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Review

The Role of IL28B Polymorphism in Regulating Innate and Adaptive Immunity Against Viral Infection Among Allogenic Stem Cells Transplant Recipients

by
Mohamed A. Eltokhy
1,*,
Bhaumik Patel
1,
Marina Curcic
1,
Faizah Alabi
1,
Shadan Modaresahmadi
1,
Omar Eltoukhy
2,
Esraa G. Abdelmageed
3 and
Sahar Radwan
3
1
Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Science Center (TTUHSC), Abilene, TX 79601, USA
2
Department of Clinical Pharmacy, Misr International University, Cairo 11566, Egypt
3
Department of Microbiology & Immunology, Faculty of Pharmacy, Cairo 11562, Egypt
*
Author to whom correspondence should be addressed.
Immuno 2025, 5(3), 38; https://doi.org/10.3390/immuno5030038
Submission received: 1 August 2025 / Revised: 29 August 2025 / Accepted: 2 September 2025 / Published: 3 September 2025
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Abstract

Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant is often delayed or functionally impaired. Emerging evidence suggests genetic variation, particularly polymorphisms in the IL28B gene (encoding IFN-λ3), as a critical factor influencing the quality and timing of immune responses during the early post-transplant period. This review explores the role of IL28B polymorphisms in shaping antiviral immunity, in general, as well as after Allo-HSCT. IL28B variants have been implicated in modulating interferon-stimulated gene (ISG) expression, natural killer (NK) cell activity, and type I/III interferon signaling, all central components of innate immune defense against viral infections. Furthermore, IL28B polymorphisms, particularly rs12979860, have been shown in both general populations and limited HSCT cohorts to alter T cell response and interferon production, affecting reactivation and clearance of multiple viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) as well as Graft vs. Host disease, thereby affecting adaptive immune reconstitution and long-term viral control. Understanding how IL28B genotype alters immune dynamics in transplant recipients could enhance risk stratification for CMV and other diseases and inform personalized prophylactic or therapeutic strategies. Therefore, this review highlights IL28B as a promising biomarker and potential immunoregulatory target in the management of viral infection post-Allo-HSCT.

1. Introduction

Hematopoietic stem cell transplantation (HSCT), or, in layman’s terms, bone marrow transplantation, is a curative therapy for various hematologic malignancies and bone marrow failures. Despite advances in transplant techniques and supportive care, post-transplant complications remain a major challenge [1]. Among these, infections, especially viral infections, are a leading cause of morbidity and mortality in transplant recipients. This vulnerability arises from profound immunosuppression and delayed immune reconstitution, which leave patients highly susceptible to opportunistic infections, especially viral reactivation [2,3].
Among the most reactivation of viruses, the herpesvirus family viruses, such as [4], cytomegalovirus (CMV), Epstein–Barr virus (EBV), and Human herpesvirus 6 (HHV-6) [5,6] are commonly observed following HSCT. Other common viruses observed to be reactivated after HSCT include hepatitis B (HBV) [7], hepatitis C (HCV) [8], adeno virus (ADV), JC virus (JCV), and polyomavirus (BKPyV) [9,10,11]. These viruses cause life-threatening complications and diseases such as pneumonitis, hepatitis, EBV-driven lymphoproliferative disorder, and BKPyV hemorrhagic cystitis. Some of these diseases manifest in recipients due to T cell-depleted grafts or intensive immunosuppression, which can be life-threatening.
Given these challenges, it is crucial to pinpoint factors that may affect infection risks to recipient. One such factor is the presence of genetic markers in both donor and recipient, which together shape post-transplant outcomes. Variations in DNA sequences of genes that govern differences in responses within a population, known as genetic polymorphisms, can either make patients more susceptible to or shield them from viral infections after HSCT [9]. A notable genetic element in this regard is the polymorphism of interleukin-28B (IL-28B), which encodes the gene for interferon lambda-3 (IFN-ƛ3). IL28A (IFN-λ2) and IL28B (IFN-λ3), collectively called IL 28/29, clustered together on the long arm of human chromosome 19 at position 19q13.13, are members of the type III interferon family and play an important role in antiviral defense [12]. In contrast to type I and type II interferon family, which produce their signal transduction through IFNGR1/2, IL28/29 binds to a distinct heterodimeric receptor comprising IL28RA and IL-10RB [12,13,14]. The expression of IL28RA is limited to epithelial cells, hepatocytes, and selective immune subtypes, explaining the IL28/29 ability to exert a localized inflammatory response compared with type I interferons [15]. This review aims to investigate the role of IL-28B polymorphism in patients following HSCT, emphasizing their vulnerability to viral infections and the resulting health outcomes. This review highlights how IL-28B/IFN-ƛ3 polymorphism contributes to the restoration of immune function post-transplant, while examining the evidence connecting IL-28B variations to infections like cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) among transplant recipients. Lastly, the clinical implications, limitations, and potential future research avenues related to this evolving field are outlined.

