Longitudinal Analysis of Levels of Immunoglobulins against BK Virus Capsid Proteins in Kidney Transplant Recipients

Randhawa, Parmjeet; Bohl, Daniel L.; Brennan, Daniel C.; Ruppert, Kristine; Ramaswami, Bala; Storch, Gregory A.; March, John B.; Shapiro, Ron; Viscidi, Raphael P.

doi:10.1128/cvi.00206-08

Cited by 48 publications

(47 citation statements)

References 46 publications

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“…In summary, our study emphasizes the BKVLP responses as being the most sensitive and an early serologic marker of BKV exposure compared to HIA, BKVP1, and BKVLT responses. This was true before and after transplantation and thereby extends the work of recently published studies (9,43). Importantly, increases in anti-BKVLP responses in KTP develop during ongoing BKV viruria and viremia occurring before changes in immunosuppression and do not correlate with the curtailing of BKV replication or significant immune control as discussed previously (15).…”

Section: Discussionsupporting

confidence: 65%

“…Since these patients potentially proceed to kidney transplantation, knowledge of the serostatus as a marker of BKV-specific immune memory may prove to be important to correctly identify patients at higher risk for BKV replication and nephropathy posttransplantation. We note that there are hardly any studies of young KTP that investigate viruria and viremia together with BKV-specific antibody responses with a longer follow-up of 24 months; instead, most studies are almost exclusively of adult KTP (9,12,26,43). In summary, our study emphasizes the BKVLP responses as being the most sensitive and an early serologic marker of BKV exposure compared to HIA, BKVP1, and BKVLT responses.…”

Section: Discussionmentioning

confidence: 74%

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Antibody Responses to Recombinant Polyomavirus BK Large T and VP1 Proteins in Young Kidney Transplant Patients

et al. 2009

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BK virus (BKV)-specific immunity is critical for polyomavirus-associated nephropathy, but antibody responses are incompletely defined. We compared the hemagglutination inhibition assay (HIA) with immunoglobulin G enzyme immunoassays (EIA) to BKV proteins expressed in baculovirus-infected insect cells. N-terminal, internal, and C-terminal domains of the BKV large T antigen (BKLT) were fused to glutathione S-transferase (GST), yielding GST-BKLTD1, GST-BKLTD2, and GST-BKLTD3, respectively. The BKV capsid VP1 was expressed as a GST fusion (BKVP1) or as a native VP1 assembled into viruslike particles (BKVLP). We tested 422 sera from 28 healthy donors (HD), 99 dialysis patients (DP; median age, 15 years; range, 3 to 32 years), and 46 age-matched kidney transplant patients (KTP; median age, 15 years; range, 2 to 33 years). In HD, HIA and BKVLP EIA both yielded a 91.7% seroreactivity, whereas all other EIA responses were lower (BKVP1, 83.3%; BKLTD1, 25%; BKLTD2, 29%; BKLTD3, 40%). HIA titers significantly correlated with EIA levels for BKVLP, BKVP1, and BKLTD1 but not for BKLTD2 or BKLTD3, which were barely above the cutoff. In DP, the seroreactivities of HIA, BKVLP, and BKLTD1 were lower than that in HD (63.6%, 86.9%, and 10.1%, respectively) and they had lower titers (P < 0.001). In KTP, seropositivities for BKVLP, BKVP1, and BKLTD1 were 78%, 50%, and 17%, respectively, but anti-BKVLP levels increased significantly in KTP with viruria and viremia, whereas anti-BKLTD1 levels increased after clearing sustained BKV viremia. In conclusion, anti-BKVLP is equivalent to HIA in HD but is more sensitive to determine the BKV serostatus in DP and KTP. In KTP, anti-BKVLP responds to recent BKV viruria and viremia, whereas anti-BKLTD1 may indicate emerging BKV-specific immune control.Polyomaviruses (PyV) have been identified in many vertebrates; the main species found in humans are BK virus (BKV) and JC virus (C. Büchen-Osmond, Polyomaviridae, International Committee on Taxonomy of Viruses Database [www .ncbi.nlm.nih.gov/ICTVdb/]). PyV are small nonenveloped double-stranded DNA viruses with icosahedral particles of ϳ42 nm in diameter and are resistant to environmental inactivation (8, 31, 32; www.ncbi.nlm.nih.gov/ICTVdb/). The genome organization of the 5.1-kb circular genome is largely conserved and encodes six major proteins (20, 31, 32). The nuclear large tumor (LT) antigen and cytoplasmic small T antigen are expressed early in the viral life cycle, followed by the late cytoplasmic agnoprotein and the capsid proteins VP1, VP2, and VP3, which are transported into the nucleus for virion assembly (31,32,44). LT is a multifunctional regulatory protein with distinct domains (45,49). PyV capsids are formed by the assembly of 72 VP1 pentamers into a Tϭ7d icosahedral lattice associating with VP2 and VP3 and the circular viral genome (11,35,39).Seroprevalence data indicate that 50 to 90% of the general population has been exposed to BKV and JC virus (25,33,47).Both viruses persist in the renourinary tract as the principal site of latenc...

