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Viral Infections

Human herpesvirus 6 infection and cytomegalovirus-specific lymphoproliferative responses in allogeneic stem cell transplant recipients

Abstract

The aim of this study was to investigate the effects of HHV-6 DNAemia on the CMV specific lymphoproliferative response after allogeneic stem cell transplantation. Twenty-one allogeneic stem cell transplantation (allo-SCT) patients were included in the study. The patients were either CMV seropositive and/or had CMV seropositive donors. We studied the effects of HHV-6 infection, documented by PCR, on CMV-specific lymphocyte proliferation response and on CMV infection documented by PCR. HHV-6 DNAemia correlated with the absence of CMV-specific lymphocyte proliferation responses after allo-SCT. Three of nine patients with persistent HHV-6 DNA had a CMV-specific lymphocyte proliferative response compared to 11 of 12 patients without persistent HHV-6 DNAemia (P = 0.02). Patients with higher HHV-6 DNA levels (>100 copies) were more likely than those with lower copy numbers not to develop a CMV-specific immune response (six of nine vs one of eight; P < 0.05). Patients who were repeatedly HHV-6 positive in three or more consecutive blood samples were also more likely to need repeated courses of preemptive antiviral therapy against CMV during the first 6 months after transplantation (P < 0.001). Our data indicate the possibility that HHV-6 can suppress the development of CMV-specific immune responses and thereby could predispose to development of late CMV disease.

Main

CMV has been one of the major causes of morbidity and mortality after SCT. Significant progress has been made concerning diagnosis, prophylaxis and treatment of CMV infection, and the risks for CMV disease and mortality due to CMV have been greatly reduced.1 However, CMV-related mortality still occurs and antiviral drugs are expensive and have considerable side-effects.2,3 Long-term prophylaxis with antiviral drugs also leads to delayed recovery of CMV-specific cytotoxic T lymphocyte (CTL) immunity, which is related to late CMV disease.4 Moreover, drug-resistant viral strains may emerge after extensive use of antiviral drugs. Thus, it is still of interest to continue defining the risk factors for CMV infection and disease in order to allow use of the available antiviral strategies in the most efficient manner.

Both CMV and HHV-6 belong to the β-herpesvirus family. More than 90% of the healthy population is HHV-6 seropositive. Like CMV, HHV-6 reactivations are common but the reactivation occurs earlier after SCT.5,6,7 HHV-6 viremia has been associated with active CMV infection after SCT.8 HHV-6 infection has also been associated with development of CMV disease after solid organ transplantation.9,10 Presence of a specific immune response to CMV has been shown to be protective against CMV disease both measured as a cytotoxic T lymphocyte (CTL) response11 and as a helper cell response.11,12 HHV-6 can productively infect human T lymphocytes, reduce interleukin 2 production and induce T lymphocyte apoptosis.13,14,15

The aim of this study was therefore to investigate the effects of HHV-6 DNAemia on the CMV-specific lymphoprolipherative response. We have longitudinally analyzed the immune response to CMV in the first 3 months after SCT. The effects of CMV and HHV-6 infections on the CMV-specific lymphocyte proliferation were examined, and the presence of CMV and HHV-6 DNA in sequential peripheral blood leukocytes (PBL) was analyzed with PCR techniques.

Materials and methods

Patients

The study included 21 adult patients receiving allogeneic SCT (Table 1). All patients were in complete remission or chronic phase of hematological malignancies. Pretransplant conditioning regimens were either cyclophosphamide and total body irradiation or busulphan and cyclophosphamide.16 Patients with unrelated donors also received either anti-T cell antibodies (Orthoclone OKT3, Ortho Biotech, NJ, USA) or anti-thymocyte globulin (Thymoglobulin, SangStat Medical Corp, CA, USA) as part of the conditioning regimen.17 Graft-versus-host disease (GVHD) was prevented with the combination of cyclosporine A and methotrexate.16,17 T cell depletion was not performed. Preemptive therapy against CMV infection was initiated based on two consecutively positive PCR findings.18 All patients received leukocyte-depleted blood products.

