The ability of human ␥␦ T cells to develop immunologic memory is still a matter of debate. We previously demonstrated the involvement of V␦2 ؊ ␥␦ T lymphocytes in the response of immunosuppressed organ recipients to cytomegalovirus (CMV). Here, we demonstrate their ability to mount an adaptive immune response to CMV in immunocompetent subjects. V␦2 ؊ ␥␦ T-cell peripheral blood numbers, repertoire restriction, and cytotoxicity against CMV-infected fibroblasts were markedly increased in CMV-seropositive, compared with CMV-seronegative, healthy persons. Whereas V␦2 ؊ ␥␦ T cells were found as naive cells in CMV ؊ patients, they virtually all exhibited the cytotoxic effector/ memory phenotype in CMV ؉ patients, which is also observed in transplanted patients challenged with CMV. This longterm complete remodeling of the V␦2 ؊ ␥␦ T-cell population by CMV predicts their ability to exhibit an adaptive anti-CMV immune response. Consistent with this, we observed that the secondary response to CMV was associated with a faster ␥␦ T-cell expansion and a better resolution of infection than the primary response. In conclusion, the increased level of effectormemory V␦2 ؊ IntroductionHuman cytomegalovirus (CMV) is a widespread ␤-herpesvirus that establishes a lifelong viral persistence without detectable symptoms in immunocompetent patients but with life-threatening consequences in immunologically immature or compromised patients. Many studies have been reported that support an important role for adaptive T lymphocytes in the control of CMV infection. [1][2][3][4] In addition, we have demonstrated that the ␥␦ T-cell subpopulation contributes to the anti-CMV immune responses. 5,6 These unconventional T cells are generally considered to be intermediates between innate and adaptive immunity because of their rapid and massive responses to very diverse immune challenges.Compelling data exist that demonstrate the importance of ␥␦ T cells in various microbial infections in humans. They exhibit in vitro reactivity against cells infected by viruses, bacteria, or parasites and are selectively expanded in the peripheral blood of infected patients. [7][8][9][10] The majority of human circulating ␥␦ T cells express a T-cell receptor (TCR) encoded by the V␥9 and V␦2 gene segments. These cells are activated after interaction with nonpeptidic phosphorylated compounds, collectively called phosphoantigens, which are metabolic intermediates of the isoprenoid biosynthetic pathway. 11,12 These phosphoantigens are expressed by a variety of bacteria and parasites and are also present in some tumors. The other ␥␦ T cells are known as V␦2 Ϫ ␥␦ T cells, are largely located in mucosal epithelia and in the spleen, and represent approximately 20% of all circulating ␥␦ T cells. These cells predominantly express a TCR containing the V␦1 region. Their repertoire in the peripheral blood of most healthy adults is restricted, whereas it is polyclonal in the thymus and in cord blood. [13][14][15] This observation suggests that unknown environmental factors encou...

BackgroundHerpes Simplex Virus (HSV) infection has been proposed as a possible risk factor of Alzheimer's Disease (AD) notably because it is neurotropic, ubiquitous in the general population and able to establish lifelong latency in the host. The fact that HSV was present in elderly subjects with AD suggests that the virus could be a co-factor of the disease. We investigated the risk of developing AD in anti-HSV immunoglobulin G (IgG) positive subjects (indicator of a lifelong infection to HSV) and IgM-positive subjects (indicator of primary infection or reactivation of the virus) in a longitudinal population-based cohort of elderly subjects living in the community.MethodsCox proportional hazard models were used to study the risk of developing AD according to the presence or not of anti-HSV IgG and IgM antibodies, assessed in the sera of 512 elderly initially free of dementia followed for 14 years.ResultsDuring the follow-up, 77 incident AD cases were diagnosed. Controlled for age, gender, educational level and Apolipoprotein E4 (APOE4) status, IgM-positive subjects showed a significant higher risk of developing AD (HR = 2.55; 95% CI [1.38–4.72]), although no significant increased risk was observed in IgG-positive subjects (HR = 1.67; 95%CI [0.75–3.73]). No modification effect with APOE4 status was found.ConclusionReactivation of HSV seropositivity is highly correlated with incident AD. HSV chronic infection may therefore be contributive to the progressive brain damage characteristic of AD.

These data show the feasibility of surveying resistance. Virological resistance was frequent in patients failing antiviral therapy. More than 1/5 resistant isolates harboured UL54 mutations alone or combined with UL97 mutations, which conferred a high level of resistance and sometimes were responsible for cross-resistance, leading to therapeutic failure.

Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in transplant recipients. Long-term protective immunity against HCMV requires both sustained specific T-cell response and neutralizing IgG production, but the interplay between these effector arms remains poorly defined. We previously demonstrated that ␥␦ T cells play a substantial role as anti-HCMV Tcell effectors. The observation that CD16 (Fc␥RIIIA) was specifically expressed by the majority of HCMV-induced ␥␦ T cells prompted us to investigate their cooperation with anti-HCMV IgG. We found that CD16 could stimulate ␥␦ T cells independently of T-cell receptor (TCR) engagement and provide them with an intrinsic antibody-dependent cell-mediated cytotoxic ( IntroductionHuman cytomegalovirus (HCMV) is a widespread herpesvirus with an average seroprevalence of around 50% that increases with age and low socioeconomic status. Primary HCMV infection in an immunocompetent host is asymptomatic, but the virus establishes lifelong latency probably associated with periodic reactivation episodes. Conversely, damaging clinical symptoms can be observed in the course of HCMV infection in fetuses, neonates, and immunocompromised patients, such as those infected with HIV, recipients of solid organ allografts, or undergoing allogeneic hematopoietic stem cell transplantation. Constant immune surveillance is thus critical to keep the virus in check, and actually HCMV is highly immunogenic and elicits all the arsenal of the host immune defense. 1 The early events associated with virus entry into host cells first trigger a robust production of type I IFN and inflammatory cytokines, such as IL12, which are critical for the recruitment and activation of innate immune cells, particularly phagocytic leukocytes. 2 The activated innate immune cells then initiate the development of a vigorous adaptive immune response that culminates with the production of neutralizing antiviral antibodies (Abs) and IFN␥-producing and/or cytotoxic CD8 T cells. Both of these effectors are required for the establishment of long-lasting immunity against HCMV reactivation, superinfection, and congenital infection, but the cooperation between humoral immunity and T-cell effectors remains to be clarified.Humoral response against HCMV is characterized by the production of neutralizing Abs directed against viral envelope glycoproteins (mostly gB and gH) and gene products of the UL131A-128 locus, which are involved in virus attachment and entry into host cells. 3 However, the majority (90%) of HCMVspecific Abs do not have virus-neutralizing activity. 4 Such Abs could cooperate with cell effectors expressing CD16, the low affinity Fc receptor for IgG (FcR␥IIIa), to generate an Abdependent cell-mediated cytotoxicity (ADCC). However, ADCC would require that Abs are directed against HCMV-infected cells, something that has never been reported. Natural killer (NK) cells are usually considered as the main effector of ADCC, but evidence for a role of this process in immune defense again...