Secondary Logo

The HIV-1 Tat protein affects human CD4+ T-cell programing and activation, and favors the differentiation of naïve CD4+ T cells

Nicoli, Francescoa,b; Gallerani, Eleonoraa; Sforza, Fabioa; Finessi, Valentinaa; Chachage, Mkundec,d; Geldmacher, Christofd,e; Cafaro, Aureliof; Ensoli, Barbaraf; Caputo, Antonellab; Gavioli, Riccardoa

doi: 10.1097/QAD.0000000000001734
BASIC SCIENCE: CONCISE COMMUNICATION
Free
SDC

Objective: HIV infection is characterized by several immune dysfunctions, such as chronic activation of the immune system, premature aging and loss of CD4+ T cells, in particular within the naïve compartment. The Tat protein of HIV is released extracellularly and enters neighboring cells affecting their functionality, for instance impacting on CD8+ T-cell programs and activity. As the presence and/or induction of anti-Tat immune responses is associated with reduced T-cell dysfunction and CD4+ T-cell loss, we investigated whether Tat impacts human resting or activated CD4+ T cells.

Methods: Purified CD4+ T cells were activated by T cell receptor engagement in the presence or absence of Tat. Cytokine production, surface phenotype and expression of transcription factors important for T-cell programing were measured. Purified naïve CD4+ T cells were cultured in nonpolarizing conditions in the presence or absence of Tat and their proliferation and differentiation was evaluated.

Results: Tat favors the secretion of IL2, IFNγ and TNFα in CD4+ T cells, as well as the upregulation of T-bet and Eomes expression. Naïve CD4+ T cells cultured in the presence of Tat showed enhanced expansion and differentiation toward memory phenotype, showing in particular recruitment into the effector memory T-cell pool.

Conclusion: Tat affects the programing and functionality of CD4+ T lymphocytes favoring the differentiation of naïve CD4+ T cells.

aDepartment of Life Sciences and Biotechnology, University of Ferrara, Ferrara

bDepartment of Molecular Medicine, University of Padova, Padova, Italy

cDepartment of Immunology, NIMR Mbeya Medical Research Centre, Mbeya, Tanzania

dDivision of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU)

eGerman Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany

fNational AIDS Center, Istituto Superiore di Sanità, Rome, Italy.

Correspondence to Prof. Riccardo Gavioli, PhD, Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 64A, 44121 Ferrara, Italy. Tel: +39 0532974407; fax: +39 0532974408; e-mail: r.gavioli@unife.it

Received 26 June, 2017

Revised 3 November, 2017

Accepted 17 November, 2017

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

Back to Top | Article Outline

Introduction

HIV infection strongly affects cellular immunity, causing the depletion of CD4+ T cells, in particular within the naïve compartment [1], and dysfunction of both CD8+ and CD4+ T lymphocytes [2–6]. This status of chronic immune dysregulation involves the whole T-cell compartment, including uninfected T cells [7], and is not completely restored during effective antiretroviral therapy (ART). There is a general consensus on the complexity of these phenomena which seem to be due not only to viral replication and CD4+ T cells loss, but also to the immunomodulatory activity of HIV products, including Tat [5,7]. Indeed, the HIV-1 Tat protein is released extracellularly [8], even during ART [9], and enters neighboring cells affecting their functionality [10–15]. In this context, it has been shown that Tat has a strong impact on CD8+ T-cell programs and activity [15] and, in murine models, favors the activation of CD8+ T cells and the modulation of antiviral responses [16], causing dysfunctions similar to those observed in HIV-infected individuals. It is also noteworthy that naturally acquired or vaccine-induced anti-Tat immunity limits T-cell dysfunction, CD4+ T-cell loss and viral load, and is associated with the reduction of proviral DNA, resulting in the delay of disease progression [17–21]. However, whether Tat has a direct or indirect effect upon the CD4+ T-cell compartment is currently unknown. To shed light on this issue, we have determined whether extracellular bioactive Tat impacts human resting or activated CD4+ T cells. Our results show that Tat promotes the activation of CD4+ T cells as well as differentiation of naïve CD4+ T cells toward memory subtypes that may result in the generation of new targets of infection.

