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Is weak CD4+ gain in the course of suppressive combination antiretroviral therapy for HIV infection a current clinical challenge? A case report and brief review of the literature

BMC Infectious Diseases volume 18, Article number: 8 (2018) Cite this article

Abstract

Background

Individuals lacking immune recovery during suppressive cART will still represent a clinical issue in the years to come, given the high proportion of HIV-infected subjects introducing therapy late in the course of disease. Understanding the mechanisms underlying poor CD4+ T-cell gain is crucial for the correct clinical management of individuals in this context.

Case presentation

An HIV-infected subject with poor CD4+ T-cell gain in the course of suppressive antiretroviral therapy was extensively investigated to identify the mechanisms behind inadequate CD4+ reconstitution. In particular, we studied the phenotype of circulating T-cells, interleukin-7 signaling in peripheral blood and bone marrow, gut function and microbial translocation markers as well as the composition of the faecal microbiota. Numerous therapeutic interventions ranging from antiretroviral therapy intensification to immunotherapy and anti-hepatitis C virus treatment were also employed in order to target the possible causes of poor immune-recovery.

Conclusions

Poor CD4+ T-cell gain on suppressive antiretroviral therapy is multifactorial and thus represents a clinical challenge. Clinicians should investigate subjects’ immune profile as well as possible causes of chronic antigenic stimulation for the administration of the most appropriate therapeutic strategies in this setting.

Peer Review reports

Background

A low CD4+ T-cell nadir upon combination Antiretroviral Therapy (cART) introduction in Human Immunedeficiency Virus (HIV) infection is linked to weak CD4+ T-cell gain [1], exposing subjects to the increased risk of clinical events [2]. Current guidelines recommend initiation of treatment early in the course of disease [3, 4], yet data from numerous study cohorts point to the steadiness of late diagnosis of HIV and thus cART start in up to 50% of infected subjects [5]. In line with these observations, it is conceivable that individuals lacking immune recovery during suppressive cART will still represent a clinical issue in the years to come. The understanding of the mechanisms underlying poor CD4+ T-cell increases in thus mandatory for the correct management of patients in this setting.

We report the case of a male subject with persistent lack of CD4+ T-cell recovery despite long-term cART. The patient underwent a plethora of targeted therapeutic interventions following thorough investigation of the possible underlying causes of poor immune response.

Case presentation

The patient was diagnosed with HIV infection at the age of 31 in 1994. The main risk factor for HIV infection was previous intravenous drug use. Nadir CD4+ T-cell count was 26/μL. Hepatitis C Virus (HCV) co-infection was present (genotype 1a) and cytomegalovirus (CMV) serology was positive. No opportunistic infections were diagnosed at the time of HIV testing.

cART was initiated with zidovudine, lamivudine and indinavir/ritonavir which was changed to tenofovir, lamivudine and lopinavir/ritonavir in 2004. Despite rapid virological suppression, poor immune recovery was observed with CD4+ T-cell counts constantly below the 200/μL threshold (Fig. 1a) and impaired CD4+/CD8+ T-cell ratio (i.e. lower than 1 [6]; Fig. 1b).

Fig. 1
figure 1

CD4+ T-cell kinetics and study of the mechanisms underlying poor immune recovery on cART. Persistent low CD4+ T-cell counts (a) and CD4+/CD8+ T-cell ratio (b) were registered in the study subject despite the administration of different suppressive cART regimens and immuno-therapy. Compared to a historical cohort of uninfected controls, the patient also displayed lower peripheral blood IL-7 levels (c), decreased IL-7Rα (CD127) expression on CD4 + T-cells (d) and IL-7Rα production in Peripheral Blood Mononuclear Cells (PBMCs) (e). In the bone marrow, we observed elevated IL-7 levels (f), increased production of IL-7 (g) and IL-7Rα (h). Lower pSTAT5- (i) and Bcl-2-expressing CD4+ T-cells (j) upon IL-7 stimulation were detected in our subject. Stable CD8+ T-cell activation (k) and impairment of CD4+ T-cell maturation (l-o) were also observed. —— represents the kinetics of CD4+ T-cell counts; −---- represents the kinetics of HIV RNA load (limit of detection: 40 cp/mL). cART: combination antiretrovrial therapy; 3TC: lamivudine; AZT: zidovudine; IDV/r: indinavir/ritonavir; IL-2: interleukin-2; TDF: tenofovir; LPV/r: lopinavir/ritonavir; T-20: enfuvirtide; FTC: emtricitabine; MVC: maraviroc; EVG/cobi: elvitegravir/cobicistat; DVG: dolutegravir; DAAs: direct acting antiretrovirals. IL-7: interleukin-7; IL-7R α: IL-7 receptor α. BBMCs: Bone Marrow Mononuclear Cells. US, unstimulated

Full size image

A low CD4+ T-cell count at the start of cART has been associated with clinical progression [2, 7] and hampered immune-reconstitution (reviewed in [8]; [9, 10]); of note, a low CD4+ T-cell nadir has also been shown to mirror the complex alterations of peripheral T-cell homeostasis in HIV infection, ranging from the impairment of lymphocyte maturation and function to increases in T-cell activation, death and T-regulatory cell (Treg) activity, which may not be reverted by treatment [9,10,11,12,13,14,15,16,17,18,19,20]. In accordance with these findings also a low CD4/CD8 T-cell ratio has been associated with skewed immune functions [21, 22] and increased clinical risk [6].

