CMV Impairs Immunity

The anti-smokers deliberately use defective studies that ignore the role of infection in order to falsely blame smoking. They cynically exploit the fact that smokers and passive smokers are more likely to have been exposed to this virus, for socioeconomic reasons.

CMV and Hospital Patients

Occult herpes family viruses may increase mortality in critically ill surgical patients. CH Cook, JK Yenchar, TO Kraner, EA Davies, RM Ferguson. Am J Surg 1998 Oct;176(4):357-360. "Twenty eligible patients had positive viral cultures during the study period, and 85% of these patients developed subsequent bacterial and/or fungal infections. Mortality was significantly higher following viral infection than in chronic SICU patients (65% vs 35%, P <0.006). Patients with thrombocytopenia complicating their viral infection had significantly higher mortality than those without thrombocytopenia (92% vs 25%, P <0.004). CONCLUSIONS: At least 14% of critically ill surgical patients have occult infection or reactivation of herpes family viruses. These viruses have known immunosuppressive effects, which may predispose chronic SICU patients to subsequent bacterial and fungal infection, and subsequent organ system failure and death."

A novel link between stress and human cytomegalovirus (HCMV) infection: sympathetic hyperactivity stimulates HCMV activation. S Prösch, CE Wendt, P Reinke, C Priemer, M Oppert, DH Krüger, HD Volk, WD Döcke. Virology 2000 Jul 5;272(2):357-365. "Here, we demonstrate that a highly stressful event in the absence of systemic inflammation, as observed in patients with acute myocardial infarction, leads to the development of an active HCMV infection in latently infected patients. Elucidating the molecular mechanism of virus activation, we could show that catecholamines directly stimulate the HCMV immediate-early (IE) enhancer/promoter in monocytic cells via beta-2 adrenergic receptors. Subsequent activation of the cAMP/PK-A-signaling pathway results in enhanced synthesis and binding of the transcription factor CREB-1/ATF-1 to the cAMP-responsive elements within the IE enhancer. Epinephrine also enhanced HCMV gene expression in infected THP-1 cells by about 50% in three of four experiments."

Human cytomegalovirus infections in nonimmunosuppressed critically ill patients. A Heininger, G Jahn, C Engel, T Notheisen, K Unertl, K Hamprecht. Crit Care Med 2001 Mar;29(3):541-547. 56 immunocompetent intensive care patients after major surgery or trauma. 20 (35.6%) experienced HCMV reactivation. "In patients with active HCMV infection, the mortality tended to be higher (55%) than in those without (36%); the duration of intensive care treatment of the survivors was significantly longer in the patients with active HCMV infection (median 30 vs. 23 days; p = .0375). Univariate testing for factors associated with active HCMV infection showed the importance of sepsis at admission (p = .011) and prolonged pretreatment on the ward or in an external ICU (p = .002); the relevance of underlying malignant disease was borderline (p = .059). Multiple regression analysis identified only sepsis to be independently associated with active HCMV infection (p = .02; odds ratio, 4.62)."

Occult herpes family viral infections are endemic in critically ill surgical patients. CH Cook, LC Martin, JK Yenchar, MC Lahm, B McGuinness, EA Davies, RM Ferguson. Crit Care Med 2003 Jul;31(7):1923-1929. "Weekly cultures for cytomegalovirus (CMV) and herpes simplex virus, viral serologies, and T-cell counts were performed. The prevalence (95% confidence interval) of positive respiratory cultures for herpes simplex or CMV was 35% (22-49%); 15% (5-25%) cultured positive for CMV, 23% (11-35%) cultured positive for herpes simplex virus, and one patient's respiratory secretions culturing positive for both CMV and herpes simplex virus. The prevalence of CMV viremia was only 5.8% (1-10%). CMV+ patients had longer hospital admissions, intensive care unit admissions, and periods of ventilator dependence than CMV- patients, despite having comparable severity of illness scores. CMV+ patients also had significantly higher numbers of blood transfusions, prevalence of steroid exposure, and prevalence of hepatic dysfunction, and all were immunoglobulin G positive at the beginning of the study."

Cytomegalovirus infection in critically ill patients: associated factors and consequences. S Jaber, G Chanques, J Borry, B Souche, R Verdier, PF Perrigault, JJ Eledjam. Chest 2005 Jan;127(1):233-241. 237 patients with fever for > 72 h, none HIV+ or transplant. CMV reactivated within 20 days in 20%. "CMV infection was linked to renal failure (58% vs 33%, respectively; p = 0.02) and steroid use (55% vs 33%, respectively; p = 0.04). Patients with CMV had a significantly longer stay in the ICU (41 +/- 28 days vs 31 +/- 22 days, respectively; p = 0.04), a longer duration of mechanical ventilation (35 +/- 27 days vs 24 +/- 20 days, respectively; p = 0.03), a higher rate of nosocomial infection (75% vs 50%, respectively; p = 0.04), and a higher mortality (50% vs 28%, p = 0.02)."

Active cytomegalovirus infection in patients with septic shock. L von Müller, A Klemm, M Weiss, M Schneider, H Suger-Wiedeck, N Durmus, W Hampl, T Mertens. Emerg Infect Dis 2006 Oct;12(10):1517-1522. Prospective study of 25 immunocompetent CMV-seropositive patients with septic shock and an intensive care unit stay of > or =7 days. "Within 2 weeks, active CMV infection with low-level pp65-antigenemia (median 3 positive/5x10(5) leukocytes) developed in 8 (32%) patients. Infection was controlled within a few weeks (median 26 days) without use of antiviral therapy. Duration of intensive care and mechanical ventilation were significantly prolonged in patients with active CMV infection. CMV reactivation was associated with concomitant herpes simplex virus reactivation (p = 0.004)."

