CMV is Implicated in Leukemia

CMV and B-Cell Leukemia

High rate of monoclonal gammopathy among immunocompetent subjects with primary cytomegalovirus infection. S Buhler, K Laitinen, H Holthofer, A Jarvinen, KO Schauman, K Hedman. Clin Infect Dis 2002 Dec 1;35(11):1430-1433. "Several immunocompetent patients with CMV infection but none with EBV infection presented with an M component, which implies that the M component connects CMV infection to a risk of B cell malignancy."

Qualitative and quantitative analysis of human herpesviruses in chronic and acute B cell lymphocytic leukemia and in multiple myeloma. S Hermouet, CA Sutton, TM Rose, RJ Greenblatt, I Corre, R Garand, AM Neves, R Bataille, JW Casey. Leukemia 2003 Jan;17(1):185-195. Patients with B-CLL, B-ALL or AML had higher rates of HHV-8 and HHV-6A infection. Adult B-ALL patients had high cell-associated CMV loads, and the rates of CMV positivity in child B-ALL patients were particularly high (>75%).

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors. E Kostareli, A Hadzidimitriou, N Stavroyianni, N Darzentas, A Athanasiadou, M Gounari, V Bikos, A Agathagelidis, T Touloumenidou, I Zorbas, A Kouvatsi, N Laoutaris, A Fassas, A Anagnostopoulos, C Belessi, K Stamatopoulos. Leukemia 2009 May;23(5):919-924. "The study group included 93 CLL cases with an intentional bias for the IGHV4-34 gene. On the basis of real-time PCR results for CMV/EBV DNA, cases were assigned to three groups: (1) double-negative (59/93); (2) single-positive (CMV- or EBV-positive; 25/93); (3) double-positive (9/93). The double-negative group was characterized by heterogeneous IGHV gene repertoire. In contrast, a bias for the IGHV4-34 gene was observed in the single-positive group (9/25 cases; 36%). Remarkably, all nine double-positive cases utilized the IGHV4-34 gene; seven of nine cases expressed the major BCR stereotype as described above. In conclusion, our findings indicate that the interactions of CLL progenitor cells expressing distinctive IGHV4-34 BCRs with viral antigens/superantigens might facilitate clonal expansion and, eventually, leukemic transformation."

Relative seroprevalence of human herpes viruses in patients with chronic lymphocytic leukaemia. C Steininger, LZ Rassenti, K Vanura, K Eigenberger, U Jäger, TJ Kipps, C Mannhalter, S Stilgenbauer, T Popow-Kraupp. Eur J Clin Invest 2009 Jun;39(6):497-506. 100 European CLL patients (cohort 1), 100 North American CLL patients (cohort 2), and 100 matched controls. In cohort 1, "CMV-seroprevalence was significantly higher in CLL cohort 1 (79%) than in the control cohort (57%, P = 0.001); the seroprevalence of EBV (89% vs. 94%), HHV-6 (73% vs. 60%), or HHV-7 (35% vs. 35%) was not.... "In cohort 2, CMV-seroprevalence was comparable with that of the control cohort (53%). Seroprevalence of EBV, HHV-6 and HHV-7 were 85%, 88% and 73% respectively."

Patients with B cell chronic lymphocytic leukaemia have an expanded population of CD4(+) perforin expressing T cells enriched for human cytomegalovirus specificity and an effector-memory phenotype. JA Walton, PM Lydyard, A Nathwani, V Emery, A Akbar, MJ Glennie, N Porakishvili. Br J Haematol 2010 Jan;148(2):274-284. 36 B-CLL patients and 20 controls. "CD4(+)PF(+)T cell expansion in B-CLL patients and controls was strongly associated with HCMV seropositivity.... CD4(+)PF(+)T cells from B-CLL patients had shorter telomeres than CD4(+)PF(-)T cells, indicating an extensive replicative history."

The number of cytomegalovirus-specific CD4+ T cells is markedly expanded in patients with B-cell chronic lymphocytic leukemia and determines the total CD4+ T-cell repertoire. B Pourgheysari, R Bruton, H Parry, L Billingham, C Fegan, J Murray, P Moss. Blood 2010 Oct 21;116(16):2968-2974. 45 patients and 35 controls. CMV-specific CD4(+) T-cell response "was markedly expanded in the patient group, averaging 11% of the CD4(+) pool compared with 4.7% in controls. The magnitude of the CMV-specific CD4(+) immune response increased with disease stage and was particularly high in patients who received chemotherapy. Within this group, the CMV-specific response comprised over 46% of the CD4(+) T-cell repertoire in some patients. Serial analysis revealed that CMV-specific immunity increased during treatment with chemotherapy and remained stable thereafter. CMV-seropositive patients exhibited a markedly altered CD4(+) T-cell repertoire with increased numbers of CD45R0(+) T cells and a reduction in CD27, CD28, and CCR7 expression."