In 2001 the patient agreed to undergo immune-adjuvant interleukin-2 (IL-2) therapy, which at the time was being explored as a possible alternative therapeutic strategy to cART alone, given its ability to induce CD4+ T-cell increases and restore CD4+ T-specific responses to both recall and HIV antigens [23]. Three cycles of IL-2 were administered subcutaneously (1 cycle: 3 × 106 IU qd, days 1–5 and 8–12) for an overall duration of 3 months. Immune-therapy accounted for transitory increases in CD4+ T-cell counts that were not, however, sustained after the interruption of IL-2 cycles (Fig. 1a, b). Furthermore, the subject was diagnosed with cutaneous VZV reactivation shortly after immune-therapy. In this respect, despite the undeniable immunological effects of adjuvant IL-2 in subjects with poor CD4+ recovery on cART [24], this strategy was abandoned for the treatment of HIV infection, given it failed to provide clinical benefit compared to antiretrovirals alone [25]. Rather, it accounted for a higher relative risk of progression to AIDS in subjects with greatest CD4+ expansion [25], finding that was linked to a sustained increase in Treg cells [26], pointing to a major pathogenic role of this subset in the clinical outcome of treated HIV disease.

Inefficient CD4+ T-cell gain during treatment has been linked to failure in de novo CD4+ T-cell production. In this respect, impaired thymic [27, 28] and bone marrow function [29,30,31] alongside fibrosis of secondary lymphoid organs [32, 33], may represent possible pathogenic mechanisms underlying poor CD4+ output. A bone marrow aspirate highlighting hypo-cellularity, matrix fibrosis as well as severe dysplasia of myeloid, erythroid and platelet precursors was performed in 2006, while inconclusive results were obtained from the study of thymic function through the measurement of T-Cell Receptor Excision Circles (TREC; not shown). Given the role played by IL-7 in thymopoiesis as well as in the proliferation and survival of peripheral cells through its interaction with the IL-7 Receptor (IL-7R) on thymocytes, T-cells and bone marrow macrophages [34], we decided to investigate the IL-7/IL-7R system in the study patient.

Compared to uninfected controls described elsewhere [30], the subject displayed lower IL-7 plasma levels (Fig. 1c), decreased circulating IL-7Rα (CD127)-expressing CD4+ (Fig. 1d) and IL-7Rα production in Peripheral Blood Mononuclear Cells (PBMCs) (Fig. 1e). In sharp contrast with what observed in the periphery, in the patient’s bone marrow we found increased levels and production of IL-7 (Fig. 1f, g) as well as heightened IL-7Rα expression in Bone Marrow Mononuclear Cells (Fig. 1h). Further, lower pSTAT5- (Fig. 1i) and Bcl-2-positive CD4+ T-cells (Fig. 1j) were detected following in vitro IL-7 stimulation of the patient’s PBMCs. While promising results have been produced following the use of adjuvant therapy with IL-7 in subjects with poor CD4+ T-cell recovery [35, 36], our findings warrant careful investigation of the possible reasons behind IL-7 administration failure in this setting [36], given that dysfunctional IL-7R signalling may feature discordant subjects [30, 37].

Excessive peripheral CD4+ T-cell destruction may represent another cause of hampered immune response on cART and may be due to several features strictly linked to each other: T-cell activation, ongoing viral replication/HIV persistence and chronic antigenic stimulation. In particular, aberrant T-cell activation leading to increased cell death has been constantly associated with discordant immune responses to therapy [16,17,18, 28, 38] and its multifactorial pathogenesis appears to be related to productive/latent HIV infection, the presence of co-pathogens (HCV, CMV) and microbial translocation.

Given that stable levels of CD8+ T-cell activation were observed over the years (Fig. 1k), in 2011 we decided to expand our knowledge on the subjects’ T-cell homeostasis by performing a thorough investigation of the CD4+ lymphocyte maturation phenotype. For this purpose, HIV-uninfected individuals were consecutively enrolled as a control group (n = 16; median age 31 years, IQR 28–35; female sex 69%; HCV co-infection 0%) for laboratory experiments. Our analysis revealed lower frequencies of naïve (Fig. 1l) and central memory cells (Fig. 1m) as well as higher CD4+ effector memory (Fig. 1n) and terminally differentiated lymphocytes (Fig. 1o) compared to controls, thus pointing to persistent skewing of T-cell homeostasis despite long-term virological suppression, immunotherapy and cART intensification (see below).