2. Bone Marrow Transplantation and Immune Reconstitution

The immune recovery process following hematopoietic stem cell transplantation (HSCT) is an extended process, often resulting in a prolonged period of immunodeficiency that can last for months or even years. During the initial pre-engraftment phase, which is typically within the first few weeks after transplantation, the innate immune components, particularly neutrophils and natural killer (NK) cells, predominate due to their rapid recovery [1,16]. In contrast, the adaptive immune responses remain largely suppressed. Neutrophils generally re-establish within 2–3 weeks, and NK cell levels tend to normalize between 3 and 6 months, providing early protection against viral infections. In contrast, complete reconstitution of T and B lymphocytes occurs more gradually. In some instances, CD8+ T cells and B cells often take ~6–12 months to recover, whereas CD4+ T cells may require 1–2 years to attain baseline levels [1]. Patients undergoing allogeneic HSCT, especially those who develop graft-versus-host disease (GVHD), tend to experience an even more delayed immune reconstitution and face a higher risk of opportunistic infections in the late post-transplant period. These complications are primarily seen in patients after allogenic HSCT, whereas autologous HSCT patients generally experience a quicker immune recovery and a lower incidence of late-onset infections [17].
In such cases where the adaptive immune response is delayed, innate immune cells are crucial for early protection following transplantation. The immune components such as natural killer (NK) cells [18], macrophages [19], and cytokines like interferons are the primary defense mechanism against viral pathogens during this initial period [20]. This is especially evident in T cell-depleted grafts, where the lack of transferred donor T cells increases susceptibility to viral reactivations, particularly, cytomegalovirus (CMV) and Epstein–Barr virus (EBV) [21,22]. This means that strategies aimed at reducing GVHD by depleting donor T cells tend to compromise adaptive immunity, thereby elevating viral infection risks. These infections are often treated with immunotherapy or antiviral treatments to prevent uncontrolled disease progression [23]. Among the chosen immune targets, the interferon (IFN) system is particularly important for antiviral defense post-transplant [24].
Type I interferons (IFN-α/β), and type III interferons (IFN-λ), are among the earliest cytokines produced in response to viral infections, initiating the expression of interferon-stimulated genes (ISGs) and establishing an antiviral state within cells [25]. Of particular interest is interferon lambda (IFN-λ), also referred to as the IL-28/IL-29 family, which is recognized as a crucial component of innate antiviral defense, especially in early post transplantation period prior to the establishment of T cell-mediated adaptive immunity [26]. The cytokine family includes IL-28A, IL-28B, and the interferon lambda receptor 1 (IFNLR) [27]. The expression of IFNLR is largely confined to epithelial cells of the mucosal layer, such as the respiratory tract, skin, and gut, and the hepatocytes in the liver. Upon activation, IFNLR triggers the expression of many antiviral genes similar to those induced by type I IFNs. However, type III IFN, IFN-λ, exerts potent antiviral effects predominantly at barrier surfaces such as the gastrointestinal tract, liver, and respiratory epithelium due to its tissue-specific expression [27]. Genetic variations in the IFN-λ pathway may influence the efficiency of viral infection control during immune reconstitution following HSCT. Notably, polymorphisms in the IL-28B gene can alter the expression and signaling of IFN-λ3 and IFN-λ4, thereby modulating the early antiviral environment following HSCT. Overall, the interplay between immune recovery and genetic variation in IL-28B highlights the importance of IFN-λ-mediated responses in determining infection outcomes after HSCT [24,28,29].

