Cytomegalovirus Cell-Mediated Immunity: Ready for Routine Use?

Abstract

Utilizing assays that assess specific T-cell-mediated immunity against cytomegalovirus (CMV) holds the potential to enhance personalized strategies aimed at preventing and treating CMV in organ transplantation. This includes improved risk stratification during transplantation compared to relying solely on CMV serostatus, as well as determining the optimal duration of antiviral prophylaxis, deciding on antiviral therapy when asymptomatic replication occurs, and estimating the risk of recurrence. In this review, we initially provide an overlook of the current concepts into the immune control of CMV after transplantation. We then summarize the existent literature on the clinical experience of the use of immune monitoring in organ transplantation, with a particular interest on the outcomes of interventional trials. Current evidence indicates that cell-mediated immune assays are helpful in identifying patients at low risk for replication for whom preventive measures against CMV can be safely withheld. As more data accumulates from these and other clinical scenarios, it is foreseeable that these assays will likely become part of the routine clinical practice in organ transplantation.

Introduction

Despite the implementation of effective antiviral therapies and sensitive molecular diagnostic assays, cytomegalovirus (CMV) infection remains as a major complication after solid organ transplantation (SOT), threatening both graft function and survival [1].

While relevant advances have been made in the understanding of the immunobiology of CMV infection in the context of organ transplantation, little translation to clinical practice has been done so far. In this regard, the T-cell arm of adaptive immunity (hereafter cell-mediated immunity [CMI]), especially CMV-specific CD4⁺ and CD8⁺ T lymphocytes, has been well-recognized as a major immune mechanism driving antiviral control [2, 3]. Robust evidence has showed a close association between CMV-CMI and the risk of developing CMV infection in different transplant settings [4–6]. Yet, current immune-risk stratification of CMV infection relies on the serological mismatch between donors and recipients, based on the premise that seronegative recipients receiving a seropositive graft (D+/R−) are at the highest risk of developing primary CMV infection due to their naïve immune status, whereas seropositive patients (R+) receiving seropositive grafts are at an intermediate risk because of previous viral immunization which should provide sufficient protection against viral replication [7]. While such paradigm has helped to predict the advent of CMV infection, this approach encompasses important limitations as a proportion of R+ individuals may unpredictably develop CMV replication and also because of the widespread use of T-cell depleting therapies that convert previously immunized patients into naïve individuals against CMV [8]. To minimize the development of CMV infection, the use of universal antiviral prophylaxis or preemptive assessment of viral replication are the two main preventive strategies used [7]. However, either approach is far from being accurate as they do not personalize the type and duration of such preventive strategies, since the dynamic immune status specific to CMV is not being considered.

Recently, novel immune assays have been used in transplantation showing their capacity to accurately measure CMV-CMI [4, 7]. While interesting clinical associations have been reported between CMV-CMI and the risk of CMV infection after transplant, the different methodological nature of these assays -which provide diverse biological insight on functionality of immune responses-, the so far limited data coming from clinical trials, as well as the distinct clinical transplant settings evaluated, makes it difficult to establish robust conclusions on how to implement these new technologies into clinical practice with the aim of improving transplant outcomes.

In this review, we first summarize the main mechanisms involved in the immunobiology of CMV in transplantation, to then address the major advances made with the assessment of CMV-CMI using different immune-monitoring assays as well as the major drawbacks currently limiting the implementation of these assays.

Immunobiology of Cytomegalovirus Infection

CMV infection in SOT recipients results from primoinfection or reactivation. In these two situations, a complex multi layered cell response is required to inhibit CMV dissemination [9]. Five main cell types have been studied during CMV infection, three belonging to adaptive immunity (in particular CD8⁺ and CD4⁺ T cells, and to a lesser extent the B cells) (Figure 1). Importantly, some patients do not develop CMV disease despite the absence of any CMV-specific CD8⁺ and CD4⁺ T cells, suggesting that other actors belonging to innate immunity (such as NK and γδ cells) could also be necessary for CMV control.