Table 1 Patient characteristics

Controls

Twenty-two healthy individuals working or studying at either the Huddinge University Hospital or the Swedish Institute for Infectious Disease Control were used as controls. Fourteen persons in the control group were female and eight were male, the average age was 39 years (range 24–60).

The study was approved by the ethics committee at Huddinge University Hospital.

Blood samples

Blood samples were collected before SCT and at 3, 4, 5, 6, 8, 10 and 12 weeks after SCT. All patients were either CMV seropositive before transplantation and/or had CMV seropositive donors. The samples were collected into heparin tubes for lymphocyte proliferation studies and into EDTA tubes for detection of HHV-6 and CMV DNA. Before transplantation we could not obtain samples from all patients. The numbers of samples analyzed are specified at each result given below. After transplantation, samples could not be obtained from all patients at all times of collection, in most cases due to transplant-related mortality.

Lymphocyte proliferation assays

The lymphocyte proliferation assays were performed as previously reported.19 Briefly, peripheral blood mononuclear cells (PBMC) isolated by Ficoll–Hypaque (Pharmacia Biotech, Uppsala, Sweden) were washed and resuspended in culture medium consisting of RPMI 1640 supplemented with glutamine, penicillin, streptomycin, 10−5 mol β2-mercaptoethanol (Life Technologies, Paisley, UK) and 10% human AB+, CMV seronegative serum. The human serum was previously assessed for its ability to support PBMC cultures stimulated with the CMV antigen and phytohemagglutinin (PHA, Murex Diagnostics, Dartford, UK). PBMC were adjusted to 1.5 × 106 cells/ml, and 100 μl of the cell suspension were added per well into 96-well flat-bottom plates (Nunclon Delta; Nunc, Aarhus, Denmark). All assays were performed in triplicate or quintuples depending on the number of available PBMC. A CMV nuclear antigen, predominantly containing viral capsid antigens, was prepared according to a previously published method, and used at previously determined optimal concentrations.16,17 Proliferation was measured by 3H-thymidine (Amersham Int, Amersham, UK) incorporation (1 μCi/well, 4 h pulse) on day 6. The cells were harvested on to glass fiber pads, and counts per minute (c.p.m.) were measured with a 1205 Beta-Plate (LKB Wallac, Turku, Finland). Results were expressed as stimulation indices (SI), which were derived from the mean c.p.m. after antigen stimulation divided by the mean c.p.m. obtained after stimulation with control antigen. The mean c.p.m. of PHA was divided by that of medium alone to obtain the SI. A response was regarded as positive if the SI was higher than 2, and the net c.p.m. (the c.p.m. of the antigen minus that of the control antigen) was more than 1000.

Serology

CMV serology of the controls was determined at the Swedish Institute for Infectious Disease Control by an ELISA method.20 CMV serology of the patients and their donors was performed at the Department of Clinical Virology, Huddinge University Hospital by an ELISA method.21

PCR methods

Peripheral blood leukocytes (PBL) collected as buffy-coats were analyzed by PCR for HHV-6 DNA.5 The sensitivity of the PCR is 20–30 genomes for both the GS (variant A) and Z 29 (variant B) strains. The DNA of 5 × 104 PBL was used for each PCR assay. HHV-6 DNA was quantified by a previously described competitive technique.6,22 This nested PCR amplifies the same region as the qualitative PCR assay and has a broad dynamic range with a lower limit of accurate quantification of 10 genome copies.

PBL were analyzed for CMV DNA by a semi-quantitative PCR as previously described and the detection limit of this method was 10 genome copies.21

Definitions

Acute GVHD was defined according to Thomas et al.23 Detection of HHV-6 DNA in a single PBL sample is very common after allo-SCT. Therefore we used a definition of persistent HHV-6 DNAemia requiring detection of HHV-6 DNA in three consecutive PBL specimens to increase the likelyhood of HHV-6 detection being clinically significant.5

CMV infection and disease were defined as previously described.21

Statistics

Proportions were compared by Fisher's exact test (two-tailed). Survival curves were constructed by the Kaplan–Meier method and compared by the log-rank test. Risk factors for the development of a CMV-specific lymphocyte proliferative response and requirement for repeated courses of preemptive therapy were analyzed by logistic regression. A P value of <0.05 was regarded as significant. P values of 0.05–0.10 were not regarded as significant, but to indicate a possible trend.