Cytomegalovirus Reactivation in "Immunocompetent" Patients: A Call for Scientific Prophylaxis. CH Cook. J Infect Dis 2007;196(9):1273-1275. "During critical illness—and specifically sepsis—CMV is reactivated in ∼30% of these latently infected individuals, a finding that has now been reproduced independently by 4 different groups.. Because these reactivation episodes are "controlled" by the immune system, one might argue that they are of no clinical consequence. Indeed, as best as can be told, patients with reactivation do not appear to be dying of fulminant CMV disease. Nonetheless, clinical studies published to date have demonstrated surprisingly consistent morbidity in these patients. Nonimmunosuppressed critically ill patients with CMV reactivation require increased duration of mechanical ventilation, prolonged hospitalization, and may have worsened survival."

Cytomegalovirus reactivation in critically ill immunocompetent patients. AP Limaye, KA Kirby, GD Rubenfeld, WM Leisenring, EM Bulger, MJ Neff, NS Gibran, ML Huang, TK Santo Hayes, L Corey, M Boeckh. JAMA 2008 Jul 23;300(4):413-422. 120 CMV-seropositive, immunocompetent adults. "Cytomegalovirus viremia at any level occurred in 33% (39/120; 95% confidence interval [CI], 24%-41%) at a median of 12 days (range, 3-57 days) and CMV viremia greater than 1000 copies/mL occurred in 20% (24/120; 95% CI, 13%-28%) at a median of 26 days (range, 9-56 days). By logistic regression, CMV infection at any level (adjusted odds ratio [OR], 4.3; 95% CI, 1.6-11.9; P = .005) and at greater than 1000 copies/mL (adjusted OR, 13.9; 95% CI, 3.2-60; P < .001) and the average CMV area under the curve (AUC) in log(10) copies per milliliter (adjusted OR, 2.1; 95% CI, 1.3-3.2; P < .001) were independently associated with hospitalization or death by 30 days. In multivariable partial proportional odds models, both CMV 7-day moving average (OR, 5.1; 95% CI, 2.9-9.1; P < .001) and CMV AUC (OR, 3.2; 95% CI, 2.1-4.7; P < .001) were independently associated with a hospital length of stay of at least 14 days."

The role of viruses in nosocomial pneumonia. L Chiche, JM Forel, L Papazian. Curr Opin Infect Dis 2011 Apr;24(2):152-6. Review. Concerning immunocompetent hospital patients: "Patients infected with these viruses show increased morbidity and, especially for CMV, mortality. An increase of bacterial or fungal superinfections was observed in ICU patients with CMV reactivation."

Cytomegalovirus infection in severe burn patients monitoring by real-time polymerase chain reaction: A prospective study. J Bordes, J Maslin, B Prunet, E d'Aranda, G Lacroix, P Goutorbe, E Dantzer, E Meaudre. Burns 2011 May;37(3):434-439. 29 immunocompetent burn patients with total burn surface area greater than 15%. "CMV reactivation was associated with a higher IGS 2 score on admission. High grade CMV viremia was associated with longer mechanical ventilation duration, higher infection number, higher transfused red blood cell number, and longer ICU stays. There were no differences on mortality rate between patients with and without CMV reactivation."

Immune risk phenotype is associated with nosocomial lung infections in elderly in-patients. A Plonquet, S Bastuji-Garin, F Tahmasebi, C Brisacier, K Ledudal, J Farcet, E Paillaud. Immun Ageing 2011 Oct 1;8:8. 97 nosocomial infections among 252 consecutive in-patients aged 70 years or over. "The main infection sites were the respiratory tract (21%) and urinary tract (17.1%) When we compared immunological parameters including cell counts determined by flow cytometry in the groups with and without nosocomial infections, we found that the group with nosocomial infections had significantly lower values for the CD4/CD8 ratio and naive CD8 and CD4 T-cell counts and higher counts of memory CD8 T-cells with a significant increase in CD28-negative CD8-T cells. Neither cytomegalovirus status (positive in 193/246 patients) nor presence of the IRP was associated with nosocomial infections. However, nosocomial pneumonia was significantly more common among IRP-positive patients than IRP-negative patients (17/60 versus 28/180; p = 0.036)."

Viral Infections in Septic Shock (VISS-Trial)-Crosslinks Between Inflammation and Immunosuppression. T Brenner, C Rosenhagen, I Hornig, K Schmidt, C Lichtenstern, M Mieth, T Bruckner, E Martin, P Schnitzler, S Hofer, MA Weigand. J Surg Res 2011 Nov 13 [Epub ahead of print]. 60 patients with septic shock. "Thirty-one patients (51.7%) were found to be positive for HSV-1, whereas in 16 patients (26.7%) CMV could be identified. Patients with a positive PCR for HSV-1 and/or CMV showed a significantly prolonged length of hospital stay and absolute time of respirator-dependant ventilation. Furthermore, survival curves of patients with a high HSV-1-load (>10E8) in tracheal secretion in comparison with those with a lower HSV-1-load (<10E8) revealed a significantly impaired survival."

Molecular detection of microorganisms in distal airways of patients undergoing lung cancer surgery. XB D'Journo, F Bittar, D Trousse, F Gaillat, C Doddoli, H Dutau, L Papazian, D Raoult, JM Rolain, PA Thomas. Ann Thorac Surg 2012 Feb;93(2):413-422. 87 patients. All were negative for the bacterial 16s ribosomal RNA gene by PCR. "Thirteen patients (15%) had a positive CMV PCR (positive-PCR group), whereas the remaining 74 patients constituted the negative-PCR group. Postoperative pneumonia occurred in 24% of the negative-PCR group and in 69% of the positive-PCR group (p = 0.003). Upon stepwise logistic regression, performance status, percent of predicted diffusion lung capacity for carbon monoxide, and positive PCR were the risk factors of postoperative respiratory complications. The CMV PCR had a positive predictive value of 0.70 in prediction of respiratory complications."