FIGURE 1

NK Cells

The monitoring of NK cells can be easily performed by flow cytometry with the following fluorochrome-coupled specific antibodies: CD3, CD16, CD56, NKG2C, CD57. In human, NK cell deficiency is associated with severe herpes viral infections, such as CMV [10]. Healthy human individuals with a history of CMV infection have an expanded population of NK cells expressing the activating CD94/NKG2C receptor [11]. In kidney transplant recipients, the number of circulating NK cell is correlated with NK cell-mediated cytotoxicity during CMV infection [12]. CMV R+ patients had preexisting memory-like NK cells (NKG2C⁺CD57⁺FcεRIγ⁻) at baseline and a subset of pre-memory-like NK cells (NKG2C⁺CD57⁺FcεRIγ^low-dim) increases during CMV DNAemia. These cells expressed a higher cytotoxic profile than preexisting memory-like NK cells at the acute phase. At later phases of viremia, a subsequent accumulation of new memory-like NK cells has been reported [13]. NK cell clonal expansion is observed after CMV infection, leading to the development of immunological memory, two features belonging to an adaptive immune response. NK cell reactivity against CMV-infected cells results from a balance governed by the activation of receptors that sense alterations in the expression of ligands on the surface of CMV-infected cells. An increase in NK activating receptors could confer to the host a better protection against CMV infection.

γδ T Cells

Gamma-delta T cells can be easily monitored in clinical routine thanks to flow cytometry using a commercially available kit gathering fluorochrome coupled specific antibodies for CD45, CD3, Vδ2 and PAN-δ.

B Cells

While the advent of long-lasting humoral immunity toward a primary viral infection is universally accepted, the contribution of antibodies for protection against and control of CMV replication in transplant recipients is still a matter of debate. Data coming from experimental models suggest a key role of B cells through CMV-specific antibody release, particularly in restricting viral dissemination and in limiting disease severity [20, 21]. CMV-specific neutralizing antibodies appear during the first 4 weeks after primary infection and are mainly directed against CMV glycoprotein B, but also H, L, and pUL128-131, all of them involved in cell attachment, penetration, and fusion of the viral envelope to the cell membrane of the host [22]. The association shown between the former use of CMV-specific immunoglobulins as prophylaxis and better outcomes among liver transplant recipients also suggests to some extend a protective role of humoral immunity against viral replication [23].

Notably, in clinical transplantation, some R+ transplant individuals remain at high risk of CMV infection despite detectable humoral immunity, suggesting either a low avidity or poor neutralizing activity of the antibody response. Post-transplant IgM and IgG antibody seroconversion has been shown not to be a reliable predictor of CMV disease [24]. Furthermore, some of D+/R− patients (20%–30%) do not develop CMV infection after transplantation, suggesting either an optimal antibody seroconversion early after transplantation or the presence of preformed CMV-specific memory B cells prior to transplantation even though undetectable circulating CMV-specific IgG antibodies [25].

CMV-Specific CD8⁺ T Cells

During primary infection, CMV-specific CD8⁺ T cells exhibit an antigen-driven early-differentiating phenotype (CD27⁺CD28⁺ CD45RO⁺CD45RA⁻) armed for cytotoxicity [26, 27]. After viral clearance in healthy CMV R+ individuals, CMV-specific CD8⁺ T cells can represent up to 10% of the memory CD8⁺ lymphocyte pool, a process described as memory inflation [28]. There are two main subsets of CMV-specific CD8⁺ T cells: a) a central memory cell population (CD27⁺ CD28⁻ CD45RO⁺) with low cytotoxic potential but high proliferation ability, and b) a TEMRA cell population, representing up to 75% of CMV-specific CD8⁺ T cells (CD27⁻ CD28⁻ CD45RA⁺), with a low proliferation ability but a major cytotoxic potential. TEMRA cells are resupplied from central memory cells and naive precursors.

During primary infection, the CMV-specific CD8⁺ T cell population is polyclonal. On the opposite, few epitope‐specific clones are predominant at the chronic phase. More than half of individuals have CD8⁺ T cell recognizing CMV peptides from the three following open reading frames (UL48, UL83, UL123). UL123 (immediate-early [IE]-1)-specific CD8⁺ T cells are associated with less CMV reactivation in SOT recipients, likely because UL123 is the first CMV protein to be expressed in infected cells. In vitro, CMV-specific CD8⁺ T cells can kill autologous CMV-infected cells and inhibit CMV dissemination. In mouse models, late effector CD8⁺ T cells maintain long-term control of viral replication [29].