CMV and Mycosis Fungoides and Sezary Syndrome

Cytomegalovirus seropositivity is significantly associated with Mycosis Fungoides and Sezary Syndrome. KL Herne, R Talpur, J Breuer-McHam, R Champlin, M Duvic. Blood 2003 Mar 15;101(6):2132-2136. 116 biopsy-proven MF/SS patients compared with health bone marrow donor controls. "By stage, 98.1% of early stage MF patients (IA, IB, IIA) (52/53) and 96.8% of late stage MF and SS patients (IIB-IVB) (61/63) were seropositive in contrast to healthy bone marrow donors whose seropositivity rate was 57.3% (757/1,322). Because the rate of CMV seropositivity increases with age, a subset of cutaneous T-cell lymphoma (CTCL) patients 55 years or younger were compared to age-matched healthy donor controls; their seropositivity rate for CMV was also significantly higher (ײ _{.05 05(df=1)} = 20.4)."

Full clinical recovery after topical acyclovir treatment of Epstein-Barr virus associated cutaneous B-cell lymphoma in patient with mycosis fungoides. MS Copur, A Deshpande, K Mleczko, M Norvell, GJ Hrnicek, S Woodward, S Frankforter, N Mandolfo, K Fu, WC Chan. Croat Med J 2005 Jun;46(3):458-462. The patient's EBV-related B-cell disease was cured, but she later died of mycosis fungoides.

CMV and Chromosome Aberrations

Induction of chromosome aberrations and mitotic arrest by cytomegalovirus in human cells. S AbuBakar, WW Au, MS Legator, T Albrecht. Environ Mol Mutagen 1988;12(4):409-420. Mostly chromatid breaks and chromosome pulverizations were observed [discussed by Fortunato et al.].

Cytomegalovirus-enhanced induction of chromosome aberrations in human peripheral blood lymphocytes treated with potent genotoxic agents. CZ Deng, S AbuBakar, MP Fons, I Boldogh, J Hokanson, WW Au, T Albrecht. Environ Mol Mutagen 1992;19(4):304-310. More chromosome aberrations were found in CMV-infected cells treated with bleomycin or hydroxyaminoquinoline-1-oxide, but not with 4-nitroquinoline-1-oxide.

Specific chromosome 1 breaks induced by human cytomegalovirus. EA Fortunato, ML Dell'Aquila, DH Spector. Proc Natl Acad Sci 2000 Jan 18;97(2):853-858. "Unlike infection on release from G0, human fibroblasts infected in S-phase are refractory to viral protein expression. The majority of the S-phase-infected cells move through mitosis and by 24 h pi (hpi) are back in G1, where viral gene expression can then initiate. If DNA damage occurred in this cycling population, the cells could divide before virus replication, resulting in one of the daughter cells being free of viral genomes. This daughter cell could be a reservoir for genetic damage, opening up the possibility that disease syndromes might stem from this early damage rather than be because of active viral replication and cell lysis in the infected individual.... A major question for the future is: what genes lie at these breakpoints? The possible targets residing near 1q42 include: the ADPRT locus involved in DNA repair and replication; a potential tumor suppressor gene, whose deletion has been connected to the development of gliomas; the major 5S rRNA locus; and the USH2A gene. The possible targets that reside near 1q21 include: a different proposed tumor suppressor gene deleted in several primary breast tumors, the PSU1 small nuclear RNA locus, and the DFNA7 gene."

Viral induction of site-specific chromosome damage. EA Fortunato, DH Spector. Rev Med Virol 2003 Jan-Feb;13(1):21-37. "[CMV's] ability to induce specific damage in chromosome 1 at two loci, 1q21 and 1q42, was only recently revealed as the cells must be in S-phase when they are infected for the breaks to be observed. In contrast to adenovirus and HSV, HCMV induction of specific breakage requires only viral entry into the cell and not de novo protein expression."