Back to Top | Article Outline

Materials and methods

Human cells and culture conditions

Buffy coats from healthy volunteers, who provided consent, were obtained from the University Hospital of Ferrara. Peripheral blood lymphocytes (PBLs) were separated by use of Ficoll–Hypaque (Lonza, Basel, Switzerland) density gradient centrifugation followed by 90 min of adhesion on a plastic support at 37 °C to remove monocytes.

Total and naïve CD4+ T cells were sorted by MACS magnetic selection (Miltenyi Biotec, Bergisch Gladbach, Germany) according to manufacturer's instructions and cultured, as detailed in Supplemental information, http://links.lww.com/QAD/B210, in the absence or presence of the Tat protein in 24-well flat-bottomed polystyrene plates precoated overnight at 4 °C with PBS or anti-CD3 mAb (0.5 μg/ml; R&D Systems, Minneapolis, Minnesota, USA). Naïve CD4+ T cells were cultured in nonpolarizing condition as previously described [22] and detailed in Supplemental information, http://links.lww.com/QAD/B210.

Back to Top | Article Outline

Tat protein

HIV-1 Tat from human T lymphotropic virus type IIIB isolate (BH10 clone) was expressed in Escherichia coli and purified by heparin-affinity chromatography and HPLC, as described previously [10]. The lyophilized Tat protein was then stored at −80 °C and handled as described [10]. Endotoxin concentration was below the detection limit (0.05 EU/μg).

Back to Top | Article Outline

Flow cytometry

Surface and intracellular staining were performed as detailed in Supplemental information, http://links.lww.com/QAD/B210.

Back to Top | Article Outline

Gene-expression analysis

Gene expression was evaluated by quantitative as detailed in Supplemental information, http://links.lww.com/QAD/B210.

Back to Top | Article Outline

Results

Tat enhances CD4+ T-cell activation

The HIV-1 Tat protein, which is released by infected cells, enhances the production of proinflammatory cytokines from activated PBLs and CD8+ T cells [15,23,24]. To understand whether soluble Tat, at physiological concentration within a nanomolar range, may induce cytokine production in CD4+ T cells, resting or anti-CD3/CD28-stimulated T helper lymphocytes from healthy donors were cultured for 4 h in the absence or presence of 0.1 μg/ml of Tat protein. As shown in Fig. 1a, Tat significantly increased the expression of IL2, IFNγ and TNFα mRNAs in anti-CD3/CD28-stimulated CD4+ T cells, but not in resting lymphocytes. This effect was observed at similar levels for Tat doses ranging from 0.01 to 1 μg/ml, and it was abolished after incubation with anti-Tat positive sera (Fig. S1, http://links.lww.com/QAD/B210). This result was confirmed by cytokine intracellular staining of the cells that demonstrated increased production of IL2, IFNγ and TNFα (Fig. 1b) after 18 h of treatment with Tat when compared with untreated cells. However, the expression of early (CD69) and late (CD25, CD38, HLA-DR) activation markers was not affected by the presence of Tat (Fig. S2, http://links.lww.com/QAD/B210). As these results indicate that, in human-activated CD4+ T cells, Tat enhances the production of Th1-type cytokines, which are under the control of T-box transcription factors [25,26], we characterized the expression of T-bet and Eomes in resting and activated CD4+ T cells cultured in the absence or in the presence of Tat. As shown in Fig. 1c, Tat did not induce the mRNA expression of T-box transcription factors in unstimulated CD4+ T cells, whereas it increased significantly the expression of T-bet and Eomes transcription factors in CD3/CD28-activated CD4+ T cells as compared with CD4+ T cells activated with CD3/CD28 and cultured in the absence of Tat. Thus, at a physiological concentration, soluble Tat protein enhances the production of proinflammatory cytokines in activated CD4+ T cells and influences the expression of transcription factors crucial for T-cell programing and functionality.