3. IL28B Polymorphisms and Viral Infections in the General Population and Solid Organ Transplant (SOT)

The role of IL-28 polymorphism became apparent in infectious disease due to its striking impact on hepatitis C virus (HCV), an RNA virus outcome. A genome-wide study carried out in 2009 identified rs12979860 single-nucleotide polymorphism (SNP) upstream of IL-28 [30,31]. This C/T SNP is known to be the strongest genetic predictor of spontaneous HCV clearance and response to interferon-based therapy. Patients with IL-28B CC allele are ~2–3 times more likely to clear HCV, either spontaneously or with treatment, compared to patients with the T allele (CT, TT). This indicates that CC allele generates a faster interferon lambda response to HCV, leading to faster resolution [30,31,32,33]. Given this fact, IL-28B is considered one of the most significant genetic factors in HCV pathogenesis. Subsequently, a deeper dive into IL-28B CC SNP, the newly discovered IFNL4 gene (IFN- λ4) responsible for a frameshift mutation that deletes IFN- λ4 production, was shown to confer better HCV clearance in these individuals compared to IL-28B TT who can produce IFN- λ4, but with suboptimal response to HCV clearance [33,34,35]. This insight demonstrates that IL-28B polymorphism is linked to IFN- λ3/4 pathway and the host antiviral interferon responses.
Beyond HCV, researchers have also investigated the role of IL-28B polymorphism in hepatitis B virus (HBV), but found little significance compared to HCV [36,37]. A 2020 meta-analysis found no association between IL-28B SNPs and the outcomes of HBV infection, including acute, chronic persistence, and clearance [37], confirming that genetic variation in IFN-λ genes does not significantly impact HBV clearance or interferon therapy. Although another study has shown that the IL-28B CC genotype is associated with slower HIV progression and better survival outcomes, this study was in individuals co-infected with HCV, suggesting that IL-28B polymorphism may be virus-specific and more crucial in certain infections than in others, especially RNA viruses such as HCV [38].
Conversely, IL-28B polymorphism has demonstrated a strong association with herpesvirus infections, particularly in transplant settings such as solid organ transplantation, and emerging, but more limited, evidence exists in HSCT. The IFN-λ pathway plays a crucial role in the innate immune response to DNA viruses such as CMV and EBV. Consequently, genetic variants may influence the balance of viral control [39,40]. Several studies, specifically involving solid organ transplant (SOT) patients, have reported that polymorphisms in IFN-λ3/4 can affect the risk of CMV replication [41,42,43]. In SOT patients not receiving prophylaxis, the IL-28B TT allele (corresponding to the IFNL4-producing genotype) was associated with a significantly reduced likelihood of CMV viremia. In contrast, the IL-28B CC allele (the IFNL4-null genotype) was linked to increased CMV replication [41]. A similar response has been observed in kidney transplant recipients, where the IL-28B rs12979860 TT allele was associated with a lower incidence of CMV post-transplant [44]. This suggests that the IL-28B polymorphisms can affect susceptibility to CMV in immunocompromised patients, elaborating that the functional impact of IFN-λ3/4 variants depends on the specific viral context.
During SARS-CoV-2 infection, both IFN-λ1 and IFN-λ3 contributed to early antiviral defense, especially in airway epithelial cells. IFN-λ3, in particular, has been associated with the inhibition of viral replication in these cells. Compared to type I interferons (IFN-α and IFN-β), the immune response mediated by type III interferons tends to be less inflammatory, which may reduce the risk of immunopathology [45]. Notably, genetic variations in IL28B, particularly rs12979860 and rs12980275 SNPs, have been linked to altering the immune response to SARS-CoV-2. Individuals carrying the rs12979860 CC or rs12980275 AA genotypes appear to mount a more effective immune response and are less likely to develop severe COVID-19. In contrast, the rs12979860 TT genotype has been associated with increased disease severity, similar to its association with poor outcomes in hepatitis C virus (HCV) infection. These findings suggest that IL28B polymorphisms may serve as useful biomarkers for identifying individuals at risk of severe COVID-19 and could help guide decisions about interferon-based therapies in the future [45,46,47,48,49,50]. Overall, IL28B polymorphism affects multiple viral infections, their clearance, and immune response as summarized in Table 1.