CMV-Specific CD4⁺ T Cells

After a primary infection in SOT recipients, CMV-specific CD4⁺ T cells can be detected 1 week after the occurrence of CMV DNAemia [30], more specifically those CD4⁺ CD28-granzyme B+ cells [30, 31]. At the chronic phase of infection after viral clearance, CMV-specific CD4⁺ T cells represent up to 9% of the memory T lymphocyte pool. They exhibit an effector memory phenotype (CD27⁻ CD28⁻ CD45RA⁻). More than half of individuals have CD4⁺ T cells recognizing CMV peptides transcribed from the five following open reading frames (UL55, UL83, UL86, UL99, UL122). CD4⁺ T cells play a central role in anti-CMV immunity by clearing cells loaded with CMV peptides, helping B cells to mount a specific humoral response against viral antigens and CD8⁺ T cells to perform their effector functions [32].

Immunosuppressive Therapy and CMV Immune Response

CMV-CMI is abrogated for one to 3 months after anti thymocyte globulin induction [8] and reduced in patients having received high-dose steroids [33]. Rejection is usually treated by these two drugs and is therefore a risk factor for CMV disease [34, 35]. In vitro, tacrolimus is a potent inhibitor of CMV-specific cytokines release [36], and completely inhibits activation and proliferation of CMV-specific T cells [37]. On the opposite, belatacept demonstrated minimal inhibitory effects on CMV-specific T cells likely because of an absence of effect on cells lacking CD28 [36, 37]. While the antiviral immune response against CMV measured in vitro appears preserved under belatacept [38], high‐risk belatacept‐treated recipients show defects in sustaining CMV control [39], and exhibit high incidence of atypical life-threatening CMV diseases [40]. Further research is needed to elucidate this gap. Finally, a dysfunctional T-cell profile (with high PD1, low CD85j expression) has been observed in CMV-infected patients receiving mycophenolic acid. On the contrary, everolimus can improve T-cell fitness and transform dysfunctional into functional cells, along with better control of CMV [41]. In summary, the analysis of these five cells types could be useful for transplant physicians to understand the impact of the immunosuppressive regimen on CMV-specific T response.

Observational Data on the Clinical Application of CMV Immune-Monitoring

A growing number of observational studies have assessed in recent years the clinical usefulness of CMV-CMI monitoring to guide patient management in different SOT populations [42]. This research mainly includes single-center studies—with some multicenter experiences [8, 33, 43–47]— and has been performed in a wide range of clinical risk scenarios (Table 1). The most common methodologies used for the measurement of CMV-CMI is the reference technique of intracellular cytokine staining (ICS) by flow cytometry [42, 44, 45, 59, 61, 62, 67–71] and the different platforms for interferon (IFN)-γ release assay (IGRA) [4, 43, 46–56, 60, 63, 65, 66, 72–75]. Out of these immune assays, only three are currently commercially available: the quantiFERON®-CMV (QTF-CMV) (Qiagen, Hilden; Germany), the T-SPOT^®.CMV (Oxford Immunotec, Abingdon, United Kingdom) and the T-Track®CMV (Mikrogen, Neuried, Germany). Available experience with the major histocompatibility complex (MHC)-tetramer staining method is more limited [64], whereas a few studies have compared the diagnostic accuracy of different approaches [54, 57, 76]. In most cases the primary study outcome is any CMV viremia, regardless of the presence or absence of symptoms or the level of DNAemia, or less often clinically significant viremia requiring antiviral therapy [46]. Since R+ patients typically have a low incidence of CMV disease [77, 78], the few studies that have primarily investigated the role of CMV-CMI monitoring to predict the occurrence of symptomatic infection (viral syndrome or end-organ disease) are focused on the high-risk group D+/R− patients [43, 48, 58]. Notably each platform has different readouts that are directly related to the nature of each immune assay. In general, all assays measure T-cell mediated effector immune responses of IFN-Ɣ production in response to two main immunogenic CMV antigens, phosphoprotein 65 (pp65) and IE-1 [79]. Importantly, while ELISA-based assays do not provide the individual response to each CMV antigen, flow-cytometry and ELISpot-based assays do deliver such the specific immunes, thus better illustrating the global burden of immune responses against CMV.