Fig. 1

Fig. 1

Back to Top | Article Outline

Tat favors the expansion and the differentiation of naïve CD4+ T cells

The HIV-related chronic immune activation plays a major role in the increased proliferation and differentiation of naïve T cells into memory cells [1,27] leading to a decline of naïve T cells. As our data clearly indicate that Tat favors the activation of CD4+ T cells and the expression of transcription factors controlling T-cell programing, we wondered whether Tat had also an effect upon proliferation and differentiation of naïve lymphocytes, thus participating in immune activation and pathogenesis of HIV infection. To address this, purified naïve CD4+ T cells were cultured, in the presence or absence of Tat, in nonpolarizing conditions (NPC) to induce their activation and differentiation toward a memory phenotype avoiding potential biases due to polarization toward some specific T helper cell subpopulations [22]. As shown in Fig. 2a, NPC induced the proliferation of naïve CD4+ T cells starting from day 7 and reaching the peak at day 12. The addition of Tat enhanced duration and magnitude of naïve T helper cell expansion which peaked at day 15 and remained higher until day 18. To determine whether Tat affected the differentiation of naïve CD4+ T cells cultured in NPC, the phenotype of T helper lymphocytes was assessed. Overall, NPC prompted the loss of CD45RA expression (Fig. 2b), suggesting a shift toward a nonnaïve phenotype that had started by day 12, with a more pronounced downregulation by day 18. Significantly, this phenomenon was more pronounced in the presence of Tat. In fact, higher numbers of central memory (CD45RA, CCR7+, CD27+), transitional memory (CD45RA, CCR7, CD27+) and effector memory (CD45RA, CCR7, CD27) CD4+ T cells were generated in the presence of Tat as compared with NPC alone (Fig. 2c). It is noteworthy that effector memory CD4+ T cells were almost absent in cultures derived from naïve CD4+ T cells activated under NPC, whereas they were strongly induced in the presence of Tat (Fig. 2c). Taken together, these data suggest that Tat supports the activation of naïve CD4+ T cells promoting their transition toward more differentiated phenotypes.

Fig. 2

Fig. 2

Back to Top | Article Outline

Discussion

The Tat protein of HIV is released by infected cells [8] and interacts with neighboring cells [10–15]. We showed here that soluble Tat favors the activation of CD4+ T cells inducing the release of proinflammatory cytokines and the expression of transcription factors such as T-bet and Eomes which are crucial for T-cell activation and differentiation. In addition, Tat increased the expansion and differentiation of naïve CD4+ T cells activated in NPC. These findings, together with the observations made in CD8+ T cells [15,16,28], confirm that Tat plays an important role in the hyperactivation of the T-cell compartment, a phenomenon characterizing the progression to AIDS and possibly the residual disease observed in successfully ART-treated individuals [29,30].

Naïve CD4+ T cells are resistant to productive HIV infection due to their quiescent state [31,32]. However, their number dramatically decreases during AIDS [1], in part due to the status of chronic immune activation which favors their differentiation into memory and effector cells [27,33]. Tat, by favoring naïve T-cell activation, promotes their recruitment into the memory compartment and, fostering the exit from a quiescent state, might also contribute to the generation of new potential targets of infection, in line with previous observations showing higher susceptibly to HIV infection by CD4+ T cells exposed to Tat [34,35]. Tat expression has been detected in tissues from patients on ART [36], whose success is dependent on the levels of naïve CD4+ T cells [37], a compartment not always fully reconstituted by ART [29]. Therefore, our data suggest that blocking Tat effects may favor therapy efficacy, as indeed observed in ART-treated individuals vaccinated with the Tat protein that showed restored T-cell responses against heterologous antigens and a rise in CD4+ T-cell count [18,19].

In previous works conducted with cell lines, Tat was alternatively shown to promote apoptosis or to have antiapoptotic effects, for instance promoting the release of IL2 [38–40]. On primary human CD4+ T cells, Tat immobilized on solid support, but not high concentrations of soluble Tat, was shown to mediate IL2 production [41,42]. In contrast, we showed here that soluble Tat, used at physiological concentrations [43], induced IL2 production in primary human CD4+ T cells. Thus, our data would argue against a direct effect of Tat on T-cell death as the main mechanism of CD4+ T-cell depletion.

Tat does not promote the exit from a quiescent state of resting lymphocytes, thus probably not affecting viral reservoirs [44]. However, in activated T helper lymphocytes, it favors the production of IL2, IFNγ and of TNFα, whose plasmatic levels are increased in HIV-infected individuals [45,46]. Significantly, loss of naïve T cells, accumulation of differentiated lymphocytes and an increased level of proinflammatory cytokines are hallmarks of the accelerated immunosenescence characterizing HIV-infected individuals [47–49]. Our data suggest that Tat may support this phenomenon through the induction of proinflammatory cytokines and differentiation of T cell receptor-stimulated naïve CD4+ T cells toward late stages of differentiation, such as effector memory T cells. Accordingly, Tat has been shown to induce production of IL6 [50], which is associated with immunosenescence [51], reduction of telomerase activity in CD4+ T cells [52] and senescence of bone marrow mesenchymal stem cells [53].