4. IL28B in Bone Marrow Transplant Patient Recipients

Numerous investigations have explored the impact of IL-28/IFNL gene polymorphisms on HSCT, encompassing both allogeneic and autologous procedures. In recipients of allogeneic transplants, evidence indicates that the IL-28B rs12979860 SNP is notably associated with the risk of CMV infection post-transplantation. Specifically, carriers of the minor T allele experienced fewer instances of CMV reactivation, implying a protective role for this allele. This effect is recorded to be most pronounced in a recessive inheritance model, where individuals with the TT genotype demonstrated a more robust response [52]. Further findings by Corrales et al. (2017) [56], provided functional immune insights by examining CMV-specific T cell reconstitution in HSCT patients stratified by IL-28B SNP status. The data revealed that carriers of the T allele developed more robust CMV-specific CD8+ and CD4+ T cell responses, evidenced by increased interferon-gamma (IFN-γ) production upon CMV antigen stimulation. Between days 90 and 180 post-transplantation, patients with TT or CT genotypes exhibited higher frequencies of CMV-specific T lymphocytes compared to those with the CC genotype [56]. These findings suggest that the protective effect associated with the rs12979860 T allele may be mediated through the enhancement of CMV-specific cellular immunity. Ultimately, IL-28B T allele carriers display not only a lower incidence of CMV viremia but also a more rapid and potent T cell response upon viral reactivation, highlighting the influence of IL-28B/IFN-λ4 variants on the kinetics of immune reconstitution against viral pathogens.
In autologous hematopoietic stem cell transplantation (HSCT), reactivation of viruses such as cytomegalovirus (CMV) occurs less frequently but can still affect high-risk populations, including those with lymphoma or myeloma who are CMV-seropositive and heavily immunosuppressed. A study conducted by Annibali et al. in 2018 examined autologous HSCT recipients (where donor and recipient are the same individual) and found that individuals carrying the IL-28B TT genotype exhibited a significantly lower incidence of CMV reactivation compared to those with the CC genotype [57]. Although data specific to autologous transplants remains limited, these findings suggest that the patient’s innate IL-28B genetic profile can influence viral outcomes independently of donor factors, since the patient essentially acts as their own donor. However, these results cannot be directly extrapolated to allogeneic settings, where donor genetics also play a critical role in shaping immune recovery and infection risk.
IL-28B has been evaluated for association with other transplant outcomes too. One example is in GVHD. A pivotal study conducted by Gadalla et al. [58] in 2020 analyzed over 1,600 allogeneic donor transplants and demonstrated that the donor’s IFNL4 genotype, determined by the IL-28B SNP, significantly influenced post-transplant outcomes. Donors with the IFNL4-positive genotype (analogous to the IL-28B T allele) were associated with an increased risk of non-relapse mortality (NRM) in recipients, largely due to higher incidences of severe GVHD and infectious complications. Conversely, donors carrying the IFNL4-null genotype (IL-28B CC) appeared to confer a protective effect, reducing GVHD-related mortality [58]. Multivariate analyses indicated that recipients of grafts from IFNL4-producing donors had a ~ 1.5–2-fold higher hazard ratio for GVHD-related mortality. One proposed mechanism is that IFN-λ4 production by donor-derived immune cells may alter dendritic cell or T cell responses in ways that amplify alloreactivity [58,59]. In contrast, the recipient’s IL-28B genotype primarily influences viral immunity early after transplant. Several studies suggest that recipients with the rs12979860 T allele experience reduced CMV reactivation and more rapid reconstitution of virus-specific T cell responses, whereas the CC genotype is associated with delayed clearance [56,59].
Beyond CMV and graft-versus-host disease (GVHD), other viral complications in HSCT recipients have been explored. For example, concerns regarding Epstein–Barr Virus (EBV)-related issues have been investigated [60]. Direct evidence connecting IL-28B polymorphism to EBV reactivation is scarce, as most genetic studies have focused on immune checkpoints and HLA loci rather than the interferon lambda (IFN-λ) pathway. Nonetheless, a survey of EBV-associated lymphoproliferative diseases showed no strong association; however, EBV DNA levels were lower in the CC allele, suggesting suppressed EBV activity in this context group [53,60]. Regarding BK polyomavirus (BKPyV), which is implicated in hemorrhagic cystitis in HSCT patients and nephropathy among renal transplant recipients, research has identified that the IL-28B rs12979860 polymorphism significantly correlates with the progression to BK virus-related nephropathy in kidney transplant populations [54]. Extrapolating these findings suggests that the IL-28B T allele could offer some protective effect against BKPyV infection in HSCT patients, although direct evidence in this setting is presently lacking. The impact of IL-28 gene variants on H1N1 influenza in HSCT recipients has not been well documented; however, animal models with IL-28B knockout exhibit variations in viral replication and disease severity. Specifically, mice with rs12979860 TT and rs8099917 GG genotypes show increased H1N1 replication and diminished response to IL-28B therapy [55]. Also, the minor allele (TG/GG) has been found to correspond with better immune response following H1N1 vaccination. This is thought to be mediated by increased Th2 T cells, B cell activation, and antibody production [43]. Further human studies are needed to confirm these observations. Overall, genetic variations in IL-28B may influence viral reactivation beyond HCV, potentially affecting the reactivation or susceptibility to other viruses like CMV, likely through modulation of innate interferon lambda responses in transplant patients. The relation between the viral infection and different genotypes affecting outcomes is summarized in Table 2.
In conclusion, emerging research in HSCT, particularly in allogeneic settings, suggests that IL-28B/IFNL4 polymorphisms in both donors and recipients can significantly impact clinical outcomes related to viral infections and GVHD as described in Figure 1. This underscores the potential value of incorporating IL-28B SNP testing into donor–recipient assessments to better predict prognosis.

5. Effect of IL28B Polymorphisms on Interferon Production and Signaling

The effects of IL28B gene variations on interferon signaling and immune gene activation have been well studied. A study by Bravo et al. adds helpful context, explaining that IL28B produces IFN-λ3, a cytokine that works through the JAK-STAT pathway to trigger interferon-stimulated genes (ISGs) [52]. Although they did not measure IFN-λ3 levels directly, the authors pointed to earlier studies showing that people with the C/C genotype tend to produce more IFN-λ3. This may create a more tolerant immune environment by encouraging the growth of regulatory T cells (Tregs). By comparison, individuals with the T/T genotype may have a more balanced immune response, capable of clearing viruses efficiently without tipping into excessive immune suppression. This contrast offers insight into how IL28B variations might shape immune behavior in the post-transplant setting.
One of the most informative studies on IL28B polymorphism and interferon signaling was conducted by Egli et al. [10], who investigated the rs12979860 SNP in the context of CMV infection. Using fibroblasts and PBMCs from donors with different IL28B genotypes (CC, CT, and TT), the researchers found that cells with the TT genotype (IFNL4 producing) showed much higher baseline and CMV-induced expression of key interferon-stimulated genes like OAS1, MX1, and ISG15. This stronger gene activation was linked to a dramatic, three-log drop in CMV replication, suggesting that people with the TT genotype have a naturally stronger antiviral response. Further experiments showed that IFN-λ3 treatment strongly upregulated ISGs in uninfected cells, but not in CMV-infected cells, suggesting viral interference with IFN-λ signaling [43]. When researchers silenced IL28B or its receptor, IL28RA, the antiviral effects disappeared, confirming that this pathway is key to the response. Interestingly, IFN-λ produced a more targeted, tissue-specific effect than IFN-α/β and caused less overall inflammation. This makes it a promising candidate for post-transplant therapies aimed at reducing complications like GVHD [43].
Taken together, the findings point to a key role for IL28B polymorphisms in shaping the response to interferon signaling. In particular, the TT genotype at rs12979860 has been linked to a naturally heightened antiviral state, marked by increased expression of interferon-stimulated genes and lower levels of viral replication [43,52]. This sets the stage for future research into how IL28B genotyping might guide more tailored approaches to immunotherapy and risk management in transplant care.

