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Mixed Cytomegalovirus Glycoprotein B Genotypes in Immunocompromised Patients

  1. Alain Coaquette,
  2. Alain Bourgeois,
  3. Carine Dirand,
  4. Audrey Varin,
  5. Wan Chen, and
  6. Georges Herbein
  1. Department of Virology, Franche-Comte University School of Medicine, Besançon, France
  1. Reprints or correspondence: Dr. Georges Herbein, Dept. of Virology, Franche-Comte University School of Medicine, Hôpital Saint-Jacques, 2, place Saint-Jacques, F-2 Besançon cedex, France (gherbein{at}chu-besancon.fr).
 
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Abstract

On the basis of sequence variation in the UL55 gene that encodes glycoprotein B (gB), human cytomegalovirus (CMV) can be classified into 4 gB genotypes. The goal of the present study was to determine the distribution of CMV gB genotypes and the effect of gB type on clinical outcomes in a cohort of immunocompromised patients, including both transplant recipients and nonrecipients. The distribution of gB genotypes was as follows: gB1, 28.9% of patients; gB2, 19.6%; gB3, 23.7%; gB4, 2.0%; and mixed infection, 25.8%. In contrast to patients infected with a single gB genotype, patients infected with multiple gB genotypes developed progression to CMV disease, had an increased rate of graft rejection, had higher CMV loads, and were significantly more often infected with other herpesviruses. The presence of multiple gB genotypes, rather than the presence of a single gB genotype, could be a critical factor associated with severe clinical manifestations in immunocompromised patients.

Cytomegalovirus (CMV) remains an important cause of morbidity in immunocompromised persons, especially in transplant recipients, and it may manifest as symptomatic end-organ disease (including hepatitis and pneumonitis) or as so-called “CMV viral syndrome,” with fever, leukopenia, and thrombocytopenia. In addition to the direct effects of CMV infection, CMV may also have an immunomodulatory effect, potentially making CMV infection an important risk factor for the development of acute and chronic allograft rejection [1] and for coinfection with other herpesviruses such as Epstein-Barr virus (EBV) [2–4]. Given the importance of CMV in immunocompromised patients, an improved understanding of the factors that contribute to reactivation from latency and the development of symptomatic CMV disease will lead to more effective methods of prevention and treatment. The virulence of different CMV strains may be an important factor in the occurrence of CMV-associated disease. Virulence among CMV strains could differ due to genetic variation in genes that are involved in host cell penetration, tissue tropism, or replication [5].

CMV glycoprotein B (gB) is the major envelope glycoprotein of CMV, and it is encoded by UL55. CMV gB has been implicated in host cell entry, cell-to-cell virus transmission, and fusion of infected cells, in addition to being an important target for both humoral and cellular immune responses [6–12]. CMV gB is expressed as a precursor molecule that is glycosylated and then cleaved at codon 461 to form a disulfide-linked complex of gp55 and gp116. A method of CMV genotyping has been devised that is based on the gB nucleotide sequence, which encodes a variable region that encompasses the protease cleavage site [13–15], demonstrating the existence of 4 different gB genotypes [14].

Many studies have attempted to find a correlation between the gB genotype and the occurrence of CMV-associated disease in immunocompromised patients; however, it remains unclear whether certain gB genotypes or mixed gB genotypes are associated with an increased frequency of disease. In the present study, the distribution of CMV gB genotypes was determined in immunocompromised patients, with a special emphasis on patients with mixed CMV infections.

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Patients, Materials, and Methods

Study population and setting. Sixty-four adult patients undergoing organ transplantation (kidney, 22 patients; liver, 26 patients; and bone marrow, 16 patients) and 28 immunocompromised patients with lymphoma or leukemia who did not receive transplants were eligible for enrollment at the Besançon University Hospital. These patients included a cohort of 92 patients who were participating in studies that assessed CMV load testing, CMV serological analysis, CMV gB genotype, and clinical outcome. Informed consent was obtained from all patients, and the local ethics committee approved the study.