Human cytomegalovirus UL76 induces chromosome aberrations. VK Siew, CY Duh, SK Wang. J Biomed Sci 2009 Nov 25;16:107. "[S]tably transfected cells expressing UL76 developed chromosome aberrations including micronuclei and misaligned chromosomes, lagging and bridging. In mitotic cells expressing UL76, aberrant spindles were increased compared to control cells. However, cells with supernumerary centrosomes were marginally increased in UL76-expressing cells relative to control cells. We further demonstrated that UL76-expressing cells activated the DNA damage signal gamma-H2AX and caused foci formation in nuclei. In addition, the number of cells with DNA breaks increased in proportion to UL76 protein levels."

CMV and immune function

Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. N Khan, A Hislop, N Gudgeon, M Cobbold, R Khanna, L Nayak, AB Rickinson, PA Moss. J Immunol 2004;173(12):7481-7489. "Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status. The functional activity of the herpesvirus-specific immune response decreases in elderly donors, although the characteristic phenotypes of CMV- and EBV-specific memory populations are retained. This demonstrates that aging is associated with a marked accumulation of CMV-specific CD8 T cells together with a decrease in immediate effector function. Moreover, infection with CMV can reduce prevailing levels of immunity to EBV, another persistent virus. These results suggest that carriage of CMV may be detrimental to the immunocompetent host by suppressing heterologous virus-specific immunity during aging."

Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. JM Fletcher, M Vukmanovic-Stejic, PJ Dunne, KE Birch, JE Cook, SE Jackson, M Salmon, MH Rustin, AN Akbar. J Immunol 2005 Dec 15;175(12):8218-8225. "We found that CMV-specific CD4+ T cells were significantly expanded in healthy young and old carriers compared with purified protein derivative-, varicella zoster virus-, EBV-, and HSV-specific populations. These CMV-specific CD4+ T cells exhibited a late differentiated phenotype since they were largely CD27 and CD28 negative and had shorter telomeres. Interestingly, in elderly CMV-seropositive subjects, CD4+ T cells of different specificities were significantly more differentiated than the same cells in CMV-seronegative individuals.... The CMV-specific CD4+ T cells in elderly subjects had severely restricted replicative capacity." "[R]ecent longitudinal studies have defined an immune risk phenotype (IRP) that is predictive of significantly decreased 2- and 4-year survival of patients above the age of 80 years. The IRP is comprised of a cluster of immune parameters, including CMV seropositivity, a CD4:CD8 T cell ratio of <1, increased proportions of highly differentiated CD8+CD28– T cells, the presence of CD8+ T cell clonal expansions, and elevated serum levels of proinflammatory cytokines. Recent studies have shown that the majority of highly differentiated oligoclonal CD8+ T cell populations that are found in elderly individuals are specific for CMV. Thus, CMV may have a more insidious effect on the immune system than previously appreciated." "Although the absolute numbers of CD4+ T cells in young and old subjects were not significantly different from each other (data not shown), the frequency of CMV-specific CD4+ T cells was significantly greater than that of the other Ags within each age group (p values indicated in Fig. 1, C and D). Furthermore, there was a significant accumulation of CMV-specific CD4+ T cells (p = 0.02) and a decrease in the frequency of VZV-specific CD4 T cells (p = 0.02) in the old compared with the young groups." "We made the unexpected observation that in elderly individuals, their CMV status had a profound impact on the differentiation state of non-CMV- specific populations of CD4+ T cells (Fig. 2D). In CMV-seropositive elderly subjects, the PPD (p < 0.005)-, VZV (p < 0.016)-, EBV (p < 0.016)-, and HSV-specific (p < 0.05) T cells were more differentiated on the basis of loss of CD27 and CD28 costimulatory molecules than the same populations in elderly individuals who were CMV seronegative (Fig. 2D). A similar trend was observed in young subjects but was not as marked as in the elderly group (Fig. 2C). These results indicate that CMV infection appeared to have a nonspecific effect on the rate of differentiation of other Ag-specific CD4+ T cells."

Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. SR Hadrup, J Strindhall, T Køllgaard, T Seremet, B Johansson, G Pawelec, P thor Straten, A Wikby. J Immunol 2006 Feb 15;176(4):2645-2653. "An increased number of CD8 T cell clones was observed in the nonagenarians, and was associated with CMV-seropositivity. Surprisingly, CMV-seropositive nonagenarians with the IRP [immune risk phenotype] had a significantly lower number of clones compared with non-IRP individuals. The decrease in clone numbers in IRP individuals was associated with shorter survival time. MHC/peptide multimer staining indicated that the frequency of CMV-specific T cells was higher in nonagenarians than in the middle-aged, but the ratio of functionally intact cells was significantly lower. The lowest ratio of functional CMV-specific T cells was found in an IRP individual."