CMV and Influenza

Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence. P Trzonkowski, J Myśliwska, E Szmit, J Wieckiewicz, K Lukaszuk, LB Brydak, M Machała, A Myśliwski. Vaccine 2003 Sep 8;21(25-26):3826-3836. "Non-responders of both ages we characterised by higher levels of anti-CMV IgG and higher percentages of CD57+CD28- lymphocytes (known to be associated with CMV carrier status) together with increased concentrations of TNFalpha and IL6 and decreased levels of cortisol."

Immunosenescence and vaccine failure in the elderly. B Grubeck-Loebenstein, S Della Bella, AM Iorio, JP Michel, G Pawelec, R Solana. Aging Clin Exp Res 2009 Jun;21(3):201-209. From a meeting of experts in immunology and gerontology in Paris, France, in April 2008. "In particular, an accumulation of late differentiated effector T cells, commonly associated with cytomegalovirus infection, contributes to a decline in the capacity of the adaptive immune system to respond to novel antigens."

CMV and Aging

Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. A Wikby, B Johansson, J Olsson, S Lofgren, BO Nilsson, F Ferguson. Exp Gerontol 2002 Jan 3;37(2-3):445-453. "Results from a previous longitudinal study, the Swedish OCTO-Immune study, indicated that the combination of higher CD8 peripheral blood lymphocytes (PBLs), decreased CD4 PBLs, and poor proliferative response to mitogenic stimulation in very old humans were associated with an increased 2 year mortality.... As in the OCTO study, the NONA-Immune data indicated that the changes are associated significantly with seropositive responses to CMV."

Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection. L Jonasson, A Tompa, A Wikby. J Intern Med 2003 Nov;254(5):472-478. 43 patients with angina and angiographically verified CAD, versus 69 clinically healthy controls. "An expansion of CD8+ T cells expressing CD57 but lacking CD28 was seen in the patient group. The numbers of CD8+ CD57+ and CD8+ CD28-T-cell subsets were independently related to CMV seropositivity (P<0.001) but also to CAD per se (P<0.05). Serum concentrations of C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were elevated in the patients but not related to CMV or CD8+ T-cell subsets."

Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MT Vossen, AT Rowshani, PM Wertheim-van Dillen, RA van Lier, IJ ten Berge. J Immunol 2004 Aug 1;173(3):1834-1841. "In this study, we show that in primary CMV infections, CD4(+)CD28(-) T cells emerge just after cessation of the viral load, indicating that infection with CMV triggers the formation of CD4(+)CD28(-) T cells. In line with this, we found these cells only in CMV-infected persons. CD4(+)CD28(-) cells had an Ag-primed phenotype and expressed the cytolytic molecules granzyme B and perforin. Importantly, CD4(+)CD28(-) cells were to a large extent CMV-specific because proliferation was only induced by CMV-Ag, but not by recall Ags such as purified protein derivative or tetanus toxoid. CD4(+)CD28(-) cells only produced IFN-gamma after stimulation with CMV-Ag, whereas CD4(+)CD28(+) cells also produced IFN-gamma in response to varicella-zoster virus and purified protein derivative. Thus, CD4(+)CD28(-) T cells emerge as a consequence of CMV infection."

Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. R Vescovini, A Telera, FF Fagnoni, C Biasini, MC Medici, P Valcavi, P di Pede, G Lucchini, L Zanlari, G Passeri, F Zanni, C Chezzi, C Franceschi, P Sansoni. Exp Gerontol 2004 Aug;39(8):1233-1243. In nonagenarians and centenarians, "The frequency and absolute number of CD8+ T cells specific for one lytic and two latent EBV-epitopes, were relatively low and mostly included within CD8+ CD28+ cells. By contrast, CMV infection was characterized by highly variable numbers of CD8+ T cells specific for two differently restricted CMV-epitopes that, in some subjects, were strikingly expanded. Moreover, the great majority of anti-CMV CD8+ T cells did not bear CD28 antigen. Notwithstanding the expansion of CMV-specific CD8+ lymphocytes, CMV-DNA detection in blood samples was invariably negative. Altogether, we suggest that CMV, but not EBV, can sustain chronic activation of the HLA-class I restricted effector arm in elderly that might have detrimental effects on age-associated diseases."

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 Dec 15;173(12):7481-7489. "CMV appears to be the most immunogenic, with the CD8 T cell response representing over 10% of the CD8 pool in many elderly donors. 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."

Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. AW Sylwester, BL Mitchell, JB Edgar, C Taormina, C Pelte, F Ruchti, PR Sleath, KH Grabstein, NA Hosken, F Kern, J. A Nelson, and LJ Picker. J Exp Med 2005;202(5):673-685. "We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ∼10% of both the CD4+ and CD8+ memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8+ T cells and was rare." "Although there are few comparative data for pan-proteome immunogenicity analysis of other human viral infections, previous reports assessing T cell responses to viral lysates, infected cells, or immunodominant epitopes strongly suggest that the frequencies of HCMV-specific T cells in healthy subjects considerably exceed those observed for other common viruses, including measles, mumps, influenza, adenovirus, poxvirus, and even other persistent Herpes family viruses (e.g., Herpes simplex, Herpes zoster) and are comparable with frequencies of HIV-specific T cells in active HIV infection." "[O]ur observation that ∼30% of adult subjects have HCMV-specific populations comprising >20% of their circulating CD4+ and/or CD8+ memory T cell repertoire suggests that HCMV-specific T cell responsiveness might be excessive in some individuals, perhaps with detrimental clinical effects." "...T cell recognition of HCMV is complex, often very broad, and poorly approximated by responses to any one or two HCMV ORFs."

Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. G Almanzar, S Schwaiger, B Jenewein, M Keller, D Herndler-Brandstetter, R Wurzner, D Schonitzer, B Grubeck-Loebenstein. J Virol 2005 Mar;79(6):3675-3683. "CD8+ T cells were analyzed in young, middle-aged, and elderly clinically healthy persons with a positive or negative CMV antibody serology. Numbers and functional properties of CMVpp65(495-503)-specific CD8+ T cells were also studied. We demonstrate that aging as well as CMV infection lead to a decrease in the size of the naive CD8+ T-cell pool but to an increase in the number of CD8+ effector T cells, which produce gamma interferon but lack substantial growth potential. The size of the CD8+ memory T-cell population, which grows well and produces interleukin-2 (IL-2) and IL-4, also increases with aging, but this increase is missing in CMV carriers. Life-long latent CMV infection seems thus to diminish the size of the naive and the early memory T-cell pool and to drive a Th1 polarization within the immune system. This can lead to a reduced diversity of CD8 responses and to chronic inflammatory processes which may be the basis of severe health problems in elderly persons."

Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. HN Schmaltz, LP Fried, QL Xue, J Walston, SX Leng, RD Semba. J Am Geriatr Soc 2005 May;53(5):747-754. 724 women. "Frailty status was based on previously validated criteria: unintentional weight loss, weak grip strength, exhaustion, slow walking speed, and low level of activity.... Eighty-seven percent of women were CMV seropositive, an indication of chronic infection. CMV was associated with prevalent frailty, adjusting for age, smoking history, elevated body mass index, diabetes mellitus, and congestive heart failure (CMV frail adjusted odds ratio (AOR)=3.2, P=.03; CMV prefrail AOR=1.5, P=.18). IL-6 interacted with CMV, significantly increasing the magnitude of this association (CMV positive and low IL-6 frail AOR=1.5, P=.53; CMV positive and high IL-6 frail AOR=20.3, P=.007; CMV positive and low IL-6 prefrail AOR=0.9, P=.73; CMV positive and high IL-6 prefrail AOR=5.5, P=.001)."

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. This suggested the involvement of bystander-secreted, differentiation-inducing factors during CMV infection. One candidate was IFN-alpha, which induced loss of costimulatory receptors and inhibited telomerase in activated CD4+ T cells and was secreted at high levels by CMV-stimulated plasmacytoid dendritic cells (PDC). The CMV-specific CD4+ T cells in elderly subjects had severely restricted replicative capacity. This is the first description of a human memory T cell population that is susceptible to being lost through end-stage differentiation due to the combined effects of lifelong virus reactivation in the presence of bystander differentiation-inducing factors."

Interleukin 12 induces T-cell recruitment into the atherosclerotic plaque. X Zhang, A Niessner, T Nakajima, W Ma-Krupa, SL Kopecky, RL Frye, JJ Goronzy, CM Weyand. Circ Res 2006 Mar 3;98(4):524-531. "(CD4+)CD28- T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation." In human atheroma-SCID mouse chimeras, "Exposure of nonstimulated (CD4+)CD28- T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, (CD4+)CD28- T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12-inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions."

The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. A Wikby, BO Nilsson, R Forsey, J Thompson, J Strindhall, S Lofgren, J Ernerudh, G Pawelec, F Ferguson, B Johansson. Mech Ageing Dev 2006 Aug;127(8):695-704. "IRP and low-grade inflammation predicted 57% of observed deaths and 97% of survival over 2 years, and was not significantly affected by individuals' health status, suggesting that the physiological ageing processes of T-cell immunosenescence and low-grade inflammation are of primary importance in late life survival. IRP non-survivors showed only a minor inflammatory activity at baseline, but had in contrast to survivors developed increased activity at follow-up. The results suggest a sequence of stages for IRP individuals that begin with acquisition of CMV infection in earlier life, followed by generation of CD8+CD28- cells to control persistent CMV infection and eventually the development of an IRP. Intriguingly, we also found that rare individuals moved out of the IRP category by a process of immune suppression, including increases in IL-6 and IL-10 and decreases in the number of CD3+CD8+CD28- cells."

Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MH Heemskerk, IJ ten Berge, RA van Lier. Blood 2006 Nov 1;108(9):3121-3127. "In the acute response, CMV-specific CD4+ T cells are highly activated and proliferating, have a CD45RA+CD45R0+CD28+CD27+ phenotype, and produce IFN after stimulation with CMV antigen in vitro. Late after primary infection, CMV-specific CD4+ T cells have returned to a resting stage, and the percentage of IFN-producing CMV-specific CD4+ T cells is considerably lower than during the acute infection. Moreover, a considerable number of CMV-specific CD4+ T cells have progressed toward a further differentiated phenotype, characterized by the loss of both CD27 and CD28 and the acquisition of cytolytic molecules such as perforin and granzyme B (grB). CD4+CD28– grB+ T cells appear to be characteristic for CMV infection because they emerge after primary CMV infection and can be found only in CMV-seropositive individuals. Consequently, proliferation and cytokine production by CD4+CD28– T cells can be induced by CMV but not by other viral antigens."