Study design. Patients were followed up prospectively with use of CMV load testing. Only those patients with test results positive for CMV were included in the study and were evaluated with CMV gB genotyping. CMV genotype was then correlated with virus load, CMV serological analysis, and clinical outcome. Among transplant recipients, only patients who received a transplant from a donor with serological test results positive for CMV and who themselves had serological test results negative for CMV before undergoing a transplant procedure (i.e., those who were donor seropositive/recipient seronegative for CMV) received antiviral prophylaxis.

CMV gB genotyping and CMV load. DNA was extracted from the biological samples, and PCR was then performed with use of primers gB-1289 (5′-TAGGTGAACTGCAGCTGN-3′) and gB-1459 (5′-TCTGCAAGGYATCAAGC-3′), as described elsewhere [16]. The amplified PCR products were hybridized with a single-stranded DNA probe specific for each gB CMV genotype and were coated on the wall of the microtiter plate wells with a streptavidin-biotin bond (Gen-Eti-K DNA enzyme immunoassay [DEIA]; DiaSorin). The following primers were used: gB-consensus sequence (5′-TGGAAYTSGAACGTTTGGCCAA-3′), gB1 (5′-AGATGGCTACAATGCAGCTGATGTATCCAAC-3′), gB2 (5′-GGTCCTGACGTCGTACGAGTGACAATAATAC-3′), gB3 (5′-CGGGCAATACGACCACTCTGTCGCTTGAAAG-3′), and gB4 (5′-CTTATGTAACGCATCTAGCTACTATGGACTCGGTA-3′). The amplified specific gB DNA sequences were detected using a DEIA, as specified by the manufacturer's instructions (Gen-Eti-K DEIA; DiaSorin), with measurement of absorbance values with a photometer at 450 nm.

For the semiquantitative measurement of CMV load, PCR was performed on DNA extracted from the biological samples using primers gB-1289 and gB-1459, with detection of the amplified fragment with a gB consensus sequence (5′-TGGAAYTSGAACGTTTGGCCAA-3′), with use of the DEIA as specified by the manufactor's instructions (Gen-Eti-K DEIA; DiaSorin). The amount of amplified CMV PCR product was quantified from 0.5+ (weakly positive) to 4+ (strongly positive). Quantitative real-time CMV PCR was performed on biological samples, according to manufacturer's instructions, using the ABI Prism 7000 (Applied Biosystem) [17]. Results were recorded as number of viral copies per mL of biological sample. The lower limit of detection was 100 copies/mL.

CMV serodiagnostic. Serum samples were assessed for anti-CMV IgG, IgM, and IgA antibodies with use of an ELISA (Biotest).

CMV isolation and pp65 antigenemia. The isolation of CMV was performed on urine, blood, or bronchoalveolar lavage fluid specimens according to the method described by Mazeron et al. [18]. The detection of CMV pp65 was performed by indirect immunofluorescence of isolated peripheral blood leukocytes obtained from EDTA or heparin-anticoagulated peripheral blood (CMV Brite Turbo; IQ Products).

Detection of other viral infections. Isolation of adenovirus was performed on biological samples according to the method described by Pham et al. [19]. The detection of BK virus, herpes simplex virus (HSV), and EBV was performed by PCR assay as previously described [20–22].

Statistical analysis. All database entry and statistical analysis was performed using SPSS software (version 9.0; SPSS). Categorical variables were analyzed using the χ2or Fisher's exact test. A 1-way analysis of variance was used to compare CMV load and the mean number of graft-rejection episodes in patients with different CMV gB genotypes.