As shown in Table 1, the available literature is not equally distributed across the different clinical scenarios involved. One of the most immediate applications of CMV-CMI monitoring is the individualization of the length of prophylaxis. Rather than the fixed-duration regimen of 3–6 months of valganciclovir—up to 12 months for lung transplant recipients—recommended by the current guidelines for high-risk patients [7, 80], the knowledge of the CMV-CMI functionality would allow for prematurely discontinuing prophylaxis in patients that have mounted a protective response, or prolonging it beyond the standard schedule in the presence of a negative (non-reactive) assay result. Manuel et al. provided early data on the usefulness of the QTF-CMV assay in a multicenter cohort of 127 D+/R− patients. The presence of a positive (reactive) assay at the end of valganciclovir prophylaxis was associated with a lower 12 months incidence of CMV disease as compared to negative or indeterminate results (6.4% versus 22.2%, respectively; p-value < 0.001), yielding a positive predictive value (PPV) for immune protection of 90% (95% confidence interval [95% CI]: 74–98). Interestingly, those patients with an indeterminate QTF-CMV result—suggestive of a profoundly abrogated immunity or absence of CMV peptide recognition—had the highest incidence of late disease [43]. These findings have been subsequently confirmed in different SOT populations [53, 57, 75]. On the other hand, a recent study has suggested that the predictive accuracy in this clinical scenario of commercially available ELISpot assays is superior of that of the QTF-CMV assay [57]. A similar conclusion may be drawn from a meta-analysis in kidney transplant recipients [81]. The next natural step is to apply this evidence to the clinical decision-making process. In addition to the interventional studies reviewed in the next section, a retrospective study in lung transplant recipients reported a lower incidence of high-level CMV replication by using a QTF-CMV-guided strategy of extended valganciclovir prophylaxis (5–11 months) as compared to a fixed 5 months regimen (43.1% versus 60.3%, respectively; p-value < 0.001) [55]. These results were replicated using the T-SPOT^®.CMV in a distinct cohort of R+ lung transplant recipients [82].

Although the ability of the QTF-CMV assay to stratify the risk of late CMV disease following the discontinuation of prophylaxis has been demonstrated for the D+/R− constellation, some studies restricted to R+ kidney transplant recipients receiving T-cell-depleting induction therapy (ATG) [54] or R+ lung transplant recipients [56] failed to find significant differences in the occurrence of viral reactivation between patients with reactive or non-reactive results. It has been proposed that the diagnostic accuracy of the QTF-CMV assay to predict protection from low-level infection among R+ patients might be improved by increasing the threshold for IFN-γ production used to define a positive result [54]. In addition, more sensitive techniques not restricted to CD8⁺ T-cell responses, such as ICS by flow cytometry and ELISpot-based assays, would perform better in this scenario, at the expense of being more time-consuming and costly [83].

