response to influenza vaccination. J Allergy Clin Immunol. 2014;133:592–4.PubMedCrossRef
30.
Pensieroso S, Cagigi A, Palma P, Nilsson A, Capponi C, Freda E, et al. Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children. Proc Natl Acad Sci U S A. 2009;106:7939–44.PubMedPubMedCentralCrossRef
31.
Cubas R, van Grevenynghe J, Wills S, Kardava L, Santich BH, Buckner CM, et al. Reversible reprogramming of circulating memory T follicular helper cell function during chronic HIV infection. J Immunol. 2015;195:5625–36.PubMedPubMedCentralCrossRef
32.
33.
George VK, Pallikkuth S, Parmigiani A, Alcaide M, Fischl M, Arheart KL, et al. HIV infection worsens age-associated defects in antibody responses to influenza vaccine. J Infect Dis. 2015;211:1959–68.PubMedPubMedCentralCrossRef
34.
Pallikkuth S, Pilakka Kanthikeel S, Silva SY, Fischl M, Pahwa R, Pahwa S. Upregulation of IL-21 receptor on B cells and IL-21 secretion distinguishes novel 2009 H1N1 vaccine responders from nonresponders among HIV-infected persons on combination antiretroviral therapy. J Immunol. 2011;186:6173–81.PubMedCrossRef
35.
Parmigiani A, Alcaide ML, Freguja R, Pallikkuth S, Frasca D, Fischl MA, et al. Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation. PLoS One. 2013;8:e79816.PubMedPubMedCentralCrossRef
36.
Meffre E, Louie A, Bannock J, Kim LJ, Ho J, Frear CC, et al. Maturational characteristics of HIV-specific antibodies in viremic individuals. JCI Insight. 2016;1:e84610.PubMedPubMedCentralCrossRef
37.
Amu S, Lavy-Shahaf G, Cagigi A, Hejdeman B, Nozza S, Lopalco L, et al. Frequency and phenotype of B cell subpopulations in young and aged HIV-1 infected patients receiving ART. Retrovirology. 2014;11:76.PubMedPubMedCentralCrossRef
38.
Pensieroso S, Galli L, Nozza S, Ruffin N, Castagna A, Tambussi G, et al. B-cell subset alterations and correlated factors in HIV-1 infection. AIDS. 2013;27:1209–17.PubMedCrossRef
39.
Blanche S, Scott-Algara D, Le Chenadec J, Didier C, Montange T, Avettand-Fenoel V, et al. Naïve T lymphocytes and recent thymic emigrants are associated with HIV-1 disease history in french adolescents and young adults infected in the perinatal period: the ANRS-EP38-IMMIP study. Clin Infect Dis. 2014;58:573–87.PubMedCrossRef
40.
Agwu AL, Fleishman JA, Mahiane G, Nonyane BA, Althoff KN, Yehia BR, et al. Comparing longitudinal CD4 responses to cART among non-perinatally HIV-infected youth versus adults: results from the HIVRN cohort. PLoS One. 2017;12:e0171125.PubMedPubMedCentralCrossRef
41.
Sottini A, Ghidini C, Zanotti C, Chiarini M, Caimi L, Lanfranchi A, et al. Simultaneous quantification of recent thymic T-cell and bone marrow B-cell emigrants in patients with primary immunodeficiency undergone to stem cell transplantation. Clin Immunol. 2010;136:217–27.PubMedCrossRef
42.
43.
Lin J, Smith DL, Esteves K, Drury S. Telomere length measurement by qPCR - Summary of critical factors and recommendations for assay design. Psychoneuroendocrinology. 2019;99:271–8.PubMedCrossRef
44.
Tolios A, Teupser D, Holdt LM. Preanalytical conditions and DNA isolation methods affect telomere length quantification in whole blood. PLoS One. 2015;10:e0143889.PubMedPubMedCentralCrossRef
45.
Hsieh AYY, Saberi S, Ajaykumar A, Hukezalie K, Gadawski I, Sattha B, et al. Optimization of a relative telomere length assay by monochromatic multiplex real-time quantitative PCR on the LightCycler 480: sources of variability and quality control considerations. J Mol Diagn. 2016;18:425–37.PubMedPubMedCentralCrossRef
46.
47.
Aviv A, Hunt SC, Lin J, Cao X, Kimura M, Blackburn E. Impartial comparative analysis of measuremente of leukocyte telomere length/DNA content by southern blots and qPCR. Nucleic Acids Res. 2011;39:e134.PubMedPubMedCentralCrossRef
48.
Sottini A, Capra R, Zanotti C, Chiarini M, Serana F, Ricotta D, et al. Pre-existing T- and B-cell defects in one progressive multifocal leukoencephalopathy patient. PLoS One. 2012;7:e34493.PubMedPubMedCentralCrossRef
49.
Akatsuka Y, Martin EG, Madonik A, Barsoukov AA, Hansen JA. Rapid screening of T-cell receptor (TR) variable gene usage by multiplex PCR: application for assessment of clonal composition. Tissue Antigens. 1999;53:122–34.PubMedCrossRef
50.
Gorochov G, Neumann AU, Kereveur A, Parizot C, Li T, Katlama C, et al. Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med. 1998;4:215–21.PubMedCrossRef
51.
52.