Data on the role of ongoing viral replication and increased reservoirs as a cause of immune activation and poor immune recovery in course of suppressive cART have been inconclusive, with proof of a relationship between such features in some studies [28, 39,40,41] and not in others [15, 39, 42,43,44]. Despite full virological suppression and no history of viral blips (Fig. 1a), in order to counteract the possible effects of persistent HIV replication below the limit of detection, in 2007 our patient underwent cART intensification with enfuvirtide in combination with additional 3 cycles of IL-2 adjuvant therapy, which did not lead to prolonged increases in CD4+ T-cell numbers (Fig. 1a). cART intensification was also carried out 4 years later with maraviroc which did not account for changes in CD4+ recovery (Fig. 1a, b), similarly to what observed in various studies evaluating the role of the CCR5-coreceptor inhibitor in subjects with discordant responses to cART [45,46,47,48], and may be due to the marginal impact of this molecule on T-cell activation in this setting [45,46,47,48]. Overall, intensification strategies with different classes of antiretrovirals have lead to modest T-cell gains [45,46,47,48,49,50,51,52] and produced controversial results regarding T-cell homeostasis [45, 46, 48, 50, 51, 53,54,55,56,57] and measures of HIV low level-replication/persistence [49, 51,52,53,54,55,56, 58,59,60,61]. Of note, in more recent years (2013-ongoing) no replication below the limit of detection (40 cp/mL) was measured in our subject, with the exception of two consecutive values, 11 cp/mL and 14 cp/mL, in 2016.

HIV/CMV co-infection has been described as an additional cause of discordant immune responses to cART [62], disturbing T-cell homeostasis [63, 64]. As mentioned above, the study subject displayed serologic positivity for previous CMV infection. Although the precise role of CMV reactivation in this setting is a matter of controversy [64, 65], valganciclovir administration was shown to suppress CMV DNA levels and lower T-cell activation levels [65]. Also HCV co-infection has been widely described as a factor contributing to impaired CD4+ T-cell recovery [66] and immune skewing in HIV disease [67, 68]. Paucity of data exists on the role of HCV clearance in influencing the course of CD4+ T-cell counts in subjects on long-term cART [69], however, treatment of HCV infection may have a beneficial effect on other determinants of discordant immune responses, i.e. T-cell activation [70] and liver fibrosis [69].

The patient showed mild progression in terms of HCV-related liver disease over the years and agreed to start anti-HCV therapy with dasabuvir, ombitasvir/paritaprevir/ritonavir and ribavirin at the end of 2016 (Fib-4: 1.62; liver stiffness measured by transient elastography: 7.1 kPa; fibrosis stage F2).). The subject displayed rapid HCV RNA abatement (from 22258cp/mL to undetectable levels at week 8) as well as a sustained virological response at week 24 (February 2017). CD4+ T-cell numbers showed a slight rise compared to previous years, yet the subject still displays persistent CD4 depletion (latest CD4 T-cell count and CD4/CD8, respectively, 135/μL and 0.17; Fig. 1a, b). Follow-up is currently ongoing and aside from information on the kinetics of CD4+ T-cell counts, it will be interesting to observe the long-term outcome of direct-acting antiviral agents (DAAs) on peripheral T-cell homeostasis and other markers of immune function in the absence of the modulatory effects of pegylated-interferon-α [71, 72].

Finally, microbial translocation has been extensively called upon as a cause for T-cell activation and inadequate CD4+ on cART [73,74,75], most likely linked to the enduring structural and anatomical defects of the gastrointestinal mucosa [76] as well as skewing of the gut microbiota, thus accounting for impaired local and systemic immunity [76] and hampered CD4+ reconstitution [77, 78]. Our subject displayed higher microbial translocation markers compared to HIV-uninfected controls (lipopolysaccharide: 459 pg/mL vs 75 pg/mL, IQR 75–79; soluble CD14: 2.2 μg/L vs 1.9 μg/L IQR 1.4–2.4), increased gut permeability parameters (lactulose/mannitole ratio: 0.03) and an outgrowth of faecal Bacteroides intestinalis/Bacteroides uniformis; further, exposure of the patient’s PBMCs to various Toll-Like Receptor bacterial agonists resulted in a down-regulation of HLA-DR/CD38 co-expression on CD8+ T-cells. These findings suggest T-cell hypo-responsiveness to subclinical endotoxemia in subjects with inadequate CD4+ recovery [73, 79] and may explain why treatment approaches targeting microbial translocation have failed to significantly reduce CD8+ T-cell activation in this setting [80].

Discussion and conclusions

The present case report highlights the multifactorial origin of poor CD4+ T-cell gain on suppressive antiretroviral therapy thus emphasizing the difficulties of its clinical management. Given that immune failure on effective treatment may still represent a common condition in the future given delayed cART introduction [5] despite current recommendations [3, 4], we call for further research on subjects’ immune profile [20] and possible causes of chronic antigenic stimulation for the administration of appropriate therapeutic strategies in this setting.

Abbreviations

cART:

Combination antiretroviral therapy

CMV:

Cytomegalovirus

DAAs:

Direct-acting antiviral agents

HCV:

Hepatitis C virus

HIV:

Human immunedeficiency virus

IL:

Interleukin

IL-7R:

IL-7 Receptor

PBMCs:

Peripheral blood mononuclear cells

TREC:

T-Cell receptor excision circles

Treg:

T-regulatory cell

VZV:

Varicella Zoster Virus

References

  1. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44(3):441–6.