The predominant population of R+ seropositive SOT recipients without ATG has been traditionally considered as an intermediate risk for CMV events, and either preemptive therapy or antiviral prophylaxis are recommended as prevention methods [7, 80]. A major contribution of the strategies for measuring the CMV-CMI has been the identification of a subgroup of R+ patients that lacks or displays very weak effective T-cell-mediated responses against CMV at the pre-transplant evaluation (non-reactive recipients [R_NR]) despite their positive anti-CMV IgG serological status. The proportion of R+ patients with no detectable baseline CMV-CMI has been estimated at about 20%–30% [44, 59, 60, 84, 85]. From a functional perspective, these patients should be considered closer to the seronegative recipients (R−) than to the so-called intermediate-risk (R+) group, which would result in a higher susceptibility to post-transplant infection if they receive an organ from a seropositive donor [25]. In a study in kidney and lung transplant recipients, Cantisán et al. found that D+/R_NR patients faced a markedly increased risk of CMV replication as compared to R+ patients with a positive (reactive) pre-transplant QTF-CMV assay (adjusted odds ratio [OR]: 10.49; 95% CI: 1.88–58.46) [60]. Comparable results have been obtained with the ICS technique [44, 59] or an ELISpot assay [51, 85]. An early assessment at post-transplant day 15 provides a predictive capacity significantly higher than at the pre-transplant evaluation since some transplant recipients with robust preformed CMV-CMI may significantly decrease their functional CMV-CMI after induction immunosuppression therapy, even in absence of ATG [44]. In this regard and unlike the QTF-CMV assay, the knowledge of the specific CMV-CMI against each individual CMV antigen that is provided by ELISpot-based assays, may further help to better stratify patients according to three distinct immunological risks, this is, at low, high, and at intermediate risk if one response against one of the two antigen is absent or very low [33]. Some factors have been reported to be associated with the absence of QTF-CMV reactivity among R+ SOT candidates such as profound lymphopenia, younger age, the type of organ to be transplanted, presence of certain recipient HLA genotypes and of non-HLA-A1/non-HLA-A2 alleles [84]. The latter finding is not unexpected as the presentation to the CD8⁺ T-cells of the viral epitopes contained in the “antigen tube” of the assay is restricted through some HLA class I alleles [86, 87].

Finally, some studies have been conducted to investigate the usefulness of post-transplant CMV-CMI monitoring among intermediate-risk recipients preemptively managed to predict protection against the development of CMV infection or, once established, the capacity of spontaneous clearance of viremia [42, 44, 49, 51, 52, 61–66]. These results pointed to the predominance of CD8⁺ T-cells in the early response to primary infection—or re-infection in the D+/R+ constellation—and CD4⁺ T-cells in the long-term control of latent infection [42, 44, 61]. The assessment of CMV-CMI at the onset of asymptomatic CMV viremia may be also useful to discern the patients that will spontaneously clear the infection from those who would eventually benefit from preemptive therapy. By applying the cut-off value for QTF-CMV positivity of ≥0.2 IU/mL of IFN-γ, Lisboa et al. reported a sensitivity and specificity in this clinical scenario of 82.8% and 75.0%, respectively, yielding a negative predictive value to predict virologic and/or clinical progression of asymptomatic viremia of 54.5% and a PPV of 90.9% to predict spontaneous clearance [65].

Few observational studies have also explored the role innate cells (NK and Non-Vγ9Vδ2 γδT cells) in different scenarios. For instance, pretransplant peripheral blood NKG2C+ NKG2A- NK cells could protect from CMV infection in kidney transplant recipients independently of the presence of CMV-specific T cells [88]. The NKG2C+ NK cell proportion in the bronchoalveolar lavage could also be a relevant biomarker for assessing risk of subsequent CMV viremia in lung transplant recipients [89]. During acute CMV infection, the NKG2C+ NK cells proliferate, become NKG2C(hi), and finally acquire CD57, a marker of “memory” NK cells that have been expanded in response to infection [90]. During CMV disease, non-Vγ9Vδ2 γδT cells expansion was correlated to the resolution of CMV infection and the emergence of CMV resistance in kidney transplant recipients, but more importantly was able to predict the absence of recurrence [15, 91]. A prospective clinical trial is ongoing to confirm this last finding (SPARCKLING study: NCT03339661).

Finally, as a complement to the assessment of the functionality of the CMV-specific T-cell response, other immunological biomarkers have been proposed to improve the process of risk stratification in the SOT population. This includes the assessment of antibodies targeting the pentameric complex (gH/gL/pUL128/pUL130/pUL131A), post-transplant hypogammaglobulinemia, absolute counts of total lymphocytes or peripheral blood subpopulations, as well as genetic markers. A detailed account of the advantage and limitations of these assays is summarized in Table 2.

Interventional Studies Evaluating CMV Immune Monitoring Strategies

The evidence generated by clinical trials on the use of CMV-CMI in transplant recipients is more limited. Most randomized controlled trials have focused on using the CMV-CMI assays for determining the duration of antiviral prophylaxis in intermediate or high-risk patients, particularly in kidney transplant recipients. In these studies, analysis of CMV-CMI has been performed using either the QTF-CMV or an ELISpot-CMV assay (Table 3).