6. Clinical Implications of IL28B Polymorphism

A key consideration related to IL-28 polymorphism involves leveraging IL-28/IFNL4 genotyping as a tool for donor selection and assessing patient risk. In the context of HLA-compatible unrelated donor transplants, where multiple potential donors are available, selecting donors with an IFNL4-null genotype may potentially reduce relapse mortality and enhance overall survival outcomes. Practically, when donors are otherwise comparable, choosing a donor harboring a favorable IL-28B genotype (such as CC, lacking functional IFN-λ4) could decrease the likelihood of severe GVHD and deadly infections in recipients. This innovative approach to donor selection extends beyond traditional matching parameters like HLA and CMV serostatus, although further validation is necessary. Existing cohort data suggest that donor IL-28B/IFNL4 genotyping provides valuable prognostic insights, supporting its potential role in clinical decision-making [58].
For patients, understanding their IL-28B genotype can be instrumental in assessing their likelihood of infection and customizing surveillance or preventive therapies. For instance, individuals with the IL-28B CC genotype, which lacks the protective T allele, may face an increased risk of CMV reactivation [61]. Such patients might benefit from more intensive virological monitoring or a heightened antiviral prophylaxis approach. Conversely, those with the TT genotype could potentially clear CMV more effectively, possibly allowing for earlier reduction in prophylactic medication; however, at present, prophylaxis strategies are not yet tailored based on genotype but could be considered in future practices. In the context of solid organ transplantation, some centers incorporate IL-28B genotyping when evaluating CMV risk in donor–recipient pairs, similar to assessments based on CMV serostatus [61,62]. This approach might eventually be adopted in hematopoietic stem cell transplantation (HSCT) protocols, where IL-28B-related risk scores could augment existing CMV risk models. Notably, recent research has shifted towards polygenic risk assessment. A study by Bodro et al. (2022) introduced a composite innate immunity score encompassing IL-28B and other genetic polymorphisms in toll-like receptors and cytokines to predict CMV infection in high-risk transplant recipients [63]. Their multi-gene model sets the stage for future research into how IL28B genotyping might guide more tailored approaches to immunotherapy and risk management in transplant care, demonstrating a modest yet meaningful improvement in predicting CMV disease development despite prophylaxis. It underscores the potential of combined genetic profiling to identify individuals who might benefit from enhanced preventive measures.
A further aspect of clinical consideration that can be incorporated includes targeted antiviral treatment based on individual genetic profiles. Specifically, the IL-28B genotype has been shown to influence patient responses to interferon-based therapies, providing a rationale for personalized treatment strategies [64]. In the context of HCV management, IL-28B genotyping has been utilized to guide therapy, as individuals with the CC genotype tend to respond more favorably and may require shorter treatment durations. Although interferon-alpha (IFN-α) is not typically employed against viruses such as CMV in HSCT settings, there is growing interest in interferon lambda (IFN-λ) as a therapeutic alternative [65]. A clinical investigation into pegylated IFN-λ has demonstrated antiviral activity in hepatitis viruses, often accompanied by a reduced side-effect profile relative to IFN-α, attributable to the cytokine’s more restricted receptor distribution to organs such as the liver [65,66]. This suggests potential applications in immunocompromised patients, where IFN-λ could enhance viral clearance with minimized inflammatory responses. For example, administering recombinant IL-29 (IFN-λ1) or IL-28B (IFN-λ3) to HSCT recipients with persistent viral infections may potentiate innate antiviral defenses. Early-phase studies in other clinical scenarios support the capacity of IFN-λ to lower viral loads while maintaining a favorable safety profile [66]. Moving forward, modulation of the IL-28B/IFN-λ signaling axis may become a component of tailored management for viral complications, where individuals with “weak” IFNL genotype might benefit from exogenous supplementation, whereas those with hyperactive responses could require careful monitoring to prevent adverse immune effects.
Lastly, the genotyping of IL-28B is a cost-effective and readily accessible diagnostic technique, often utilizing PCR-based methods [67]. Many transplant facilities already preserve DNA samples from donors and recipients, making the integration of this biomarker into routine clinical workflows feasible. Its application can aid in various clinical decisions, including selecting suitable donors, determining the frequency of viral surveillance, and adjusting the intensity of immunosuppressive therapy. For instance, patients possessing the CC genotype, associated with increased risk of CMV infection, may warrant more cautious use of T cell-depleting agents or the implementation of antiviral prophylaxis during the initial 100 days post-transplant, a period regarded as critical in HSCT. Currently, combining IL-28B genotyping with additional biomarkers such as CMV-specific T cell counts, cytokine profiles, and viral load kinetics may enable more personalized approaches to managing infections in HSCT patients.