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Results

Patient demographics. Ninety-two immunocompromised patients with CMV infection (61 male and 31 female subjects) were included in the study between 1998 and 2001. Demographic characteristics are shown in table 1. The mean age was 46.8 years (range, 19–77 years). Among the 92 immunocompromised patients, 64 (69.6%) were transplant recipients and 28 (30.4%) were immunocompromised patients who did not receive transplants. Among transplant recipients, 22 received kidney transplants, 26 received liver transplants, and 16 received bone marrow transplants. Among liver transplant recipients, underlying diseases included hepatitis C (in 4 patients), hepatitis B (in 5), primary sclerosing cholangitis (in 1), primary biliary cirrhosis (in 1), alcoholic liver disease (in 12), and other diseases (in 3). Among kidney transplant recipients, underlying diseases included glomerulonephritis (in 7 patients), interstitial nephropathy (in 8), polycystic disease (in 2), and other diseases (in 5). Among bone marrow transplant recipients, underlying diseases included acute lymphoblastic leukemia (in 4 patients), acute myeloid leukemia (in 4), chronic myeloid leukemia (in 3), myelodysplastic syndrome (in 1), and other diseases (in 4). Among 28 immunocompromised patients who did not receive transplants, underlying diseases included lymphoma (in 12 patients), leukemia (in 13), and other diseases (in 3). Transplant recipients were treated with an immunosuppressive regimen, and patients with graft rejections were treated as described elsewhere [23].

Figure 1
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Figure 1

Cytomegalovirus (CMV) glycoprotein B (gB) genotype and CMV load, as measured by real-time PCR, in plasma samples obtained from immunocompromised patients.

Table 1
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Table 1

Demographic and clinical characteristics of 92 immunocompromised patients with cytomegalovirus (CMV) infection.

CMV gB genotype in biological samples. DNA extracted from 97 CMV isolates was successfully amplified with use of PCR. The CMV gB genotype distribution of the isolates was as follows: gB1, 28 (28.9%) of 97; gB2, 19 (19.6%); gB3, 23 (23.7%); and gB4, 2 (2.0%) (table 2). The remaining samples (25 [25.8%] of 97) had a combination of ⩾2 different CMV gB genotypes. Twenty-one of these samples (21.6% of 97) had 2 distinct gB genotypes; 2 (2.0%) were gB1 and gB2, 3 (3.1%) were gB1 and gB3, 12 (12.4%) were gB2 and gB3, and 4 (4.1%) were gB2 and gB4. Among the remaining samples, 3 (3.1%) had 3 distinct genotypes (gB1, gB2, and gB3), and 1 (1.0%) had 4 distinct genotypes (gB1, gB2, gB3, and gB4). Six isolates were chosen for sequencing to confirm the restriction results. The results confirmed the restriction patterns of types 1, 2, 3, and 4. The 4 genotypes could be found in several biological samples, including samples of plasma, whole blood, leukocytes, urine, and bronchoalveolar lavage fluid (table 2). In contrast to infection with a single gB genotype, mixed infections were detected more often in samples of whole blood (11 [34.4%] of 32 samples) than in plasma samples (5 [15.6%]) (P < .05). The detection of mixed infection with 3 or 4 distinct genotypes was observed mostly in samples of purified leukocytes (3 [75%] of 4 samples), rather than in samples of plasma, whole blood, or urine. A mixed infection composed of the 4 genotypes was observed only once, and it was isolated from a samples of purified leukocytes.

Table 2
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Table 2

Distribution of cytomegalovirus (CMV) glycoprotein B (gB) genotypes isolated from 97 biological samples obtained from immunocompromised patients.

CMV gB genotype and virus load. CMV load was compared in patients with different CMV gB genotypes. We measured the CMV load using 2 distinct methods—a semiquantitative method and a quantitative method based on real-time PCR (figure 1 and table 3). Using the quantitative PCR (figure 1), the mean value of CMV load for each genotype was as follows: gB1, 931 copies/mL (range, <100–4896 copies/mL); gB2, 882 copies/mL (range, <100–6689 copies/mL); gB3, 4193 copies/mL (range, <100–55,776 copies/mL); and gB4, 239 copies/mL (only 1 sample) (P, not significant). Altogether, the mean value of peak virus load for single gB genotype infection was 1965 copies/mL (range, <100–55,776 copies/mL) and for mixed infection, 15,370 copies/mL (range, <100–112,937 copies/mL; P < .05 for differences between groups). In addition, we performed a semiquantitative PCR that allowed us to quantify virus load from 0.5+ to 4+ (table 3). When the semiquantitative PCR assay was used, no significant difference in the virus load was observed between patients infected with a single genotype gB1 (1.42+), gB2 (0.95+), gB3 (1.19+), or gB4 (2.12+) (P value, not significant). By contrast, higher virus loads were measured in patients infected with 2 genotypes (1.42+), compared with patients infected with a single genotype (1.23+) (P < .05).