    Article  PubMed  Google Scholar 

  2. Lapadula G, Cozzi-Lepri A, Marchetti G, Antinori A, Chiodera A, Nicastri E, Parruti G, Galli M, Gori A, Monforte A, et al. Risk of clinical progression among patients with immunological nonresponse despite virological suppression after combination antiretroviral treatment. AIDS. 2013;27(5):769–79.

    Article  CAS  PubMed  Google Scholar 

  3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2015.

  4. EACS guidelines v.8.0. 2015.

  5. Mocroft A, Lundgren J, Antinori A, Monforte A, Brännström J, Bonnet F, Brockmeyer N, Casabona J, Castagna A, Costagliola D, et al. Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013. Euro Surveill. 2015;20(47):30070.

    Article  Google Scholar 

  6. Mussini C, Lorenzini P, Cozzi-Lepri A, Lapadula G, Marchetti G, Nicastri E, Cingolani A, Lichtner M, Antinori A, Gori A, et al. CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study. Lancet HIV. 2015;2(3):e98–106.

    Article  PubMed  Google Scholar 

  7. May MT, Vehreschild JJ, Trickey A, Obel N, Reiss P, Bonnet F, Mary-Krause M, Samji H, Cavassini M, Gill MJ, et al. Mortality according to CD4 count at start of combination antiretroviral therapy among HIV-infected patients followed for up to 15 years after start of treatment: collaborative cohort study. Clin Infect Dis. 2016;62(12):1571–7.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gazzola L, Tincati C, Bellistrì GM, Monforte A, 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(3):328–37.

    Article  PubMed  Google Scholar 

  9. Negredo E, Massanella M, Puig J, Pérez-Alvarez N, Gallego-Escuredo JM, Villarroya J, Villarroya F, Moltó J, Santos JR, Clotet B, et al. Nadir CD4 T cell count as predictor and high CD4 T cell intrinsic apoptosis as final mechanism of poor CD4 T cell recovery in virologically suppressed HIV-infected patients: clinical implications. Clin Infect Dis. 2010;50(9):1300–8.

    Article  PubMed  Google Scholar 

  10. Massanella M, Gómez-Mora E, Carrillo J, Curriu M, Ouchi D, Puig J, Negredo E, Cabrera C, Clotet B, Blanco J. Increased ex vivo cell death of central memory CD4 T cells in treated HIV infected individuals with unsatisfactory immune recovery. J Transl Med. 2015;13:230.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bai F, Bellistrì GM, Tincati C, Savoldi A, Pandolfo A, Bini T, Carpani G, Sinigaglia E, Marchetti G, d'Arminio Monforte A. Reduced CD127 expression on peripheral CD4+ T cells impairs immunological recovery in course of suppressive highly active antiretroviral therapy. AIDS. 2010;24(16):2590–3.

    Article  CAS  PubMed  Google Scholar 

  12. Bai F, Tincati C, Merlini E, Pacioni C, Sinigaglia E, Carpani G, d'Arminio Monforte A, Marchetti G. Reduced central memory CD4+ T cells and increased T-cell activation characterise treatment-naive patients newly diagnosed at late stage of HIV infection. AIDS Res Treat. 2012;2012:314849.

    PubMed  Google Scholar 

  13. Horta A, Nobrega C, Amorim-Machado P, Coutinho-Teixeira V, Barreira-Silva P, Boavida S, Costa P, Sarmento-Castro R, Castro AG, Correia-Neves M. Poor immune reconstitution in HIV-infected patients associates with high percentage of regulatory CD4+ T cells. PLoS One. 2013;8(2):e57336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Saison J, Maucort Boulch D, Chidiac C, Demaret J, Malcus C, Cotte L, Poitevin-Later F, Miailhes P, Venet F, Trabaud MA, et al. Increased regulatory T-cell percentage contributes to poor CD4(+) lymphocytes recovery: a 2-year prospective study after introduction of antiretroviral therapy. Open Forum Infect Dis. 2015;2(2):ofv063.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Saison J, Ferry T, Demaret J, Maucort Boulch D, Venet F, Perpoint T, Ader F, Icard V, Chidiac C, Monneret G, et al. Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients. Clin Exp Immunol. 2014;176(3):401–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Piconi S, Trabattoni D, Gori A, Parisotto S, Magni C, Meraviglia P, Bandera A, Capetti A, Rizzardini G, Clerici M. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. AIDS. 2010;24(13):1991–2000.

    Article  CAS  PubMed  Google Scholar 

  17. Massanella M, Negredo E, Pérez-Alvarez N, Puig J, Ruiz-Hernández R, Bofill M, Clotet B, Blanco J. CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART. AIDS. 2010;24(7):959–68.

    Article  CAS  PubMed  Google Scholar 

  18. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, Gripshover B, Salata RA, Taege A, Lisgaris M, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011;204(8):1217–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Marchetti G, Gazzola L, Trabattoni D, Bai F, Ancona G, Ferraris L, Meroni L, Galli M, Clerici M, Gori A, et al. Skewed T-cell maturation and function in HIV-infected patients failing CD4+ recovery upon long-term virologically suppressive HAART. AIDS. 2010;24(10):1455–60.