7. Predictive Value of IL28B Genotyping in Donor/Recipient Matching in Allogenic-HSCT

Post-allogenic-HSCT, the donor and recipient matching play a significant role in predicting outcomes of certain viruses’ reactivation such as CMV. In recipients with genotypes of IL-28B, CC allele at rs12979860 were shown to have a greater risk for CMV reactivation [56]. In fact, in recipients of HSCT, CMV is one of the most responsible viruses for higher morbidity and mortality. Moreover, the donor IL-28B genotype plays a significant role in shaping the immunity post-allogenic-HSCT [68]. CMV disease is defined as the presence of symptoms and signs consistent with CMV end-organ infection, together with detection of the virus by a validated method including immunohistochemistry or viral culture. PCR positivity in tissue without other evidence of disease is not considered diagnostic of CMV disease [69].
Post-HSCT, CMV infection occurs primarily due to reactivation of latent infection in recipients who were seropositive pre-transplant. This reactivation of CMV infection is generally of recipient origin, in which control is mediated by donor-derived immune effectors, which explains the differential risk according to donor and recipient serostatus. The highest risk group is seropositive recipients (R+) receiving grafts from seronegative donors (D−) in which reactivation occurs in up to 80% of cases, while R+/D+ are at moderate risk, R−/D+ at lower risk, with reactivation rate less than 10%, and primary infection in R−/D− transplants is rare [70,71,72]. The R−/D+ cases are now rare due to the introduction of screening for CMV serostatus of blood donors and the use of leucodepleted blood products [73].
In-depth analysis of R+D− scenarios shows that immune recovery is slower but does occur, in which T cells from the transplant donor are the sole source of CMV control. As recipient immune effectors are ablated by the myeloablative regimen for transplantation, the immune recovery is mediated by naïve donor T cells derived from progenitors in the graft. After achievement of full donor chimerism, recipient IL28B polymorphisms may still exert influence indirectly, for example, through early-phase immune reconstitution or interactions with residual recipient immune cells. However, in case of stem cell transplants conditioned with reduced intensity protocols, recipient CMV-specific T cells contribute to CMV immunity, where recipients’ IL-28B SNP status plays an integral role in providing T cell response and IFN-λ production, particularly early after transplant and before achievement of full lymphoid chimerism [74,75,76]. This is based on limited studies and requires further validation in prospective cohorts.
Research by Gadalla et al. demonstrated that IL28B-related IFNL4 genotypes affect immune outcomes in human transplant patients [58]. In a retrospective study of 404 recipients of Allo-HSCT, they found that donors with the IFNL4-positive genotype showed higher expression of interferon-stimulated genes (ISGs) in the blood and were more likely to experience non-relapse mortality. While the study mainly focused on infection and survival, the elevated ISG levels pointed to an overactive interferon response, potentially impairing the delicate equilibrium between immune surveillance and tolerance. The findings from Gadalla et al. raise the possibility that a donor’s IL28B genotype might influence not only how well viral infections are controlled but also how quickly and effectively the recipient’s immune system rebuilds, particularly in tissues like the gut and lymph nodes where epithelial and immune cells interact closely [58].
Other risk factors include in vivo or ex vivo T cell depletion, high-dose steroids, HLA-mismatched or unrelated donors, and GVHD [77]. A notable study by Henden et al. looked at this connection by testing the effects of interferon lambda (IFN-λ) in a mouse model of acute gastrointestinal GVHD [23]. In the study, mice that had received allogeneic bone marrow transplants were given recombinant IFN-λ2, the murine version of human IFN-λ3, which is encoded by the IL28B gene, after conditioning. The treatment led to a clear reduction in the severity of GVHD symptoms in the gut compared to untreated controls. Histological analysis revealed preservation of intestinal epithelial architecture and stem cell populations in the crypts of Lieberkühn, suggesting that IFN-λ promoted epithelial regeneration and protected barrier function [78]. The study showed that IL28B gene-encoded IFN-λ helps protect against gastrointestinal GVHD by boosting pathways that support epithelial cell survival while also downregulating key inflammatory signals like TNF-α and IL-6. Crucially, the protective effects of IFN-λ were limited to the gastrointestinal tract and did not lead to broad immune suppression. This suggests that IFN-λ treatment could help control GVHD-related inflammation while preserving the beneficial graft-versus-leukemia effect [78]. As a result, IL28B stands out as a promising option for targeted immune modulation after transplant.
There is an increasing amount of evidence that polymorphisms similar to IL28B are also involved in the CMV-host interaction, affecting the incidence rate and natural history of CMV post-transplant. These include SNPs in the chemokine receptor 5 (CCR5), monocyte chemoattractant protein 1 (MCP-1), interleukin (IL) 10, toll-like receptors (TLR) 8 and 9, and dendritic cell-specific molecule-3-grabbing non-integrin (DC-SIGN). SNPs in these genes in donor and recipient have been associated with the incidence rate of CMV infection, reactivation, duration, the peak levels of CMV viral load, and the development of CMV end-organ disease [52,79].
Thus, the relationship of viraemia to immune recovery is bidirectional. While immune recovery is required for control, the presence of antigen stimulation is also required to stimulate clonal proliferation of antigen-specific T cells. Overall, the idea of using IL28B genotyping to guide immune management after transplant aims to harness its protective benefits while avoiding the risks of excessive immune activation.
Future studies should explore specific combinations between the donor and recipient IL-28B genotypes, such as IFNL4-producing and null genotypes, which is related to the risk of CMV reactivation and GVHD after HSCT.