Results

Lymphocyte proliferation in healthy controls and patients before allo-SCT

CMV-specific proliferation was demonstrated in 16 of 17 (94%) CMV seropositive healthy individuals and in 10 of 11 (91%) CMV seropositive patients, where blood samples were available before allo-SCT. None of the five CMV seronegative controls had CMV-specific responses detected. Lymphocyte proliferative responses to PHA were present in all the individuals studied. There was no difference in the intensity of the CMV-specific responses between the healthy individuals and patients before allo-SCT (data not shown).

Lymphocyte proliferation after allo-SCT

Of the 21 patients enrolled in this study, 19 were CMV seropositive before transplantation and two were CMV seronegative but had CMV seropositive donors. Fourteen of the 21 patients (67%) responded to CMV antigen in the lymphocyte proliferation assays after allo-SCT. All of them had previously reactivated CMV, detected as CMV-DNA by PCR. The intensity of the responses to the CMV antigen was similar in the patients before and after transplantation (data not shown), and the frequency of positive responses increased from the 8th week after allo-SCT (Figure 1).

Figure 1
figure1

Kinetics of HHV-6 DNAemia, CMV DNAemia and CMV-specific lymphocyte proliferation responses, n is of samples available at each time point. HHV-6 and CMV DNA in peripheral blood leukocytes were analyzed with PCR methods.

Detection of viral DNA before and after SCT

Thirteen of the 21 patients had PBL samples available for CMV DNA analysis before transplantation. Only one of them (8%) had detectable CMV DNA in PBL before transplantation compared with 19 of 21 patients (90%) after transplantation (P < 0.001). Fifteen patients had PBL samples available for HHV-6 DNA analysis before transplantation and four of them (27%) had HHV-6 DNA detected in PBL vs 17 of 21 patients (81%) after transplantation (P < 0.01). Nine patients had persistent HHV-6 DNAemia (positive in three or more consecutive samples). There was a correlation between the HHV-6 viral load and the likelihood to be persistently HHV-6 DNA positive in PBL. In the group with persisting HHV-6 infection the mean log number of HHV-6 DNA copies was 2.50 ± 0.59 (s.e.m.) compared to 1.05 ± 0.29 (s.e.m.) in the group that did not have a persisting HHV-6 infection (P = 0.04).

The effect of HHV-6 infection on CMV DNAemia and use of preemptive therapy

Patients with persistent HHV-6 infection had higher numbers of PBL samples positive for CMV DNA (31 of 44) during the first 3 months after transplantation PBL. The corresponding number from patients with no or intermittent HHV-6 DNAemia was 24 of 81 (P < 0.001). This resulted in different patterns concerning the number of preemptive therapy courses against CMV between the groups. Fourteen of the 19 patients that reactivated CMV after allo-SCT needed preemptive antiviral therapy against CMV. Of the nine patients that were persistently HHV-6 DNA positive in PBL, one had no CMV DNA detected at any time and one had CMV DNA detected in only one blood sample, but the remaining seven were given anti-CMV treatment. These seven patients all required repeated anti-CMV treatment courses in the first 6 months after transplantation (average three courses, range 2–4), while all the seven patients without persistent HHV-6 infection only needed a single course (P < 0.001). Similarly, there was a significant correlation between the HHV-6 viral load and the likelihood of requiring more than one course of preemptive therapy against CMV (data not shown, P = 0.03).

None of the patients developed CMV disease. There was no difference in survival between patients with (33%) or without persistent (66%) HHV-6 DNAemia.