Massive Load of Functional Effector CD4+ and CD8+ T Cells against Cytomegalovirus in Very Old Subjects. R Vescovini, C Biasini, FF Fagnoni, AR Telera, L Zanlari, M Pedrazzoni, L Bucci, D Monti, MC Medici, C Chezzi, C Franceschi, and P Sansoni. J Immunol 2007;179: 4283-4291. "Results indicate that pp65 and, to a lesser extent, IE-1 constitute major Ags against which aged people target functionally efficient T cell effector responses with massive production of Th1 cytokines and exhibition of CD107a degranulation marker. As a result, the production of IFN- induced in T cells by both Ags was seven to eight times greater in very old than in young subjects. The comparative analysis of pp65-specific responses in these very long-term carriers revealed a reciprocal relationship between CD4+ and CD8+ producing IFN- in the same individuals. These results indicate that CMV represents an important pathogen responsible for a strong immune activation in human aging. Such a remarkable burden of effector CD4+ and CD8+ T cells may be necessary to protect the elderly from CMV endogenous reactivation, but can turn detrimental by giving a substantial contribution to the proinflammatory status that accompanies the main age-related diseases."

Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis. WW Lee, ZZ Yang, G Li, CM Weyand, JJ Goronzy. J Immunol 2007 Aug 15;179(4):2609-2615. Expression of CD70 was the most striking difference between CD4(+)CD28(-) and CD4(+)CD28(+) T cells; and "CD70 on bystander CD4(+)CD28(-) T cells functioned by lowering the threshold for T cell activation; admixture of CD4(+)CD28(-) T cells augmented TCR-induced responses of autologous naive CD4(+)CD28(+) T cells, particularly of low-avidity T cells."

Cytomegalovirus Infection: A Driving Force in Human T Cell Immunosenescence. S Koch, A Larbi, D Ozcelik, R Solana, C Gouttefangeas, S Attig, A Wikby, J Strindhall, C Franceschi, G Pawelec. Ann N Y Acad Sci 2007 Oct;1114:23-35. REVIEW. "It has recently emerged that the common herpesvirus, cytomegalovirus (CMV), which establishes persistent, life-long infection, usually asymptomatically, may well be the driving force behind clonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. In those few who are not CMV-infected, another even more common herpesvirus, the Epstein-Barr virus, appears to have the same effect. These virus-driven changes are less marked in "successfully aged" centenarians, but most marked in people whom longitudinal studies have shown to be at higher risk of death, that is, those possessing an "immune risk profile" (IRP) characterized by an inverted CD4:8 ratio (caused by the accumulation primarily of CD8(+) CD28(-) cells). These findings support the hypothesis that persistent herpesviruses, especially CMV, act as chronic antigenic stressors and play a major causative role in immunosenescence and associated mortality."

Functional killer Ig-like receptors on human memory CD4+ T cells specific for cytomegalovirus. J van Bergen, EM Kooy-Winkelaar, H van Dongen, FA van Gaalen, A Thompson, TW Huizinga, MC Feltkamp, RE Toes, F Koning. J Immunol 2009 Apr 1;182(7):4175-4182. "Although very few CD4(+) T cells express killer Ig receptors (KIR), a large proportion of CD4(+) T cells with a late memory phenotype, characterized by the absence of CD28, does express KIR. Here, we show that KIR expression on CD4(+) T cells is also associated with memory T cell function, by showing that the frequency of CMV-specific cells is higher in CD4(+)KIR(+) than CD4(+)KIR(-) T cells. In addition, engagement of an inhibitory KIR inhibited the CMV-specific proliferation of these CD4(+)KIR(+) memory T cells, but had no detectable effect on cytokine production. Our data reveal that, in marked contrast with CD8(+) T cells, the activity of a subset of CMV-specific CD4(+) T cells is modulated by HLA class I-specific KIR. Thus, the CMV-induced down-regulation of HLA class I may in fact enhance memory CMV-specific CD4(+) T cell responses restricted by HLA class II."

Cytomegalovirus infection reduces telomere length of the circulating T cell pool. PJ van de Berg, SJ Griffiths, SL Yong, R Macaulay, FJ Bemelman, S Jackson, SM Henson, IJ en Berge, AN Akbar, RA van Lier. J Immunol 2010 Apr 1;184(7):3417-3423. "After primary CMV infection, we observed an increase in highly differentiated cells that coincided with a steep drop in telomere length. Moreover, we found in a cohort of 159 healthy individuals that telomere shortening was more rapid in CMV-seropositive individuals and correlated with the amount of differentiated T cells in both CD4(+) T cells and CD8(+) T cells. Finally, we found that telomere length measured in blood leukocytes is correlated with lymphocyte telomere length."

Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4+ CD45RA+ CD27⁻ T cells: the potential involvement of interleukin-7 in this process. V Libri, RI Azevedo, SE Jackson, D Di Mitri, R Lachmann, S Fuhrmann, M Vukmanovic-Stejic, K Yong, L Battistini, F Kern, MV Soares, AN Akbar. Immunology 2011 Mar;132(3):326-339. "Using multiple linear regression analysis we found that age itself is a stronger predictor than CMV seropositivity for the decrease in CD45RA+ CD27+ CD4+ T cells over time. In contrast, the increase in CD45RA⁻ CD27⁻ and CD45RA+ CD27⁻ CD4+ T cells is almost exclusively the result of CMV seropositivity, with age alone having no significant effect. Furthermore, the majority of the CD45RA⁻ CD27⁻ and CD45RA+ CD27⁻ CD4+ T cells in CMV-seropositive donors are specific for this virus. CD45RA+ CD27⁻ CD4+ T cells have significantly reduced CD28, interleukin-7 receptor α (IL-7Rα) and Bcl-2 expression, Akt (ser473) phosphorylation and reduced ability to survive after T-cell receptor activation compared with the other T-cell subsets in the same donors.... Finally we showed that the proportion of CD45RA+ CD27⁻ CD4+ T cells of multiple specificities was significantly higher in the bone marrow than the blood of the same individuals, suggesting that this may be a site where these cells are generated."