Table 3
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Table 3

Cytomegalovirus (CMV) glycoprotein B (gB) genotype and CMV load in 123 plasma samples obtained from immunocompromised patients.

CMV gB genotype and clinical manifestations. CMV disease occurred in 74 (80.4%) of 92 immunocompromised patients (table 4). CMV disease manifested as CMV hepatitis, CMV gastrointestinal disease, CMV viral syndrome, and CMV pneumonitis. In transplant recipients, the risk of progressing to CMV disease was 62.5% (5 of 8) for patients with gB 1, 72.7% (8 of 11) for patients with gB2, 64.3% (9 of 14) for patients with gB3, and 100% (1 of 1) for patients with gB4. Thus, the risk of progression to CMV disease was 67.6% (23 of 34) among patients with infection with a single gB genotype, and it was 93.3% (28 of 30) for patients with mixed infections. Therefore, the risk of progression to CMV disease was significantly higher in patients with mixed infection than in patients infected with a single gB genotype (P < .05).

Table 4
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Table 4

Clinical features and cytomegalovirus (CMV) glycoprotein B (gB) genotypes in 92 immunocompromised patients.

Acute graft rejection occurred in 49 (76.6%) of 64 patients. The rates of rejection in each CMV gB group were as follows: for gB1, 3 (37.5%) of 8 patients; for gB2, 9 (81.8%) of 11 patients; for gB3, 8 (57.1%) of 14 patients; and for gB4, 1 (100%) of 1 patient. Thus, the rate of acute graft rejection was 61.8% (21 of 34) for patients infected with a single gB genotype and was 93.3% (28 of 30) for patients with mixed infections (table 4). There was no statistically significant difference between the rates of graft rejection in patients infected with the different CMV gB genotypes. By contrast, the rate of graft rejection in patients with mixed gB infection was significantly higher than in patients infected with a single gB genotype (P < .05). In immunocompromised patients who did not receive a transplant, the risk of progression to CMV disease was 78.3% (18 of 23) in patients infected with a single gB genotype, compared with 100% (5 of 5) in patients with mixed infections (P < .05).

CMV gB genotype and other viral infections. Among the 92 patients tested for gB genotype, we observed that 20 were coinfected with EBV. Among patients coinfected with EBV and CMV, 7 (35%) of 20 were infected with a single gB genotype, and 13 (65%) of 20 had mixed CMV gB infection (table 5) (P < .05). Among the 92 immunocompromised patients, 4 had CMV/HSV coinfections—2 of these 4 patients had mixed gB infections with 3 distinct genotypes (gB1, gB2, and gB3 in one patient and gB2, gB3, and gB4 in the other). We also detected either BK virus or adenovirus in 2 patients with mixed CMV infection (table 5).

Table 5
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Table 5

Virological and clinical features of mixed cytomegalovirus (CMV) infections in 35 immunocompromised patients.

CMV gB genotype and primary infection/reactivation. Regardless of whether patients had CMV primary infection or reactivation, we did not observe a significant difference in the distribution of gB genotypes (table 5; data not shown). The rate of mixed gB infection was not significantly different in patients with primary CMV infection than in those with CMV reactivation (table 5).