Effects of CMV and HHV-6 infection on CMV-specific lymphocyte proliferative responses after allo-SCT

A CMV-specific lymphocyte proliferative response was detected in 14 of 19 (74%) patients with detectable CMV DNA in PBL compared with neither of two patients without detectable CMV DNA in PBL. Of the 19 patients with detectable CMV DNA in PBL, three of eight patients with persistent HHV-6 infection responded with CMV-specific lymphocyte proliferation compared to 11 of 11 patients without persistent HHV-6 infection (P = 0.005). Seventeen patients reactivated HHV-6. Of those, the patients with higher HHV-6 DNA levels (>100 copies) were more likely not to develop a CMV-specific immune response than those with lower numbers of copies (six of nine vs one of eight; P < 0.05). The number of HHV-6 DNA copies was significantly higher in the group that lacked a CMV-specific lymphocyte proliferative response than in the group of patients who were able to mount a lymphoproliferative response to CMV antigen (Figure 2). All but one patient responded to PHA stimulation.

Figure 2
figure2

Effect of HHV-6 viral load on CMV-specific lymphocyte proliferation responses. The middle line corresponds to the mean of the log number of DNA copies and the box to the s.e.m.

To further analyze the effect of CMV and HHV-6 infection on CMV-specific lymphocyte proliferation, a time-dependent analysis was performed in which only the patients with CMV DNAemia were included and a CMV-specific response was only considered if it was detected after persistent HHV-6 DNAemia. In this analysis, there was a trend for persistent HHV-6 infection to correlate with absence of CMV-specific proliferation (two of seven patients with persistent HHV-6 infection responded vs nine of 12 without; P = 0.07).

Effects of donor type and CMV status, acute GVHD, and type of transplant

Fewer patients, who either had undergone transplant from unrelated donors (UD) or developed acute GVHD II–IV, responded by lymphocyte proliferation to CMV antigen (P = 0.06 and P = 0.02, respectively, data shown in Table 2). The patients with UD or acute GVHD grade II–IV were also more likely to have persistent HHV-6 infection (P = 0.06 and P = 0.02, respectively, data shown in Table 2). In the group of patients transplanted with UD, five of 11 developed CMV-specific lymphocyte proliferative responses. All 11 patients with UD were CMV positive before transplant. When the patients were subdivided according to the donor's CMV status, five of seven patients with CMV positive UD developed a CMV-specific immune response compared to none of four patients with CMV negative UD (P = 0.06, data shown in Table 2).

Table 2 Effect of donors, CMV serology donor–recipient, type of transplants and acute GVHD on lymphocyte proliferation responses to CMV antigen

An attempt was made to analyze the effects of HHV-6 viral load, acute GVHD grade, and donor type on CMV DNAemia and development of a CMV-specific immune response. In univariate logistic regression both HHV-6 viral load (OR 0.38; 0.13–0.97) and acute GVHD (OR 0.07; 0.01–0.96) influenced development of a CMV-specific lymphoproliferative response while donor type or transplant type did not. However, in a multivariate model, none of the factors significantly influenced the development of a CMV-specific lymphoproliferative response, but the number of patients included are too few for us to draw any conclusions. Similarly, both a high HHV-6 viral load (OR 2.9; 1.0–7.9) and acute GVHD grade II–IV (OR 14.8; 1.1–185.2) influenced the likelihood that a patient required more than one course of preemptive CMV therapy while donor type or transplant type did not. In a multivariate model, none of the factors significantly increased the risk, but the number of patients included was too few to make an adequate analysis.

Discussion

CMV disease remains an important cause of morbidity and mortality after allogeneic SCT. The most significant risk factor for CMV disease after allo-SCT is the occurrence of CMV reactivation, in particular viremia.24 Acute GVHD is associated with development of CMV reactivation.25,26 The risk for CMV disease is increased in unrelated and mismatched donor SCT.1,27