Association of detectable cytomegalovirus (CMV) DNA in monocytes rather than positive CMV IgG serology with elevated neopterin levels in community-dwelling older adults. SX Leng, H Li, QL Xue, J Tian, X Yang, L Ferrucci, N Fedarko, LP Fried, RD Semba. Exp Gerontol 2011 Aug;46(8):679-684. "52 (73.2%) participants were CMV seropositive, of whom 30 (57.5%) had detectable CMV DNA. CMV seropositive and seronegative participants did not differ in their neopterin levels, but individuals with detectable CMV DNA had higher neopterin than those without (10.6 ± 4.4 vs 8.0 ± 1.9 nM, respectively, p<.0001) adjusting for demographic and clinical covariates and interferon (IFN)-γ levels." "As positive IgG serology does not distinguish between past and persistent infections, these results suggest that CMV seropositive older adult population is heterogeneous in regard to the status of chronic CMV infection."

Expression of the RAE-1 Family of Stimulatory NK-Cell Ligands Requires Activation of the PI3K Pathway during Viral Infection and Transformation. M Tokuyama, C Lorin, F Delebecque, H Jung, DH Raulet, L Coscoy. PLoS Pathog 2011;7(9):e1002265. "We observed that MCMV activates the PI3K pathway and that this activation is required for NKG2D ligand expression. We also found that the expression of NKG2D ligands on cancer cell lines is dependent on this pathway. Our data suggest that NKG2D ligand expression, and thus recognition of infected and cancer cells by NK cells, is associated with a dysregulation in the PI3K pathway."

Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65(495-503)-specific CD8 (+) T cells in older adults. SX Leng, T Qu, RD Semba, H Li, X Yao, T Nilles, X Yang, B Manwani, JD Walston, L Ferrucci, LP Fried, JB Margolick, JH Bream. Age (Dordr) 2011 Dec;33(4):607-614. 16 HLA-A2-positive elderly volunteers. "While all participants had positive CMV IgG serology by enzyme-linked immunosorbent assays, only nine (56%) had detectable CMV DNA by nested polymerase chain reaction. These nine individuals had significantly higher percentages of CMV pp65(495-503) tetramer-positive CD8(+) T cells (median = 1.3%) than those without detectable CMV DNA (median = 0.1%; p < 0.001). Absolute CMV IgG antibody titers did not differ between these two groups (median = 54.6 vs 44.2 EU/ml, respectively, p = 0.4)."

Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans. E Derhovanessian, AB Maier, K Hähnel, R Beck, AJ de Craen, EP Slagboom, RG Westendorp, G Pawelec. J Gen Virol 2011 Dec;92(Pt 12):2746-2756. "Individuals harbouring CMV were confirmed to possess lower frequencies of naïve CD8+ T-cells (defined as CD45RA+CCR7+CD27+CD28+) and greater proportions of late-differentiated effector memory (CD45RA-CCR7-CD27-CD28-) and so-called TEMRA (CD45RA+CCR7-CD27-CD28-) CD4 and CD8 subsets, independent of HSV seropositivity. In CMV-seronegative donors, HSV did not affect T-cell subset distribution significantly."

The Human Cytomegalovirus UL11 Protein Interacts with the Receptor Tyrosine Phosphatase CD45, Resulting in Functional Paralysis of T Cells. I Gabaev, L Steinbrück, C Pokoyski, A Pich, RJ Stanton, R Schwinzer, TF Schulz, R Jacobs, M Messerle, PC Kay-Fedorov. PLoS Pathog 2011;7(12): e1002432. "CD45 has a pivotal function regulating T cell signaling thresholds; in its absence, the Src family kinase Lck is inactive and signaling through the T cell receptor (TCR) is therefore shut off.... Binding of the CMV pUL11 protein to CD45 on T cells prevents signal transduction via the TCR and restricts T cell proliferation."

NK-cells have an impaired response to acute exercise and a lower expression of the inhibitory receptors KLRG1 and CD158a in humans with latent cytomegalovirus infection. AB Bigley, TW Lowder, G Spielmann, JL Rector, H Pircher, JA Woods, RJ Simpson. Brain Behav Immun 2012 Jan;26(1):177-186. Twenty healthy males (age: 28.4±5.4 years). "CMVpos had lower proportions of NK-cells expressing inhibitory receptors (KLRG1+ and CD158a+) and higher proportions of terminally differentiated NK-cells (KLRG1-/CD57+) compared to CMVneg. CMVpos mobilized far fewer (132 cells/μL vs. 245 cells/μL) NK-cells in response to exercise despite having similar baseline NK-cell counts and physiological responses to exercise as CMVneg, although terminally differentiated NK-cells were equally responsive to exercise regardless of CMV serostatus (p=0.658). EBVpos had higher proportions of CD8+ NK-cells, but cellular responses to exercise were not influenced by EBV. The frequency and exercise-responsiveness of γδ T-cells was not affected by CMV or EBV serostatus (p>0.05)."

CMV Causes Mental Decline

Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. SE Strandberg, KH Pitkala, KH Linnavuori, RS Tilvis. Stroke 2003 Sep;34(9):2126-2131. Among 383 home-dwelling elderly with cardiovascular diseases (mean age, 80 years): "At baseline, 58 individuals (15.1%) had cognitive impairment, which after adjustments was significantly associated with seropositivity for 3 viruses (hazard ratio, 2.5; 95% CI, 1.3 to 4.7). MMSE score decreased in 150 (43% of 348) during 12-month follow-up. After adjustment for MMSE score at baseline and with 0 to 1 seropositivities as reference (1.0), the hazard ratios were 1.8 (95% CI, 0.9 to 3.6) and 2.3 (95% CI, 1.1 to 5.0) for 2 and 3 seropositivities, respectively. The prevalence of possible or definite dementia according to CDR also increased with viral burden. No significant associations were observed between bacterial burden and cognition." They noted that "all our study participants had some kind of atherosclerotic disease at baseline, which may attenuate the observed association between infection and cognitive impairment."