In conclusion, our data suggest that Tat may contribute to the exacerbation of several immune dysfunctions observed during AIDS progression, such as chronic immune activation and premature aging. Therefore, the induction of anti-Tat immune responses by Tat administration can be an effective strategy for restoration of the immune system.

Back to Top | Article Outline

Acknowledgements

F.N. and R.G. conceived and designed the experiments and analyzed the data. F.N., F.S., E.G., V.F. and M.C. performed the experiments. F.N., A.C., A.C., C.G., B.E. and R.G. wrote the article. This work was supported by grants from the University of Ferrara and by the Gilead Fellowship Program. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the article.

Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

References

1. Di Mascio M, Sereti I, Matthews LT, Natarajan V, Adelsberger J, Lempicki R, et al. Naive T-cell dynamics in human immunodeficiency virus type 1 infection: effects of highly active antiretroviral therapy provide insights into the mechanisms of naive T-cell depletion. J Virol 2006; 80:2665–2674.
2. Harari A, Petitpierre S, Vallelian F, Pantaleo G. Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood 2004; 103:966–972.
3. Migueles SA, Weeks KA, Nou E, Berkley AM, Rood JE, Osborne CM, et al. Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J Virol 2009; 83:11876–11889.
4. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 2006; 12:1198–1202.
5. Catalfamo M, Wilhelm C, Tcheung L, Proschan M, Friesen T, Park JH, et al. CD4 and CD8 T cell immune activation during chronic HIV infection: roles of homeostasis, HIV, type I IFN, and IL-7. J Immunol 2011; 186:2106–2116.
6. Papagno L, Spina CA, Marchant A, Salio M, Rufer N, Little S, et al. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol 2004; 2:E20.
7. Haas A, Zimmermann K, Oxenius A. Antigen-dependent and -independent mechanisms of T and B cell hyperactivation during chronic HIV-1 infection. J Virol 2011; 85:12102–12113.
8. Chang HC, Samaniego F, Nair BC, Buonaguro L, Ensoli B. HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region. AIDS 1997; 11:1421–1431.
9. Mediouni S, Darque A, Baillat G, Ravaux I, Dhiver C, Tissot-Dupont H, et al. Antiretroviral therapy does not block the secretion of the human immunodeficiency virus Tat protein. Infect Disord Drug Targets 2012; 12:81–86.
10. Fanales-Belasio E, Moretti S, Nappi F, Barillari G, Micheletti F, Cafaro A, Ensoli B. Native HIV-1 Tat protein targets monocyte-derived dendritic cells and enhances their maturation, function, and antigen-specific T cell responses. J Immunol 2002; 168:197–206.
11. Gavioli R, Gallerani E, Fortini C, Fabris M, Bottoni A, Canella A, et al. HIV-1 Tat protein modulates the generation of cytotoxic T cell epitopes by modifying proteasome composition and enzymatic activity. J Immunol 2004; 173:3838–3843.
12. Gavioli R, Cellini S, Castaldello A, Voltan R, Gallerani E, Gagliardoni F, et al. The Tat protein broadens T cell responses directed to the HIV-1 antigens Gag and Env: implications for the design of new vaccination strategies against AIDS. Vaccine 2008; 26:727–737.
13. Debaisieux S, Rayne F, Yezid H, Beaumelle B. The ins and outs of HIV-1 Tat. Traffic 2012; 13:355–363.
14. Huigen MC, Kamp W, Nottet HS. Multiple effects of HIV-1 trans-activator protein on the pathogenesis of HIV-1 infection. Eur J Clin Invest 2004; 34:57–66.
15. Sforza F, Nicoli F, Gallerani E, Finessi V, Reali E, Cafaro A, et al. HIV-1 Tat affects the programming and functionality of human CD8(+) T cells by modulating the expression of T-box transcription factors. AIDS 2014; 28:1729–1738.