8. Potential Clinical and Predictive Role of IL28B in HSCT

Genetic polymorphism in IL-28b plays an important role as patients with IL-28B CC genotype of rs12979860 have a better response to interferon-based therapy and have a better viral clearance [31]. The introduction of direct-acting antivirals has limited the impact of IL-28B genotyping in HCV, as all the genotypes tend to exert similar efficacy with direct-acting antivirals [80]. In cases of liver transplantation, IL28B genotyping is important to aid in HCV recurrence treatment and not prophylaxis, where a study showed that the donor with the rs12979860 CC genotype showed a favorable outcome in the treatment of HCV recurrence [81]. This case is not exclusive to HCV only, but studies showed a similar effect in HBV when being treated with interferons [82]. The severity of nonalcoholic liver disease was also linked to the genotyping of IL-28B, where the CC genotype had milder inflammation compared to other genotypes [83]. The proposed mechanism by which IL28B exerts its beneficial action is related to activation of the JAK-STAT pathway and upregulation of the interferon-stimulated genes (ISG) contributing to the antiviral immunity [84]. The IL28B CC genotype of rs12979860 was associated with lower baseline ISG levels, which is easier to induce upregulation upon administering the interferon therapy, while patients with the TT genotype of rs12979860 had a higher level of ISG and lower inducibility upon interferon administration [31]. It is possible that this mechanism also contributes to post-Allo-HSCT viral infection control, although direct evidence is still lacking.
Several clinical studies have confirmed the effect of IL28B polymorphisms in HCV but only limited data are available in Allo-HSCT recipients. For example, in patients with HCV genotype 4 receiving interferon and ribavirin therapy, the rs12979860 CC and rs12979860 AA genotypes were significantly associated with sustained virological response. By contrast, IL28B polymorphisms were not consistently associated with response in HCV genotypes 2 and 3, and in genotype 1 patients, rs8099917 was linked to an increased risk of treatment failure [85]. Similarly, Bota et al. demonstrated that HCV patients with the CC genotype achieved higher sustained virological response rates when treated with interferon, ribavirin, and direct-acting antivirals [86]. Consistent results were obtained in a study using sofosbuvir plus daclatasvir, where individuals with the rs12979860 CC genotype again showed superior treatment outcomes [87]. When considering CMV, evidence is more fragmented. One experimental study in human foreskin fibroblasts and PBMCs showed that the rs8099917 TT genotype was associated with stronger induction of antiviral genes following CMV infection [43]. Another study reported that in neonates with congenital CMV infection (not HSCT recipients), those carrying the IL28B TT genotype exhibited lower rates of viral reactivation compared with other genotypes [57]. Although this population differs substantially from transplant recipients, these findings suggest potential parallels that merit further exploration in HSCT settings. Conversely, a separate investigation in congenital CMV did not observe a clear association between IL28B variants and viral load, highlighting the need for context-specific studies [88].
Taken together, current data indicate that IL28B genotyping holds predictive value in HCV and possibly CMV, but direct evidence in Allo-HSCT remains limited. Extrapolation from non-HSCT populations (e.g., congenital CMV or fibroblast models) should be interpreted cautiously. Nevertheless, these observations support the rationale for incorporating IL28B polymorphism analysis into larger HSCT-focused studies to clarify its role in risk stratification and outcome prediction.

9. Conclusions

The role of IL28B polymorphisms in shaping immune responses after transplant is becoming increasingly well understood. Studies have consistently shown that certain genotypes, especially the rs12979860 variant and IFNL4-related profiles, are linked to making differences in how well patients control CMV, levels of interferon-stimulated gene (ISG) expression, and rates of complications like non-relapse mortality and GVHD.
These findings underscore the key role of type III interferon signaling in transplant immunity and point to IL28B as a promising biomarker for guiding clinical decisions. Genotyping both donor and recipient for IL28B and IFNL4 could improve patients’ risk levels and pave the way for more personalized approaches to antiviral prophylaxis, monitoring, and post-transplant care.