Immune consequences of the spontaneous pro-inflammatory status in depressed elderly patients. P Trzonkowski, J Myśliwska, B Godlewska, E Szmit, K Łukaszuk, J Wieckiewicz, L Brydak, M Machała, J Landowski, A Myśliwski. Brain Behav Immun 2004 Mar;18(2):135-148. 10 elderly depressed patients and 10 controls. "Higher levels of anti-CMV, higher percentage of the CD28- CD57+ cells, and elevated levels of TNFalpha, IL6, and cortisol concomitant with decreased levels of ACTH and insufficient production of IL10 (which increased the IFNgamma+ /IL10+ ratio) were found in the patients suffering from depression, in comparison to healthy controls. The subjects with depression revealed a low NK cytotoxicity, while a level of CD3+ CD8+ IFNgamma+ cells was comparable between the groups."

The influence of latent viral infection on rate of cognitive decline over 4 years. AE Aiello, M Haan, L Blythe, K Moore, JM Gonzalez, W Jagust. J Am Geriatr Soc 2006 Jul;54(7):1046-1054. In 1204 community-dwelling elderly aged 60 to 100, "[t]here was a significantly higher rate of cognitive decline over the 4-year period in subjects with the highest CMV antibody levels at baseline than in individuals with the lowest levels (beta=-0.053, standard error =0.018; P=.003), after controlling for age, sex, education, income, and chronic health conditions. There was no association between HSV-1 antibody levels and cognitive decline. CRP did not modify the relationship between viral antibody levels and cognitive decline."

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.)

Cytomegalovirus seroprevalence among women of childbearing age during a 10-year period. GS Marshall, GG Stout. Am J Perinatol 2005 Oct;22(7):371-376. "Overall, 58% of 2992 women were seropositive. After stratification by socioeconomic status (SES), nonwhite race was strongly associated with seropositivity (odds ratio, 3.0; 95% confidence interval [CI], 2.5 to 3.8), and after stratification by race, lower SES also was associated (odds ratio, 2.0; 95% CI, 1.7 to 2.3). There were no trends in seroprevalence over time in any demographic group.... Seropositivity ranged from 40% among older, white primigravidas of upper SES to 89% among older, nonwhite, multigravid women of lower SES."

Seroprevalence of Cytomegalovirus Infection in the United States, 1988–1994. SAS Staras, SC Dollard, KW Radford, WD Flanders, RF Pass, MJ Cannon. Clin Infect Dis 2006;43:1143-1151. Based on age-specific CMV seroprevalences from the Third National Health and Nutrition Examination Survey (NHANES III). "CMV seroprevalence increased gradually with age, from 36.3% in 6–11-year-olds to 90.8% in those aged 80 years. CMV seroprevalence differed by race and/or ethnicity as follows: 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans."

Incidence of cytomegalovirus infection among the general population and pregnant women in the United States. FA Colugnati, SA Staras, SC Dollard, MJ Cannon. BMC Infect Dis 2007 Jul 2;7:71. Based on age-specific CMV seroprevalences from the Third National Health and Nutrition Examination Survey (NHANES III). "The average age of CMV infection was 28.6 years. Force of infection was significantly higher among non-Hispanic Blacks (5.7) and Mexican Americans (5.1) than among non-Hispanic Whites (1.4). Force of infection was significantly higher in the low household income group (3.5) than in the middle (2.1) and upper (1.5) household income groups."

Socioeconomic gradients in immune response to latent infection. JB Dowd, MN Haan, L Blythe, K Moore, AE Aiello. Am J Epidemiol 2008 Jan 1;167(1):112-20. 1,503 California participants in the 1998-1999 Sacramento Area Latino Study on Aging aged 60-100 years. "The odds ratio for being in a higher tertile of cytomegalovirus antibodies was 1.54 (95% confidence interval: 1.18, 2.01) for those in the lowest educational group, and the odds ratio for being in a higher tertile of herpes simplex virus type 1 was 1.63 (95% confidence interval: 1.25, 2.13). The relation between education and cytomegalovirus and herpes simplex virus type 1 antibody levels remained strong after controlling for baseline health conditions, smoking status, and body mass index." Comment: They seem to be missing the fundamental point that lower SES people are more likely to have high antibody levels to CMV because they are more likely to have been infected in the first place, not because of any inherent defect of immune function. Note that in the full article, they do not appear to have restricted the analysis of antibody levels to only those persons who have been infected by the virus!

Persistent pathogens linking socioeconomic position and cardiovascular disease in the US. AM Simanek, JB Dowd, AE Aiello. Int J Epidemiol 2009 Jun;38(3):775-87. NHANES subjects >/=45 years old. Socioeconomic position "was associated with CMV, HSV-1 and seropositivity to both pathogens. CMV seropositivity was associated with cardiovascular disease history even after adjusting for confounders as well as SEP. The odds of reporting a history of cardiovascular disease for those with less than a high school education compared with those with more than a high school education decreased by 7.7% after adjusting for CMV (Sobel mediation test for CMV, P = 0.0006)."

Socioeconomic and psychosocial gradients in cardiovascular pathogen burden and immune response: The multi-ethnic study of atherosclerosis. AE Aiello, A Diez-Roux, AM Noone, N Ranjit, M Cushman, MY Tsai, M Szklo. Brain Behav Immun 2009 Jul;23(5):663-71. 999 subjects. "Low education was a strong and significant independent predictor of higher pathogen burden after adjustment for covariates (adjusted odds ratio (OR) 95% confidence interval (CI) 1.37, 1.19-1.57)."

Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. MJ Cannon, DS Schmid, TB Hyde. Rev Med Virol 2010 Jul;20(4):202-213. "In this literature review, we found that CMV infection was relatively common among women of reproductive age, with seroprevalence ranging from 45 to 100%. CMV seroprevalence tended to be highest in South America, Africa and Asia and lowest in Western Europe and United States. Within the United States, CMV seroprevalence showed substantial geographic variation as well, differing by as much as 30 percentage points between states, though differences might be explained by variation in the types of populations sampled. Worldwide, seroprevalence among non-whites tended to be 20-30 percentage points higher than that of whites (summary prevalence ratio (PR) = 1.59, 95% confidence interval (CI) = 1.57-1.61). Females generally had higher seroprevalences than males, although in most studies the differences were small (summary PR = 1.13, 95% CI = 1.11-1.14). Persons of lower socioeconomic status were more likely to be CMV seropositive (summary PR = 1.33, 95% CI = 1.32-1.35)."

Family poverty is associated with cytomegalovirus antibody titers in U.S. children. JB Dowd, TM Palermo, AE Aiello. Health Psychol 2012 Jan;31(1):5-10. 2,226 children aged 6-16 from the 1999-2004 National Health and Nutrition Examination Survey (NHANES). "Poverty was significantly associated with increased antibody levels among seropositive individuals. The association between income and antibody levels exhibited a threshold effect, with additional income beyond the poverty line not associated with increased antibody titers."

CMV and Infections in Children

Role of cytomegalovirus infection in the incidence of viral acute respiratory infections in children attending day-care centers. JJ Chomel, JP Allard, D Floret, D Honneger, L David, B Lina, M Aymard. Eur J Clin Microbiol Infect Dis 2001 Mar;20(3):167-172. "The percentage of children becoming CMV positive was significantly (P<0.001) higher in day-care centers where more than 40 children were enrolled. Nine outbreaks due to respiratory syncytial virus, rhinovirus and enterovirus were recorded in 8 of 29 (27.6%) day-care centers. Viral acute respiratory infections were significantly (P<0.05) more frequently recorded in day-care centers in which CMV and respiratory viruses cocirculated and were significantly (P<0.001) more frequently reported in CMV-infected children."

Deliberate anti-smoker scientific fraud: Charlatans exploit socioeconomic differences in CMV infection to falsely blame passive smoking:

Effects of parental smoking on interferon {gamma} production in children. G Tebow, DL Sherrill, IC Lohman, DA Stern, AL Wright, FD Martinez, M Halonen, and S Guerra. Pediatrics 2008 Jun;121(6):e1563-e1569. While purposely ignoring the fact that cytomegalovirus infection reduces IFN-gamma responses, and the fact that, for socioeconomic reasons, smokers and passive smokers (and their children) are more likely to have been infected by CMV, these criminals falsely pretended that passive smoking causes "impairment of the immune system function." This bogus study was undoubtably concocted for use in Surgeon General reports, which have always systematically ignored the role of infection in a multitude of diseases in order to falsely blame smoking. The SG reports are instigated by politicians, and their corrupt authors are never subjected to scientific scrutiny!

Cytomegalovirus infection induces T-cell differentiation without impairing antigen-specific responses in Gambian infants. DJ Miles, M Sanneh, B Holder, S Crozier, S Nyamweya, ES Touray, MS Palmero, SM Zaman, S Rowland-Jones, M van der Sande, H Whittle. Immunology 2008 Jul;124(3):388-400. "While the concentration of undifferentiated (CD27(+) CD28(+) CCR7(+)) T-cells in peripheral blood was unaffected by CMV, there was a large increase in differentiated (CD28(-) CD57(+)) CD8 T-cells and a smaller increase in differentiated CD4 cells. One week post-vaccination, the CD4 cell interferon-gamma (IFN-gamma) response to measles was lower among CMV-infected infants, but there were no other differences between the cytokine responses, or between the cytokine or proliferative responses 4 months post-vaccination."

Herpesvirus seropositivity in childhood associates with decreased monocyte-induced NK cell IFN-gamma production. S Saghafian-Hedengren, Y Sundström, E Sohlberg, C Nilsson, A Linde, M Troye-Blomberg, L Berg, E Sverremark-Ekström. J Immunol 2009 Feb 15;182(4):2511-2517. "SP children had a significantly reduced proportion of IFN-gamma(+) NK cells and cognate intracellular IFN-gamma levels, which was more pronounced in CMV-coinfected subjects. Also, resting PBMCs of SP children displayed lower proportions of proinflammatory monocytes. IFN-gamma production by NK cells was dependent on interactions with monocytes, with the proinflammatory subset inducing the highest IFN-gamma. Finally, SP children had markedly lower levels of plasma IFN-gamma, concurrent with in vitro findings."

Human cytomegalovirus infant infection adversely affects growth and development in maternally HIV-exposed and unexposed infants in Zambia. UA Gompels, N Larke, M Sanz-Ramos, M Bates, K Musonda, D Manno, J Siame, M Monze, S Filteau; CIGNIS Study Group. Clin Infect Dis 2012 Feb 1;54(3):434-442. 811 infants from a double-blind, randomized controlled trial of micronutrient-fortified infant foods. "All HCMV-seropositive infants had decreased length-for-age by 18 months compared with seronegative infants (standard deviation [z]-score difference: -0.44 [95% confidence interval {CI}, -.72 to -.17]; P = .002). In HIV-exposed infants, those who were HCMV positive compared with those who were negative, also had reduced head size (mean z-score difference: -0.72 [95% CI, -1.23 to -.22]; P = .01) and lower psychomotor development (Bayley test score difference: -4.1 [95% CI, -7.8 to -.5]; P = .03). HIV-exposed, HCMV-viremic infants were more commonly referred for hospital treatment than HCMV-negative infants. The effects of HCMV were unaffected by micronutrient fortification."

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cast 02-26-12