16. Nicoli F, Finessi V, Sicurella M, Rizzotto L, Gallerani E, Destro F, et al. The HIV-1 Tat protein induces the activation of CD8(+) T cells and affects in vivo the magnitude and kinetics of antiviral responses. PLoS One 2013; 8:e77746.
17. Nicoli F, Chachage M, Clowes P, Bauer A, Kowour D, Ensoli B, et al. Association between different anti-Tat antibody isotypes and HIV disease progression: data from an African cohort. BMC Infect Dis 2016; 16:344.
18. Ensoli F, Cafaro A, Casabianca A, Tripiciano A, Bellino S, Longo O, et al. HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial. Retrovirology 2015; 12:33.
19. Ensoli B, Bellino S, Tripiciano A, Longo O, Francavilla V, Marcotullio S, et al. Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART. PLoS One 2010; 5:e13540.
20. Bellino S, Tripiciano A, Picconi O, Francavilla V, Longo O, Sgadari C, et al. The presence of anti-Tat antibodies in HIV-infected individuals is associated with containment of CD4+ T-cell decay and viral load, and with delay of disease progression: results of a 3-year cohort study. Retrovirology 2014; 11:49.
21. Zauli G, La Placa M, Vignoli M, Re MC, Gibellini D, Furlini G, et al. An autocrine loop of HIV type-1 Tat protein responsible for the improved survival/proliferation capacity of permanently Tat-transfected cells and required for optimal HIV-1 LTR transactivating activity. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 10:306–316.
22. Bosque A, Planelles V. Studies of HIV-1 latency in an ex vivo model that uses primary central memory T cells. Methods 2011; 53:54–61.
23. Ott M, Emiliani S, Van Lint C, Herbein G, Lovett J, Chirmule N, et al. Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway. Science 1997; 275:1481–1485.
24. Ott M, Lovett JL, Mueller L, Verdin E. Superinduction of IL-8 in T cells by HIV-1 Tat protein is mediated through NF-kappaB factors. J Immunol 1998; 160:2872–2880.
25. Stienne C, Michieletto MF, Benamar M, Carrie N, Bernard I, Nguyen XH, et al. Foxo3 transcription factor drives pathogenic T helper 1 differentiation by inducing the expression of eomes. Immunity 2016; 45:774–787.
26. Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 2002; 295:338–342.
27. Hazenberg MD, Hamann D, Schuitemaker H, Miedema F. T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nat Immunol 2000; 1:285–289.
28. Sicurella M, Nicoli F, Gallerani E, Volpi I, Berto E, Finessi V, et al. An attenuated Herpes Simplex Virus type 1 (HSV1) encoding the HIV-1 Tat protein protects mice from a deadly mucosal HSV1 challenge. PLoS One 2014; 9:e100844.
29. Robbins GK, Spritzler JG, Chan ES, Asmuth DM, Gandhi RT, Rodriguez BA, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384. Clin Infect Dis 2009; 48:350–361.
30. d’Ettorre G, Paiardini M, Ceccarelli G, Silvestri G, Vullo V. HIV-associated immune activation: from bench to bedside. AIDS Res Hum Retroviruses 2011; 27:355–364.
31. Kamata M, Nagaoka Y, Chen IS. Reassessing the role of APOBEC3G in human immunodeficiency virus type 1 infection of quiescent CD4+ T-cells. PLoS Pathog 2009; 5:e1000342.
32. Zack JA, Kim SG, Vatakis DN. HIV restriction in quiescent CD4(+) T cells. Retrovirology 2013; 10:37.
33. Alanio C, Nicoli F, Sultanik P, Flecken T, Perot B, Duffy D, et al. Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients. Elife 2015; 4:
34. Li CJ, Ueda Y, Shi B, Borodyansky L, Huang L, Li YZ, Pardee AB. Tat protein induces self-perpetuating permissivity for productive HIV-1 infection. Proc Natl Acad Sci U S A 1997; 94:8116–8120.
35. Secchiero P, Zella D, Capitani S, Gallo RC, Zauli G. Extracellular HIV-1 tat protein up-regulates the expression of surface CXC-chemokine receptor 4 in resting CD4+ T cells. J Immunol 1999; 162:2427–2431.
36. Johnson TP, Patel K, Johnson KR, Maric D, Calabresi PA, Hasbun R, Nath A. Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. Proc Natl Acad Sci U S A 2013; 110:13588–13593.
