Cross-reactivity of HLA-B*1801-restricted T-lymphocyte clones with target cells expressing variants of the human cytomegalovirus 72kDa-IE1 protein.

The impact of natural polymorphism in a cytomegalovirus-dominant HLA-B(*)1801-restricted epitope, IE1(199-206), on the specific responses of T-cell clones was assessed by measuring their cytolytic activity against target cells expressing mutated recombinant IE1 proteins. Our results suggest an in vivo selection of T lymphocytes that cross-react with multiple IE1 variants.

Modulation of HLA-A*0201-restricted T cell responses by natural polymorphism in the IE1(315-324) epitope of human cytomegalovirus.

Cytotoxic T lymphocytes play a central role in the control of persistent human CMV (HCMV) infection and reactivation. In healthy virus carriers, the specific CD8(+) CTL response is almost entirely directed against the virion tegument protein pp65 and/or the 72-kDa major immediate early protein, IE1. Studies that included a large panel of HCMV(+) donors suggested that immunorelevance of pp65 and IE1 was directly related with individual HLA haplotype difference. Nevertheless, there are no data on the incidence of HCMV natural polymorphism on virus-specific CTL responses. To assess the impact of IE1 polymorphism on CTL response, we have sequenced in 103 clinical isolates the DNA region corresponding to IE1(315-324), an immunodominant epitope presented by HLA-A*0201 molecules. Seven peptidic variants were found with extensive difference in their frequencies. The response of four HLA-A*0201-restricted anti-IE1 T lymphocyte clones, which were previously generated from one donor against autologous B lymphoblastoid cells expressing a recombinant clinical variant of IE1, was then evaluated using target cells loaded with mutant synthetic peptides or expressing rIE1 variants. One of four clones, which have been sorted 19 times among 22 clones targeted against IE1(315-324), recognized six of the seven tested variant epitopes. All three other clones showed distinct reactivity patterns to target cells loaded with the different mutant peptides or expressing IE1 variants. Therefore, in the HLA-A2 context, clonal expansions of anti-IE1 memory CTLs may confer a protection against HCMV successive infections and reactivations by killing cells presenting most of the naturally occurring IE1(315-324) epitope variants.

Association of glycoprotein B and immediate early-1 genotypes with human leukocyte antigen alleles in renal transplant recipients with cytomegalovirus infection.

BACKGROUND: Numerous risk factors for cytomegalovirus (CMV) infection or disease, or both, such as serostatus of donor and recipient, immunosuppressive regimen, or intensity of viral load, have been identified in renal transplant recipients. Additional parameters may be involved, notably, genetic variability of both host and virus, which could modulate the efficacy of the immune response. METHODS: Active CMV infection was analyzed retrospectively in 634 renal transplant recipients, according to human leukocyte antigen (HLA)-A, HLA-B, and HLA-DR alleles; CMV serostatus; presentation of the disease; and variations in the coding sequences of glycoprotein (g) B and IE1 proteins. RESULTS: Active infection occurred in 141 of 634 patients: seropositivity of the donor and the recipient were identified as risk factors. Patients carrying the HLA-A11, HLA-A32, or HLA-DR11 allele developed active infection more frequently, whereas none of the patients with the HLA-B16 or HLA-B55 allele was actively infected. Significant independent associations between some genotypes and particular HLA alleles were observed: gB1 was more frequent in the HLA-A24 or HLA-B7 context and underrepresented in patients with HLA-DR11; gB2 was more frequent in HLA-A32 or HLA-DR11 carriers; and an increased frequency of gB3 was observed in the HLA-A29 context. Considering the IE1-2 genotype, increased frequency was noted for HLA-A3 carriers, whereas this type was underrepresented for patients with the HLA-DR11 allele. CONCLUSION: Data strongly suggest that differential presentation of polymorphic gB or IE peptides by HLA molecules or differential recognition by host CD8+ and CD4+ T lymphocytes, or both, should modulate immunologic response and then CMV pathogenesis in renal transplant patients.