Dollfus C, Le Chenadec J, Faye A, Blanche S, Briand N, Rouzioux C, et al. Long-term outcomes in adolescents perinatally infected with HIV-1 and followed up since birth in the French perinatal cohort (EPF/ANRS CO10). Clin Infect Dis. 2010;51:214–24.PubMedCrossRef
53.
Massanella M, Negredo E, Clotet B, Blanco J. Immunodiscordant responses to HAART-mechanisms and consequences. Expert Rev Clin Immunol. 2013;9:1135–49.PubMedCrossRef
54.
Gazzola L, Tincati C, Bellistrì GM, Ad M, Marchetti G. The absence of CD4+ T cell count recovery despite receipt of virologically suppressive highly active antiretroviral therapy: clinical risk, immunological gaps, and therapeutic options. Clin Infect Dis. 2009;48:328–37.PubMedCrossRef
55.
Rodríguez-Gallego E, Gómez J, Pacheco YM, Peraire J, Viladés C, Beltrán-Debón R, et al. A baseline metabolomic signature is associated with immunological CD4+ T-cell recovery after 36 months of antiretroviral therapy in HIV-infected patients. AIDS. 2018;32:565–73.PubMed
56.
Ferrando-Martinez S, De Pablo-Bernal RS, De Luna-Romero M, De Ory SJ, Genebat M, Pacheco YM, et al. Thymic function failure is associated with human immunodeficiency virus disease progression. Clin Infect Dis. 2017;64:1191–7.PubMedPubMedCentralCrossRef
57.
Pornprasert S, Traisathit P, Singboottra P, Huong NN. Treatment of opportunistic infections prior to HAART initiation does not affect immune reconstitution in HIV-infected patients. Curr HIV Res. 2012;10:592–6.PubMedCrossRef
58.
Cotè HC, Soudeyns H, Thorne A, Alimenti A, Lamarre V, Maan EJ, et al. Leukocyte telomere length in HIV-infected and HIV-exposed uninfected children: shorter telomeres with uncontrolled HIV viremia. PLoS One. 2012;7:e39266.PubMedPubMedCentralCrossRef
59.
Liu X, Takahashi H, Harada Y, Ogawara T, Ogimura Y, Mizushina Y, et al. 3′-Azido-2′,3′-dideoxynucleoside 5′-triphosphates inhibit telomerase activity in vitro, and the corresponding nucleosides cause telomere shortening in human HL60 cells. Nucleic Acids Res. 2007;35:7140–9.PubMedPubMedCentralCrossRef
60.
Borghans J, Ribeiro RM. The maths of memory. Elife. 2017;6:e26754.
61.
Conrad JA, Ramalingam RK, Duncan CB, Smith RM, Wei J, Barnett L, et al. Antiretroviral therapy reduces the magnitude and T cell receptor repertoire diversity of HIV-specific T cell responses without changing T cell clonotype dominance. J Virol. 2012;86:4213–21.PubMedPubMedCentralCrossRef
62.
Heather JM, Best K, Oakes T, Gray ER, Roe JK, Thomas N, et al. Dynamic perturbations of the T-cell receptor repertoire in chronic HIV infection and following antiretroviral therapy. Front Immunol. 2016;6:644.PubMedPubMedCentralCrossRef
63.
Pahwa S, Chitnis V, Mitchell RM, Fernandez S, Chandrasekharan A, Wilson CM, Douglas SD. CD4+ and CD8+ T cell receptor repertoire perturbations with normal levels of T cell receptor excision circles in HIV-infected, therapy-naïve adolescents. AIDS Res Hum Retrovir. 2003;19:487–95.PubMedCrossRef
64.
Veel E, Westera L, van Gent R, Bont L, Otto S, Ruijsink B, et al. Impact of aging, cytomegalovirus infection, and long-term treatment for human immunodeficiency virus on CD8+ T-cell subsets. Front Immunol. 2018;9:572.PubMedPubMedCentralCrossRef
65.
Payne H, Chain G, Adams S, Hunter P, Luckhurst N, Gilmour K, et al. Naïve B cell output in HIV-infected and HIV-uninfected children. AIDS Res Hum Retrovir. 2019;35:33–9.PubMedCrossRefPubMedCentral
66.
Lai T-P, Zhang N, Noh J, Mender I, Tedone E, Huang E, et al. A method for measuring the distribution of the shortest telomeres in cells and tissues. Nat Commun. 2017;8:1356.PubMedPubMedCentralCrossRef
67.
Lai T-P, Wright WE, Shay JW. Comparison of telomere length measurement methods. Philos Trans R Soc Lond B Biol Sci. 2018;373:e:20160451.CrossRef
68.
Montpetit AJ, Alhareeri AA, Montpetit M, Starkweather AR, Elmore LW, Filler K, et al. Telomere length: a review of methods for measurement. Nurs Res. 2014;63:289–99.PubMedPubMedCentralCrossRef
Metadata
Title
Lymphocyte homeostasis is maintained in perinatally HIV-infected patients after three decades of life
Authors
S. Paghera
E. Quiros-Roldan
A. Sottini
M. Properzi
F. Castelli
L. Imberti
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Immunity & Ageing / Issue 1/2019
Electronic ISSN: 1742-4933
DOI
https://doi.org/10.1186/s12979-019-0166-7

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