Human cytomegalovirus subverts the functions of monocytes, impairing chemokine-mediated migration and leukocyte recruitment. G Frascaroli, S Varani, B Moepps, C Sinzger, MP Landini, T Mertens. J Virology 2006 Aug;80(15):7578-7589. Endothelial and fibroblast cells infected by endotheliotropic strains of HCMV efficiently recruited leukocytes, while infected monocytes were unable to recruit lymphocytes, monocytes, and neutrophils.

Cytomegalovirus infection in Gambian infants leads to profound CD8 T-cell differentiation. DJ Miles, M van der Sande, D Jeffries, S Kaye, J Ismaili, O Ojuola, M Sanneh, ES Touray, P Waight, S Rowland-Jones, H Whittle, A Marchant. J Virol 2007 Jun;81(11):5766-5776. "Cytomegalovirus (CMV) infection is endemic in Gambian infants, with 62% infected by 3 months and 85% by 12 months of age.... At 12 months of age, the CD8 T-cell population of CMV-infected infants was more differentiated than that of uninfected infants. Although the subpopulation of CMV-specific cells remained constant, the CMV peptide-specific gamma interferon response was lower in younger infants and increased with age. As the CD8 T-cell phenotype induced by CMV is indicative of immune dysfunction in the elderly, the existence of a similar phenotype in large numbers of Gambian infants raises the question of whether CMV induces a similarly deleterious effect."

The CMV-specific CD4+ T cell response expands with age and markedly alters the CD4+ T cell repertoire. B Pourgheysari, N Khan, D Best, R Bruton, L Nayak, PA Moss. Journal of Virology 2007 July;81(14):7759-7765. "Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8+ T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4+ T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4+ T-cell immune response increases from a mean of 2.2% of the CD4+ T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4+ T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4+ T-cell repertoire in healthy aged donors, including an increase in CD57+ expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4+ T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals."

The association between cytomegalovirus infection and aging process. V Kanapeckiene, J Kalibatas, E Redaitiene, J Ceremnych. Medicina (Kaunas) 2007;43(5):419-424. "146 healthy elderly women aged 60-90 years were divided into three groups: Group 1--slow aging group (37 women, 25.4%); Group 2--physiological aging group (58 women, 39.7%); Group 3--premature aging group (51 women, 34.9%). Immune response to cytomegalovirus was studied using methods of enzyme immunoassay and indirect immunofluorescence. RESULTS: Comparing immune response to cytomegalovirus in different aging groups, highest titres of both IgG antibodies against early antigens and IgA antibodies against late structural antigens were found in premature aging group. Results showed that premature aging was associated with an increased level of IgA antibodies characteristic for cytomegalovirus symptomatic infection and its frequent reactivations."

Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation. KM Hertoghs, PD Moerland, A van Stijn, EB Remmerswaal, SL Yong, PJ van de Berg, SM van Ham, F Baas, IJ Ten Berge, RA van Lier. J Clin Invest 2010 Oct 1. pii: 42758. doi: 10.1172/JCI42758. [Epub ahead of print]. "HCMV infection induced acute and lasting changes in the transcriptomes of virus-reactive T cells collected from HCMV-seropositive patients at distinct stages of infection. Enhanced cell cycle and metabolic activity was restricted to the acute phase of the response, but at all stages, HCMV-specific CD8+ T cells expressed the Th1-associated transcription factors T-bet (TBX21) and eomesodermin (EOMES), in parallel with continuous expression of IFNG mRNA and IFN-γ-regulated genes. The cytolytic proteins granzyme B and perforin as well as the fractalkine-binding chemokine receptor CX3CR1 were found in virus-reactive cells throughout the response. During HCMV latency, virus-specific CD8+ T cells lacked the typical features of exhausted cells found in other chronic infections. Persistent effector cell traits together with the permanent changes in chemokine receptor usage of virus-specific, nonexhausted, long-lived CD8+ T cells may be crucial to maintain lifelong protection from HCMV reactivation."

CMV & social class

The prevalence of CMV infection varies with social class: "In developed countries, 10% to 15% of children are infected with CMV by early adolescence; this varies by socioeconomic class, with greater seroprevalence correlating with lower income and homosexual adolescents and men. From late adolescence to adulthood, seroprevalence of CMV in the United States increases from 15% to 50%." (From: Treatment of cytomegalovirus (CMV) retinitis in the era of highly active anti-retroviral therapy. DF Martin. Medscape HIV/AIDS Clinical Management 1999 Aug 30;4.)

See Also:

cast 10-23-10