    Article  PubMed  Google Scholar 

  20. Pérez-Santiago J, Ouchi D, Urrea V, Carrillo J, Cabrera C, Villà-Freixa J, Puig J, Paredes R, Negredo E, Clotet B, et al. ART-suppressed subjects with low CD4 T-cell counts segregate according to opposite immunological phenotypes. AIDS. 2016;30(15):2275–87.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sainz T, Serrano-Villar S, Díaz L, González Tomé MI, Gurbindo MD, de José MI, Mellado MJ, Ramos JT, Zamora J, Moreno S, et al. The CD4/CD8 ratio as a marker T-cell activation, senescence and activation/exhaustion in treated HIV-infected children and young adults. AIDS. 2013;27(9):1513–6.

    Article  CAS  PubMed  Google Scholar 

  22. Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, Ferre AL, Hayes TL, Somsouk M, Hsue PY, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog. 2014;10(5):e1004078.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Carcelain G, Autran B. Immune interventions in HIV infection. Immunol Rev. 2013;254(1):355–71.

    Article  PubMed  Google Scholar 

  24. Marchetti G, Franzetti F, Gori A. Partial immune reconstitution following highly active antiretroviral therapy: can adjuvant interleukin-2 fill the gap? J Antimicrob Chemother. 2005;55(4):401–9.

    Article  CAS  PubMed  Google Scholar 

  25. Abrams D, Lévy Y, Losso MH, Babiker A, Collins G, Cooper DA, Darbyshire J, Emery S, Fox L, Gordin F, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361(16):1548–59.

    Article  CAS  PubMed  Google Scholar 

  26. Weiss L, Letimier FA, Carriere M, Maiella S, Donkova-Petrini V, Targat B, Benecke A, Rogge L, Levy Y. In vivo expansion of naive and activated CD4+CD25+FOXP3+ regulatory T cell populations in interleukin-2-treated HIV patients. Proc Natl Acad Sci U S A. 2010;107(23):10632–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ventevogel MS, Sempowski GD. Thymic rejuvenation and aging. Curr Opin Immunol. 2013;25(4):516–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Marchetti G, Gori A, Casabianca A, Magnani M, Franzetti F, Clerici M, Perno CF, Monforte A, Galli M, Meroni L. Comparative analysis of T-cell turnover and homeostatic parameters in HIV-infected patients with discordant immune-virological responses to HAART. AIDS. 2006;20(13):1727–36.

    Article  PubMed  Google Scholar 

  29. Vishnu P, Aboulafia DM. Haematological manifestations of human immune deficiency virus infection. Br J Haematol. 2015;171(5):695–709.

    Article  PubMed  Google Scholar 

  30. Bellistrì GM, Casabianca A, Merlini E, Orlandi C, Ferrario G, Meroni L, Galli M, Magnani M, Monforte A, Marchetti G. Increased bone marrow interleukin-7 (IL-7)/IL-7R levels but reduced IL-7 responsiveness in HIV-positive patients lacking CD4+ gain on antiviral therapy. PLoS One. 2010;5(12):e15663.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Isgrò A, Leti W, De Santis W, Marziali M, Esposito A, Fimiani C, Luzi G, Pinti M, Cossarizza A, Aiuti F, et al. Altered clonogenic capability and stromal cell function characterize bone marrow of HIV-infected subjects with low CD4+ T cell counts despite viral suppression during HAART. Clin Infect Dis. 2008;46(12):1902–10.

    Article  PubMed  Google Scholar 

  32. Asmuth DM, Pinchuk IV, Wu J, Vargas G, Chen X, Mann S, Albanese A, Ma ZM, Saroufeem R, Melcher GP, et al. Role of intestinal myofibroblasts in HIV-associated intestinal collagen deposition and immune reconstitution following combination antiretroviral therapy. AIDS. 2015;29(8):877–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sanchez JL, Hunt PW, Reilly CS, Hatano H, Beilman GJ, Khoruts A, Jasurda JS, Somsouk M, Thorkelson A, Russ S, et al. Lymphoid fibrosis occurs in long-term nonprogressors and persists with antiretroviral therapy but may be reversible with curative interventions. J Infect Dis. 2015;211(7):1068–75.

    Article  PubMed  Google Scholar 

  34. Sieg SF. Interleukin-7 biology in HIV disease and the path to immune reconstitution. Curr HIV Res. 2012;10(4):341–7.

    Article  CAS  PubMed  Google Scholar 

  35. Lévy Y, Sereti I, Tambussi G, Routy JP, Lelièvre JD, Delfraissy JF, Molina JM, Fischl M, Goujard C, Rodriguez B, et al. Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis. 2012;55(2):291–300.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Thiébaut R, Jarne A, Routy JP, Sereti I, Fischl M, Ive P, Speck RF, D'Offizi G, Casari S, Commenges D, et al. Repeated cycles of recombinant human interleukin 7 in HIV-infected patients with low CD4 T-cell reconstitution on antiretroviral therapy: results of 2 phase II multicenter studies. Clin Infect Dis. 2016;62(9):1178–85.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Shive CL, Clagett B, McCausland MR, Mudd JC, Funderburg NT, Freeman ML, Younes SA, Ferrari BM, Rodriguez B, McComsey GA, et al. Inflammation perturbs the IL-7 Axis, promoting senescence and exhaustion that broadly characterize immune failure in treated HIV infection. J Acquir Immune Defic Syndr. 2016;71(5):483–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, Deeks SG. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003;187(10):1534–43.