Author Contributions

Conceptualization, M.A.E. and S.R.; investigation, M.A.E., B.P., M.C., F.A. and S.M.; resources, O.E. and E.G.A.; data curation, M.A.E. and E.G.A.; writing—original draft preparation, M.A.E., B.P., M.C., F.A., S.M., O.E. and E.G.A.; writing—review and editing, M.A.E. and B.P. supervision, S.R.; project administration, M.A.E. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Role of IL28B polymorphism in viral infection post-Allo-HSCT.
Figure 1. Role of IL28B polymorphism in viral infection post-Allo-HSCT.
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Table 1. Impact of IL-28B polymorphism in different viral infections correlating with outcome.
Table 1. Impact of IL-28B polymorphism in different viral infections correlating with outcome.
VirusImpact of IL-28B PolymorphismFavorable GenotypeClinical SettingReferences
HCVStrong: Predicts spontaneous and treatment-induced clearancers12979860 C/TPopulation with IL28B CC allele (IFNL4-null) → better clearance[30,31,32,33,34,35]
HBVMinimal or no significant impact_No consistent association; not predictive of outcome[36,37]
HIVMinimal (except in HIV/HCV co-infection)CC allele in co-infectionBetter outcomes observed only in HCV/HIV co-infected individuals[38,51]
CMVModerate: Influences viremia/reactivation in transplant patientsTT (rs12979860)
(IFNL4-producing genotype)		In solid organ and HSCT patients, TT allele is linked to lower CMV viremia and better control[43,52]
EBVWeak evidencePossibly CCFew studies; no strong association, but lower EBV DNA in CC genotype patient[53]
BKPyVPossible association: Linked to nephropathy risk in kidney transplantTT allele Studies in renal transplant patients suggest TT allele may protect against BK virus nephropathy; limited data in HSCT[54]
Influenza (H1N1)Experimental evidence onlyPossibly TG/GG (rs8099917) and TT (rs12979860) alleleAnimal models suggest that genotype affects viral replication and vaccine response[43,55]
SARS-CoV-2 (COVID-19)Possible association: Protection from severe COVID-19CC (rs12979860), AA (rs12980275Associated with resistance to infection and milder disease; TT genotype is linked to severe outcomes[45,46,47,48,49,50]
Table 2. Correlation between viral infection/disease with IL-28B genotype in transplant setting and the expected outcome after HSCT.
Table 2. Correlation between viral infection/disease with IL-28B genotype in transplant setting and the expected outcome after HSCT.
Virus/DiseaseGenotypeEffectReferences
CMVTT allele↑CMV-specific T cell response, lower incidence of CMV viremia[52,56]
GVHDCC allele↓Mortality[58,59]
EBVCC allele↓EBV DNA levels and reactivation[53]
BKPyVTT allele↓BKPyV-related nephropathy[54]
H1N1TT and GG alleles↑H1N1 replication in mice models[43,55]
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Eltokhy, M.A.; Patel, B.; Curcic, M.; Alabi, F.; Modaresahmadi, S.; Eltoukhy, O.; Abdelmageed, E.G.; Radwan, S. The Role of IL28B Polymorphism in Regulating Innate and Adaptive Immunity Against Viral Infection Among Allogenic Stem Cells Transplant Recipients. Immuno 2025, 5, 38. https://doi.org/10.3390/immuno5030038

AMA Style

Eltokhy MA, Patel B, Curcic M, Alabi F, Modaresahmadi S, Eltoukhy O, Abdelmageed EG, Radwan S. The Role of IL28B Polymorphism in Regulating Innate and Adaptive Immunity Against Viral Infection Among Allogenic Stem Cells Transplant Recipients. Immuno. 2025; 5(3):38. https://doi.org/10.3390/immuno5030038

Chicago/Turabian Style

Eltokhy, Mohamed A., Bhaumik Patel, Marina Curcic, Faizah Alabi, Shadan Modaresahmadi, Omar Eltoukhy, Esraa G. Abdelmageed, and Sahar Radwan. 2025. "The Role of IL28B Polymorphism in Regulating Innate and Adaptive Immunity Against Viral Infection Among Allogenic Stem Cells Transplant Recipients" Immuno 5, no. 3: 38. https://doi.org/10.3390/immuno5030038

APA Style

Eltokhy, M. A., Patel, B., Curcic, M., Alabi, F., Modaresahmadi, S., Eltoukhy, O., Abdelmageed, E. G., & Radwan, S. (2025). The Role of IL28B Polymorphism in Regulating Innate and Adaptive Immunity Against Viral Infection Among Allogenic Stem Cells Transplant Recipients. Immuno, 5(3), 38. https://doi.org/10.3390/immuno5030038

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