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 74%

Antibody Responses to Recombinant Polyomavirus BK Large T and VP1 Proteins in Young Kidney Transplant Patients

et al. 2009

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“…At the start of the study, 16 RTRs were BKV-seronegative, and 14 of them seroconverted during the following year. Seventeen of the 91 RTRs who were seropositive at baseline seroreverted (Randhawa et al, 2008). These patients showed large changes in seroprevalence and serostability over time, possibly due to disease or their immunosuppressive therapy after transplantation.…”

Section: Discussionmentioning

confidence: 98%

“…To our knowledge, there are only two longitudinal serological studies on BKV and JCV, one in immunosuppressed patients (Randhawa et al, 2008) and the other in pregnant women (the Finnish Maternity Study; Stolt et al, 2003). Randhawa et al (2008) investigated BKV antibodies in samples from 107 renal transplant recipients (RTRs) over a 1 year period with Table 2. Serostability for BKV and JCV in samples collected at three time points over 4.5 years (1992,1993,1996: n5458) VLP-based ELISA.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and stability of antibodies to the BK and JC polyomaviruses: a long-term longitudinal study of Australians

Antonsson

Green

Mallitt

et al. 2010

Journal of General Virology

128

106

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Serology has been used to indicate past infection by the human polyomaviruses BK virus (BKV) and JC virus (JCV), because the site of primary infection is not established fully. Little is known about BKV and JCV antibody stability over time. We investigated BKV and JCV seroprevalence and antibody stability over time in an Australian population-based study. Serum was collected from 458 adults participating in a longitudinal skin cancer study in Queensland in 1992, 1993 and 1996, and 117 people had a fourth sample collected in 2003. Serum samples were analysed for BKV and JCV VP1 antibodies by multiplex detection using the Luminex platform. The seroprevalence for BKV and JCV over 4.5 years was 97 and 63 %, respectively. The BKV seroprevalence was 99 % in 25-60-year-olds, and 94 % in people older than 60 years. JCV seroprevalence was around 60 % in people younger than 50 years, 68 % in people 50-70 years of age and 64 % in people older than 70 years. BKV seroprevalence was very stable over 11 years, with 96 % of people staying seropositive and 2 % remaining seronegative. JCV antibody status over time was less stable; 57 % of participants remained seropositive and 31 % seronegative. The same proportion of people (4 % each) seroconverted, seroreverted or had fluctuating JCV antibody levels. These results confirm the previously believed stability of polyomavirus antibodies, with BKV antibodies being highly stable and JCV antibodies moderately so. Thus, a single measure can be used as a reasonable indicator of long-term antibody status in epidemiological studies aiming to understand associations between polyomaviruses and disease.