    Article  CAS  PubMed  Google Scholar 

  39. Steel A, Cox AE, Shamji MH, John L, Nelson M, Henderson DC, Gotch FM, Gazzard BG, Kelleher P. HIV-1 viral replication below 50 copies/ml in patients on antiretroviral therapy is not associated with CD8+ T-cell activation. Antivir Ther. 2007;12(6):971–5.

    CAS  PubMed  Google Scholar 

  40. Mavigner M, Delobel P, Cazabat M, Dubois M, L'faqihi-Olive FE, Raymond S, Pasquier C, Marchou B, Massip P, Izopet J. HIV-1 residual viremia correlates with persistent T-cell activation in poor immunological responders to combination antiretroviral therapy. PLoS One. 2009;4(10):e7658.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tincati C, Merlini E, Braidotti P, Ancona G, Savi F, Tosi D, Borghi E, Callegari ML, Mangiavillano B, Barassi A, et al. Impaired gut junctional complexes feature late-treated individuals with suboptimal CD4+ T-cell recovery upon virologically suppressive combination antiretroviral therapy. AIDS. 2016;30(7):991–1003.

    Article  CAS  PubMed  Google Scholar 

  42. Taiwo B, Hunt PW, Gandhi RT, Ellingson A, McKenna M, Jacobson JM, Gripshover B, Bosch RJ. CD8+ T-cell activation in HIV-1-infected patients experiencing transient low-level viremia during antiretroviral therapy. J Acquir Immune Defic Syndr. 2013;63(1):101–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chun TW, Murray D, Justement JS, Hallahan CW, Moir S, Kovacs C, Fauci AS. Relationship between residual plasma viremia and the size of HIV proviral DNA reservoirs in infected individuals receiving effective antiretroviral therapy. J Infect Dis. 2011;204(1):135–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Poizot-Martin I, Faucher O, Obry-Roguet V, Nicolino-Brunet C, Ronot-Bregigeon S, Dignat-George F, Tamalet C. Lack of correlation between the size of HIV proviral DNA reservoir and the level of immune activation in HIV-infected patients with a sustained undetectable HIV viral load for 10 years. J Clin Virol. 2013;57(4):351–5.

    Article  CAS  PubMed  Google Scholar 

  45. Hunt PW, Shulman NS, Hayes TL, Dahl V, Somsouk M, Funderburg NT, McLaughlin B, Landay AL, Adeyemi O, Gilman LE, et al. The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial. Blood. 2013;121(23):4635–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rusconi S, Vitiello P, Adorni F, Colella E, Focà E, Capetti A, Meraviglia P, Abeli C, Bonora S, D'Annunzio M, et al. Maraviroc as intensification strategy in HIV-1 positive patients with deficient immunological response: an Italian randomized clinical trial. PLoS One. 2013;8(11):e80157.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wilkin TJ, Lalama CM, McKinnon J, Gandhi RT, Lin N, Landay A, Ribaudo H, Fox L, Currier JS, Mellors JW, et al. A pilot trial of adding maraviroc to suppressive antiretroviral therapy for suboptimal CD4+ T-cell recovery despite sustained virologic suppression: ACTG A5256. J Infect Dis. 2012;206(4):534–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. van Lelyveld SF, Drylewicz J, Krikke M, Veel EM, Otto SA, Richter C, Soetekouw R, Prins JM, Brinkman K, Mulder JW, et al. Maraviroc intensification of cART in patients with suboptimal immunological recovery: a 48-week, placebo-controlled randomized trial. PLoS One. 2015;10(7):e0132430.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Negredo E, Massanella M, Puertas MC, Buzón MJ, Puig J, Pérez-Alvárez N, Pérez-Santiago J, Bonjoch A, Moltó J, Jou A, et al. Early but limited effects of raltegravir intensification on CD4 T cell reconstitution in HIV-infected patients with an immunodiscordant response to antiretroviral therapy. J Antimicrob Chemother. 2013;68(10):2358–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Massanella M, Negredo E, Puig J, Puertas MC, Buzón MJ, Pérez-Álvarez N, Carrillo J, Clotet B, Martínez-Picado J, Blanco J. Raltegravir intensification shows differing effects on CD8 and CD4 T cells in HIV-infected HAART-suppressed individuals with poor CD4 T-cell recovery. AIDS. 2012;26(18):2285–93.

    Article  CAS  PubMed  Google Scholar 

  51. Llibre JM, Buzón MJ, Massanella M, Esteve A, Dahl V, Puertas MC, Domingo P, Gatell JM, Larrouse M, Gutierrez M, et al. Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: a randomized 48-week study. Antivir Ther. 2012;17(2):355–64.