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Discussion

Our results show that, in contrast to infection with a single gB CMV genotype, infection with multiple gB genotypes in immunocompromised patients is associated with a higher virus load, a higher prevalence of CMV disease, and a higher rate of graft rejection. We also found that mixed gB infections in immunocompromised patients are often concomitant to infection with other herpesviruses.

In agreement with previous reports [13, 24, 25], we found that CMV infection with genotypes gB1, gB2, and gB3 was relatively common and occurred in similar proportions (28.9%, 19.6%, and 23.7% of subjects, respectively) and that infection with genotype gB4 was uncommon (occurring in 2.0% of subjects). Although some of these studies found a greater predominance of genotype gB1 than we did, differences in genotype frequencies may, in part, be due to variation in the geographical distribution of the CMV genotypes [26]. In agreement with previous reports [27], we did not observe a significant difference among gB genotypes with regard to the development of symptomatic disease, acute graft rejection, or CMV load. Other recent studies in kidney or liver transplant recipients have not observed a significant correlation between the different gB genotypes and acute graft rejection [28, 29]. By contrast, studies in other groups of immunocompromised hosts have yielded more-conflicting results [30], and a study by Rosen et al. [25] of 53 liver transplant recipients found that infection with genotype gB1 correlated with a higher mean number of acute graft rejection episodes, although no correlation with rejection severity or the development of chronic graft rejection was seen.

We observed that infection with mixed genotypes was not uncommon. A prospective analysis of CMV gB genotypes conducted in renal transplant recipients indicated that up to 70% of patients were infected with >1 gB genotype during follow-up [28]. A study by Sarcinella et al. [29] indicates that liver transplant recipients infected with multiple CMV gB genotypes developed progression to CMV disease. In agreement with this latter observation, our data indicate that, among the patients with mixed infection, 94% developed CMV disease (P < .05, vs. infection with a single gB genotype) [31]. It is interesting to note that patients infected with multiple genotypes appeared to be more heavily immunosuppressed than were other patients in the cohort, especially as a result of treatment with antilymphocyte globulins, which suggests a potential role of immunodeficiency in the appearance of CMV infections with multiple genotypes [32]. Recently, a study of solid-organ transplant recipients with CMV disease and a high prevalence of multiple-genotype infection indicated that CMV gB genotype did not significantly influence CMV-load kinetics or clinical response to therapy [27]. According to the results of our study, routine testing for multiple genotypes should be performed and preemptive treatment indicated if multiple genotypes are detected.

The immunoreactivation of EBV due to CMV infection has been reported in patients receiving immunosuppressive therapy after organ transplantation [2–4]. In agreement with these data, we observed a high prevalence of EBV/CMV coinfection and, to a lesser extent, of HSV/CMV coinfection in immunocompromised patients infected with multiple gB genotypes. A high level of immunosuppression might account for the appearance of a higher rate of both infection with multiple CMV gB genotypes and herpesvirus infection.

Previous studies in immunocompromised patients found that the prevalence of gB genotypes differed if samples were obtained from different tissues [33]. Our results indicate the presence of all 4 gB genotypes in leukocytes isolated from 1 patient. Also, we simultaneously detected a high number of distinct gB genotypes in purified leukocytes but not in whole blood or plasma samples. Therefore, we hypothesize that leukocytes might allow a switch from one genotype to another during the progression of the disease. In agreement with this hypothesis, leukocytes are one of the major CMV reservoirs [34].

Our results provide evidence that, in immunocompromised patients, severe clinical manifestations occur mostly in patients infected with multiple CMV gB genotypes. Further studies will be necessary to specify the exact role of CMV gB genotypes in virulence and tissue tropism and might ultimately shed light on the relevance of gB to the development of CMV-associated disease.

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Acknowledgments

We thank A. Vacheret for technical assistance.

Financial support. DiaSorin provided reagents.

Conflict of interest. All authors: No conflict.

  • Received December 19, 2003.
  • Accepted January 25, 2004.
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  1. Clin Infect Dis. (2004) 39 (2): 155-161. doi: 10.1086/421496
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