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“…The inverse relationship between recipient BK antibody titer and JC viruria, however, points to humoral cross-protection. Although these anti-BK antibodies cannot clear well-established BK infections with high copy numbers, 16,18 they may play a prophylactic role against subsequent JC infection with low copy numbers. Our finding parallels the observation that, in immunocompetent individuals, JC viruria was more prevalent in subjects seropositive for only JC viruria compared with subjects seropositive for both JC viruria and BK viruria.…”

mentioning

confidence: 99%

Inhibitory Interactions between BK and JC Virus among Kidney Transplant Recipients

Cheng¹,

Bohl²,

Storch³

et al. 2011

Journal of the American Society of Nephrology

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The human polyomaviruses, JC and BK, cause asymptomatic childhood infections and then persist in various sites including the uroepithelium. 1 Reactivation in the renal-urinary system manifests as viruria. 1,2 In healthy Swiss blood donors, viruria rates were 7 and 19% for BK and JC virus, respectively. 2 After renal transplantation, the incidence of viruria for each virus increases to 58%. [3][4][5][6][7] BK is the major etiologic agent of polyomavirus-associated nephritis occurring in up to 10% of renal transplant recipients (RTRs). 8 -10 JC nephropathy, in contrast, is rare and comparatively benign. 8 -10 Most studies report that urinary co-activation of both viruses in non-RTRs is unusual. 2,7,[11][12][13] However, large prospective studies examining the interaction of JC and BK reactivation and serology in RTRs are lacking. Our study determined the incidence of JC viruria and viremia in prospectively collected urine and blood samples from 200 RTRs initially tested for BKV; 8 were lost to follow-up and excluded. 14 -17 We also explored the interactions of JC and BK serology on the incidence of JC and BK infection.JC viruria was detected in 30 (16%) recipients. Twelve were anuric at the time of transplant, and no pretransplant urine sample was available. The first post-transplant urine samples were collected at 6 to 18 days after transplant; six of these first samples already contained detectable JC DNA but no BK DNA. Of the recipients who developed JC viruria, 16 (53%) were viruric within 1 week, 9 (30%) at between week 1 and 1 month, and 5 (17%) at Ͼ1 month after transplantation. The median time to onset of JC viruria was 11 days. No recipient developed JC viremia, and no JC-polyomavirus associated nephropathy was detected. The median JC viruria viral load was 6.39 log 10 copies/ml (range 3 to 8.83 log 10 copies/ml) compared with the median BK viruria viral load of 8.98 log 10 copies/ml determined previ- ABSTRACTBK and JC polyomaviruses can reactivate after transplantation, causing renal dysfunction and graft loss. The incidence of JC reactivation after renal transplant is not well understood. Here, we characterized JC reactivation using samples collected during the first year after transplantation from 200 kidney recipients. We detected BK and JC viruses in the urine of 35 and 16% of transplant recipients, respectively. The median viral load in the urine was 400 times higher for BK virus than JC virus. The presence of BK viruria made concurrent JC viruria less likely: JC viruria was detected in 22% of non-BK viruric recipients compared with 4% of BK viruric recipients (P ϭ 0.001). The codetection rate was 1.5%, which is less than the expected 5.6% if reactivation of each virus was independent (P ϭ 0.001). We did not observe JC viremia, JC nephropathy, or progressive multifocal leukoencephalopathy. The onset of JC viruria was associated with donor, but not recipient, JC-specific antibody in a titer-dependent fashion and inversely associated with donor and recipient BK-specific antibody. Donor and recipie...

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Longitudinal Analysis of Levels of Immunoglobulins against BK Virus Capsid Proteins in Kidney Transplant Recipients

Cited by 48 publications

References 46 publications

Antibody Responses to Recombinant Polyomavirus BK Large T and VP1 Proteins in Young Kidney Transplant Patients

Antibody Responses to Recombinant Polyomavirus BK Large T and VP1 Proteins in Young Kidney Transplant Patients

Prevalence and stability of antibodies to the BK and JC polyomaviruses: a long-term longitudinal study of Australians

Inhibitory Interactions between BK and JC Virus among Kidney Transplant Recipients

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