    Article  CAS  PubMed  Google Scholar 

  52. Chege D, Kovacs C, la Porte C, Ostrowski M, Raboud J, Su D, Kandel G, Brunetta J, Kim CJ, Sheth PM, et al. Effect of raltegravir intensification on HIV proviral DNA in the blood and gut mucosa of men on long-term therapy: a randomized controlled trial. AIDS. 2012;26(2):167–74.

    Article  CAS  PubMed  Google Scholar 

  53. Cillo AR, Hilldorfer BB, Lalama CM, McKinnon JE, Coombs RW, Tenorio AR, Fox L, Gandhi RT, Ribaudo H, Currier JS, et al. Virologic and immunologic effects of adding maraviroc to suppressive antiretroviral therapy in individuals with suboptimal CD4+ T-cell recovery. AIDS. 2015;29(16):2121–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vallejo A, Gutierrez C, Hernandez-Novoa B, Diaz L, Madrid N, Abad-Fernandez M, Dronda F, Perez-Elias MJ, Zamora J, Muñoz E, et al. The effect of intensification with raltegravir on the HIV-1 reservoir of latently infected memory CD4 T cells in suppressed patients. AIDS. 2012;26(15):1885–94.

    Article  CAS  PubMed  Google Scholar 

  55. Hatano H, Hayes TL, Dahl V, Sinclair E, Lee TH, Hoh R, Lampiris H, Hunt PW, Palmer S, McCune JM, et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis. 2011;203(7):960–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yukl SA, Shergill AK, McQuaid K, Gianella S, Lampiris H, Hare CB, Pandori M, Sinclair E, Günthard HF, Fischer M et al: Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS 2010, 24(16):2451-2460.

  57. Buzón MJ, Massanella M, Llibre JM, Esteve A, Dahl V, Puertas MC, Gatell JM, Domingo P, Paredes R, Sharkey M, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010;16(4):460–5.

    Article  PubMed  Google Scholar 

  58. Hatano H, Strain MC, Scherzer R, Bacchetti P, Wentworth D, Hoh R, Martin JN, McCune JM, Neaton JD, Tracy RP, et al. Increase in 2-long terminal repeat circles and decrease in D-dimer after raltegravir intensification in patients with treated HIV infection: a randomized, placebo-controlled trial. J Infect Dis. 2013;208(9):1436–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gandhi RT, Coombs RW, Chan ES, Bosch RJ, Zheng L, Margolis DM, Read S, Kallungal B, Chang M, Goecker EA, et al. No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J Acquir Immune Defic Syndr. 2012;59(3):229–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, Kallungal B, Palmer S, Medvik K, Lederman MM, et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 2010;7(8).

  61. McMahon D, Jones J, Wiegand A, Gange SJ, Kearney M, Palmer S, McNulty S, Metcalf JA, Acosta E, Rehm C, et al. Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. Clin Infect Dis. 2010;50(6):912–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Appay V, Fastenackels S, Katlama C, Ait-Mohand H, Schneider L, Guihot A, Keller M, Grubeck-Loebenstein B, Simon A, Lambotte O, et al. Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS. 2011;25(15):1813–22.

    Article  CAS  PubMed  Google Scholar 

  63. Freeman ML, Mudd JC, Shive CL, Younes SA, Panigrahi S, Sieg SF, Lee SA, Hunt PW, Calabrese LH, Gianella S, et al. CD8 T-cell expansion and inflammation linked to CMV Coinfection in ART-treated HIV infection. Clin Infect Dis. 2016;62(3):392–6.

    Article  PubMed  Google Scholar 

  64. Jacobson MA, Ditmer DP, Sinclair E, Martin JN, Deeks SG, Hunt P, Mocarski ES, Shiboski C. Human herpesvirus replication and abnormal CD8+ T cell activation and low CD4+ T cell counts in antiretroviral-suppressed HIV-infected patients. PLoS One. 2009;4(4):e5277.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Hunt PW, Martin JN, Sinclair E, Epling L, Teague J, Jacobson MA, Tracy RP, Corey L, Deeks SG. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011;203(10):1474–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tsiara CG, Nikolopoulos GK, Dimou NL, Bagos PG, Saroglou G, Velonakis E, Hatzakis A. Effect of hepatitis C virus on immunological and virological responses in HIV-infected patients initiating highly active antiretroviral therapy: a meta-analysis. J Viral Hepat. 2013;20(10):715–24.

    Article  CAS  PubMed  Google Scholar 

  67. Sajadi MM, Pulijala R, Redfield RR, Talwani R. Chronic immune activation and decreased CD4 cell counts associated with hepatitis C infection in HIV-1 natural viral suppressors. AIDS. 2012;26(15):1879–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hodowanec AC, Brady KE, Gao W, Kincaid SL, Plants J, Bahk M, Landay AL, Huhn GD. Characterization of CD4+ T-cell immune activation and interleukin 10 levels among HIV, hepatitis C virus, and HIV/HCV-coinfected patients. J Acquir Immune Defic Syndr. 2013;64(3):232–40.

    Article  CAS  PubMed  Google Scholar 

  69. Milazzo L, Foschi A, Mazzali C, Viola A, Ridolfo A, Galli M, Antinori S. Short communication: impact of hepatitis C viral clearance on CD4+ T-lymphocyte course in HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin. AIDS Res Hum Retrovir. 2012;28(9):989–93.