37. Schacker TW, Bosch RJ, Bennett K, Pollard R, Robbins GK, Collier AC, et al. Measurement of naive CD4 cells reliably predicts potential for immune reconstitution in HIV. J Acquir Immune Defic Syndr 2010; 54:59–62.
38. Gibellini D, Caputo A, Celeghini C, Bassini A, La Placa M, Capitani S, Zauli G. Tat-expressing Jurkat cells show an increased resistance to different apoptotic stimuli, including acute human immunodeficiency virus-type 1 (HIV-1) infection. Br J Haematol 1995; 89:24–33.
39. Chen D, Wang M, Zhou S, Zhou Q. HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. EMBO J 2002; 21:6801–6810.
40. Gibellini D, Bassini A, Pierpaoli S, Bertolaso L, Milani D, Capitani S, et al. Extracellular HIV-1 Tat protein induces the rapid Ser133 phosphorylation and activation of CREB transcription factor in both Jurkat lymphoblastoid T cells and primary peripheral blood mononuclear cells. J Immunol 1998; 160:3891–3898.
41. Secchiero P, Zella D, Curreli S, Mirandola P, Capitani S, Gallo RC, Zauli G. Pivotal role of cyclic nucleoside phosphodiesterase 4 in Tat-mediated CD4+ T cell hyperactivation and HIV type 1 replication. Proc Natl Acad Sci U S A 2000; 97:14620–14625.
42. Zauli G, Gibellini D, Celeghini C, Mischiati C, Bassini A, La Placa M, Capitani S. Pleiotropic effects of immobilized versus soluble recombinant HIV-1 Tat protein on CD3-mediated activation, induction of apoptosis, and HIV-1 long terminal repeat transactivation in purified CD4+ T lymphocytes. J Immunol 1996; 157:2216–2224.
43. Xiao H, Neuveut C, Tiffany HL, Benkirane M, Rich EA, Murphy PM, Jeang KT. Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc Natl Acad Sci U S A 2000; 97:11466–11471.
44. Nicoli F, Sforza F, Gavioli R. Different expression of Blimp-1 in HIV infection may be used to monitor disease progression and provide a clue to reduce immune activation and viral reservoirs. AIDS 2015; 29:133–134.
45. Haissman JM, Vestergaard LS, Sembuche S, Erikstrup C, Mmbando B, Mtullu S, et al. Plasma cytokine levels in Tanzanian HIV-1-infected adults and the effect of antiretroviral treatment. J Acquir Immune Defic Syndr 2009; 52:493–497.
46. Cervia JS, Chantry CJ, Hughes MD, Alvero C, Meyer WA 3rd, Hodge J, et al. Associations of proinflammatory cytokine levels with lipid profiles, growth, and body composition in HIV-infected children initiating or changing antiretroviral therapy. Pediatr Infect Dis J 2010; 29:1118–1122.
47. Appay V, Fastenackels S, Katlama C, Ait-Mohand H, Schneider L, Guihot A, et al. Old age and anticytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS 2011; 25:1813–1822.
48. Appay V, Almeida JR, Sauce D, Autran B, Papagno L. Accelerated immune senescence and HIV-1 infection. Exp Gerontol 2007; 42:432–437.
49. Appay V, Kelleher AD. Immune activation and immune aging in HIV infection. Curr Opin HIV AIDS 2016; 11:242–249.
50. Zauli G, Furlini G, Re MC, Milani D, Capitani S, La Placa M. Human immunodeficiency virus type 1 (HIV-1) tat-protein stimulates the production of interleukin-6 (IL-6) by peripheral blood monocytes. New Microbiol 1993; 16:115–120.
51. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000; 908:244–254.
52. Comandini A, Naro C, Adamo R, Akbar AN, Lanna A, Bonmassar E, Franzese O. Molecular mechanisms involved in HIV-1-Tat mediated inhibition of telomerase activity in human CD4(+) T lymphocytes. Mol Immunol 2013; 54:181–192.
53. Beaupere C, Garcia M, Larghero J, Feve B, Capeau J, Lagathu C. The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation. Aging Cell 2015; 14:534–546.
Keywords:

CD4+; HIV; immune activation; Tat; T-cell programing

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2018 Wolters Kluwer Health, Inc.