HLA restricted cytotoxic T lymphocyte (CTL) function has been reported to be the most important for immune protection against CMV disease and mortality.11 However, SCT patients who develop CMV disease frequently have no detectable CMV-specific proliferative response.12,28 The lymphocyte proliferation assay mainly detects the function of CD4+ T lymphocytes.29 Thus, lymphocyte proliferation in response to CMV antigens has been proposed to be an important marker of immune protection against CMV infection and CMV disease. In addition, patients with deficient CD4+ T lymphocyte responses quickly lose the activity of infused CTL clones.4,30 In the present study, CMV-specific lymphocyte proliferation was detected in more than 90% of CMV seropositive healthy individuals and patients before transplantation compared with none of the CMV seronegative persons. These results are similar to previous data.31,32 CMV-specific lymphocyte proliferation was not detected in any patient following transplantation without previously detectable CMV DNA by PCR, confirming previous findings that CMV-specific proliferative responses return only after an active CMV infection after allo-SCT.31,32 Furthermore, patients without a CMV-specific lymphoproliferative response more frequently had CMV DNA detected despite repeated preemptive anti-CMV therapy. Our results are consistent with previous findings that a CMV-specific immune response is necessary for long-term CMV control after allogeneic SCT.12,28,32

As previously described, we had fewer samples to analyze than was originally planned, mostly due to TRM. This makes the results more difficult to interpret. However, we found that persistence of HHV-6 DNA in three or more consecutive blood samples, as well as a high number of HHV-6 DNA copies, reduced the likelihood of development of a CMV-specific lymphocyte proliferative response. Persistent HHV-6 infection also correlated with prolonged CMV DNAemia necessitating repeated courses of preemptive antiviral therapy. HHV-6 infects CD4+ cells which are the cells mainly measured by the lymphocyte proliferation assay. Einsele et al33 reported that patients with acute GVHD are more likely to have CMV infections, but that lymphocytopenia correlated with CMV disease. Interestingly, we have found that lymphocytopenia in this setting is mainly due to HHV-6 rather than CMV infection.19 These findings indicate that an increased exposure to HHV-6 suppresses the immune response to CMV. HHV-6 can productively infect human T lymphocytes, reduce interleukin 2 production and induce T lymphocyte apoptosis.13,14,15 In contrast, productive infection of T lymphocytes by CMV has never been proven.34 In vivo it has been suggested that HHV-6 infection inhibits the immune system and thereby contributes to other infectious diseases, as CMV. This hypothesis has yet to be proven.

The question then is whether HHV-6 is the cause of the suppressed CMV-specific immunity or a marker of a generally more immune suppressed group of patients. Previously, we have not been able to show any relationship between HHV-6 infection and acute GVHD.19 Acute GVHD has been shown to increase the risk for CMV reactivation.26,27 In this study, both acute GVHD grade II–IV and HHV-6 viral load were associated with lack of a CMV-specific proliferation response and need of repeated preemptive antiviral therapy, in univariate but not in multivariate analysis. It is therefore impossible to ascertain the relative roles of HHV-6 infection and acute GVHD on CMV-specific immune response in this small number of patients. In the unrelated donor setting we also saw an association between CMV negative donor to CMV positive patient and lack of CMV-specific proliferation. In this small group of patients it is impossible to analyze the relative importance of this finding compared to the other two risk factors found.

In conclusion, our data suggest that HHV-6 infection might inhibit the CMV-specific immune response and thereby may contribute to prolonged and possibly more severe CMV infections after allo-SCT. We will try to clarify this correlation in further studies.

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Acknowledgements

This study was supported by the Swedish Children's Cancer Fund and the Swedish Cancer Society. We are grateful to Vince Emery and Duncan A Clark at Royal Free Hospital School of Medicine for help with the quantitative, competitive PCR analyses. We also thank Kirsti Niemele, RN, and Mari Svensson, RN, at Huddinge University Hospital for collecting the samples.

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Wang, FZ., Larsson, K., Linde, A. et al. Human herpesvirus 6 infection and cytomegalovirus-specific lymphoproliferative responses in allogeneic stem cell transplant recipients. Bone Marrow Transplant 30, 521–526 (2002). https://doi.org/10.1038/sj.bmt.1703657

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Keywords

  • cytomegalovirus
  • human herpesvirus 6
  • allogeneic stem cell transplantation
  • immunity

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