    CAS  PubMed  Google Scholar 

  70. Gonzalez VD, Falconer K, Blom KG, Reichard O, Mørn B, Laursen AL, Weis N, Alaeus A, Sandberg JK. High levels of chronic immune activation in the T-cell compartments of patients coinfected with hepatitis C virus and human immunodeficiency virus type 1 and on highly active antiretroviral therapy are reverted by alpha interferon and ribavirin treatment. J Virol. 2009;83(21):11407–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Serti E, Chepa-Lotrea X, Kim YJ, Keane M, Fryzek N, Liang TJ, Ghany M, Rehermann B. Successful interferon-free therapy of chronic hepatitis C virus infection normalizes natural killer cell function. Gastroenterology. 2015;149(1):190–200.e192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mondelli MU. Direct-acting Antivirals cure innate immunity in chronic hepatitis C. Gastroenterology. 2015;149(1):25–8.

    Article  PubMed  Google Scholar 

  73. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365–71.

    Article  CAS  PubMed  Google Scholar 

  74. Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B, Landay A, Martin J, Sinclair E, Asher AI, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis. 2009;199(8):1177–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Marchetti G, Bellistrì GM, Borghi E, Tincati C, Ferramosca S, La Francesca M, Morace G, Gori A, Monforte AD. Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS. 2008;22(15):2035–8.

    Article  CAS  PubMed  Google Scholar 

  76. Tincati C, Douek DC, Marchetti G. Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection. AIDS Res Ther. 2016;13:19.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Merlini E, Bai F, Bellistrì GM, Tincati C, d'Arminio Monforte A, Marchetti G. Evidence for polymicrobic flora translocating in peripheral blood of HIV-infected patients with poor immune response to antiretroviral therapy. PLoS One. 2011;6(4):e18580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Serrano-Villar S, Rojo D, Martínez-Martínez M, Deusch S, Vázquez-Castellanos JF, Bargiela R, Sainz T, Vera M, Moreno S, Estrada V, et al. Gut bacteria metabolism impacts immune recovery in HIV-infected individuals. EBioMedicine. 2016;8:203–16.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Merlini E, Tincati C, Biasin M, Saulle I, Cazzaniga FA, d'Arminio Monforte A, Cappione AJ, Snyder-Cappione J, Clerici M, Marchetti GC. Stimulation of PBMC and Monocyte-derived macrophages via toll-like receptor activates innate immune pathways in HIV-infected patients on virally suppressive combination antiretroviral therapy. Front Immunol. 2016;7:614.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Tenorio AR, Chan ES, Bosch RJ, Macatangay BJ, Read SW, Yesmin S, Taiwo B, Margolis DM, Jacobson JM, Landay AL, et al. Rifaximin has a marginal impact on microbial translocation, T-cell activation and inflammation in HIV-positive immune non-responders to antiretroviral therapy - ACTG A5286. J Infect Dis. 2015;211(5):780–90.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank Giusi M. Bellistrì for conducting laboratory experiments, Andrea Gori for helpful advice, the staff and patients at the Clinic of Infectious Diseases, ASST Santi Paolo e Carlo and ASST Fatebenefratelli-Sacco, University of Milan, Italy. We are also grateful to the study patient for agreeing to undergo numerous treatments and procedures as well as believing in clinical research.

Funding

This work was supported by Gilead Fellowship Program 2012 [grant number F61bd8c044] and the Italian Ministry of Health, Regione Lombardia, grant “Giovani Ricercatori” [number GR-2009-1592029].

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Health Sciences, Clinic of Infectious Diseases and Tropical Medicine, ASST Santi Paolo e Carlo, University of Milan, San Paolo Hospital, Via di Rudinì 8, 20142, Milan, Italy

    Camilla Tincati, Esther Merlini, Antonella d’Arminio Monforte & Giulia Marchetti

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  1. Camilla Tincati
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  2. Esther Merlini
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  3. Antonella d’Arminio Monforte
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  4. Giulia Marchetti
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Contributions

CT analyzed the patient data and wrote the manuscript. EM performed the laboratory experiments. AdM supervised clinical management and manuscript preparation. GM designed the clinical studies in which the patient participated, managed the patient and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Camilla Tincati.

Ethics declarations

Ethics approval and consent to participate

The ethics committee of the “San Paolo” and “Luigi Sacco” Hospitals in Milan, Italy approved the studies in which the patient and uninfected controls participated. The study subject provided written informed consent to diagnostic procedures and experimental therapeutic interventions. Written informed consent was also obtained from uninfected controls for the study of the IL-7/IL-R system, T-cell homeostasis and microbial translocation.

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Written Consent for Publication was obtained from the patient.

Competing interests

The authors declare that they have no competing interests.

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Tincati, C., Merlini, E., d’Arminio Monforte, A. et al. Is weak CD4+ gain in the course of suppressive combination antiretroviral therapy for HIV infection a current clinical challenge? A case report and brief review of the literature. BMC Infect Dis 18, 8 (2018). https://doi.org/10.1186/s12879-017-2942-3

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Keywords

BMC Infectious Diseases

ISSN: 1471-2334

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