In the study by [106] 118 lung transplant recipients were randomized to receive a fixed duration of antiviral prophylaxis (5 months), or a duration based on the results of the QTF-CMV assay, performed at 5, 8 and 11 months after transplantation. Antiviral prophylaxis was continued in case of a negative result of the assay in the intervention group. CMV replication measured by PCR in the bronchoalveolar lavage was observed in 58% in the control group as compared to 37% in the intervention group (p = 0.03), and this effect was probably due to the longer duration of prophylaxis in patients in the intervention group. A significant number of patients (39%), mostly D+/R−, remained with undetectable CMV-CMI at the end of prophylaxis period.

In the TIMOVAL trial [107], R+ kidney transplant recipients receiving induction therapy with ATG were randomized to receive a fixed duration of 3 months of prophylaxis (control group) or a duration based of immune-monitoring every 2–4 weeks using the QTF-CMV assay. Despite receiving ATG, up to 45% of patients had a QTF-CMV result as soon as 30 days after transplantation. Incidence of CMV infection (17% immune-monitoring vs. 13% control) was similar between groups while duration of antiviral prophylaxis was shorter in the intervention group. Incidence of neutropenia was lower in the immune-monitoring arm.

In the CMV-CMI study from Switzerland [108] 185 kidney or liver transplant R+ recipients receiving ATG or D+/R− were randomized to receive 3 or 6 months of prophylaxis (depending on the risk group) or immune monitoring once monthly with the T-Track-CMV^®. Overall, the incidence of clinically significant CMV infections was similar between groups (30.9% immune-monitoring vs. 31.1% group) although non-inferiority was not proven (p = 0.06). The duration of antiviral prophylaxis was significantly shorter in the intervention group (−26 days, p < 0.001). The impact of the intervention was more pronounced in R+ patients.

Kumar et al. [109] performed a single-arm interventional study using a QTF-CMV assay at the end of antiviral therapy for clinically significant CMV infection (both CMV disease and asymptomatic replication). Patients with a positive QTF-CMV result did not receive additional antiviral therapy while patients with a negative result received valganciclovir for 8 additional weeks. Of the 27 SOT recipients included, 14 patients had detectable IFN-γ levels and 13 had undetectable levels. Only 1/14 (7%) patient with a positive assay result had a relapse of CMV replication in contrast with 9/13 (69%) in the group with a negative assay result.

Finally, in the RESPECT trial [26], Jarque et al. used the T-SPOT. CMV at the time of transplant to stratify patients as being low-risk (positive assay) or at high-risk (negative assay) based on IE-1 CMV-CMI for predicting post transplant CMV replication. Patients were then randomized to receive antiviral prophylaxis or a preemptive approach. Patients with a positive CMV-CMI test had significantly lower rates of CMV replication/disease irrespective of the preventive strategy used. However, the best performance of the assay was when performed at 15 days post transplant (81% of CMV infection if test negative vs. 9% if test positive).

FIGURE 2

Conclusion

In this review we show the advances made in the field of CMV immune-risk stratification with the development of new sensitive assays measuring CMV-CMI. While most of the studies strongly suggest an added value of measuring CMV-CMI to better stratify the risk of CMV, in particular among R+ SOT recipients, yet some concerns arise when translating these immune tools into clinical practice; the precise predictive values illustrating the risk at the patient-individual level should be noted with caution to ultimately establish safe, guided preventive strategies. Specific cut-offs, the biological insight provided by each type of assay, and the precise clinical settings where to be implemented need to be further investigated through the implementation of clinical trials.

With the implementation of artificial intelligence, including highly powerful machine-learning algorithms, the combination of distinct clinical as well as immunological variables at distinct biological level could further refine the individual risk of transplant patients to develop CMV infection. Notably, this is the ultimate goal of the large multicenter European project (HORUS¹) by developing a dynamic multidimensional biomarker algorithm to robustly assess the risk of developing CMV infection.

Therefore, an effort should be made among the transplant community to confirm the added value of cell-mediated immune assays over current clinical management, as though if confirmed, they could revolutionize the management of CMV infection by personalizing the type and duration of preventive therapy against CMV infection after SOT.

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