Explore the vast range of titles available.

In the 1970s–1980s, a striking increase in the number of disseminated human cytomegalovirus (HCMV) infections occurred in immunosuppressed patient populations. Autopsy findings documented the in vivo disseminated infection (besides fibroblasts) of epithelial cells, endothelial cells, and polymorphonuclear leukocytes. As a result, multiple diagnostic assays, such as quantification of HCMV antigenemia (pp65), viremia (infectious virus), and DNAemia (HCMV DNA) in patient blood, were developed. In vitro experiments showed that only low passage or endothelial cell-passaged clinical isolates, and not laboratory-adapted strains, could reproduce both HCMV leuko- and endothelial cell-tropism, which were found through genetic analysis to require the three viral genes UL128, UL130, and UL131 of the HCMV UL128 locus (UL128L). Products of this locus, together with gH/gL, were shown to form the gH/gL/pUL128L pentamer complex (PC) required for infection of epithelial cells/endothelial cells, whereas gH/gL and gO form the gH/gL/gO trimer complex (TC) required for infection of all cell types. In 2016, following previous work, a receptor for the TC that mediates entry into fibroblasts was identified as PDGFRα, while in 2018, a receptor for the PC that mediates entry into endothelial/epithelial cells was identified as neuropilin2 (Nrp2). Furthermore, the olfactory receptor family member OR14I1 was recently identified as a possible additional receptor for the PC in epithelial cells. Thus, current data support two models of viral entry: (i) in fibroblasts, following interaction of PDGFRα with TC, the latter activates gB to fuse the virus envelope with the cell membrane, whereas (ii) in epithelial cells/endothelial cells, interaction of Nrp2 (and OR14I1) with PC promotes endocytosis of virus particles, followed by gB activation by gH/gL/gO (or gH/gL) and final low-pH entry into the cell.

Congenital infection with cytomegalovirus is a major cause of morbidity in neonates. In this phase 2, placebo-controlled trial, hyperimmune globulin given to mothers with primary CMV infection at 5 to 26 weeks of gestation did not significantly alter the course of infection. Every year, approximately 0.6% of all newborns in the United States and the European Union are congenitally infected with human cytomegalovirus (CMV). 1 , 2 Approximately 20% of these infected newborns are symptomatic at birth or will have sequelae such as sensorineural hearing loss, cognitive defects, and motor defects. 3 Primary CMV infection that develops in a woman during pregnancy confers the highest risk of congenital infection and disease. 4 Identification of pregnant women with primary CMV infection is feasible by means of detection of virus-specific IgM and low IgG avidity. However, the unavailability of a therapeutic intervention of proven efficacy in the case . . .

Containment measures have been applied in several countries in order to limit the diffusion of the SARS-CoV-2 epidemic. The scope of this study is to analyze the evolution of the first wave of the SARS-CoV-2 epidemic throughout Italy and factors associated to the different way it spread in the Italian Regions, starting from the day that the first indigenous cases were detected through day 81 (6 days after the end of the strict lockdown). Data were obtained from daily reports and are represented as number (and percentage) of cases/100,000 persons. A lockdown with movement restrictions, especially across Regions, was declared at day 20. At day 81, 219,070 cases (363/100,000 persons) were diagnosed. A regression analysis based on the Gompertz model predicts a total number 233,606 cases (386/100,000 persons) at the end of the epidemic. The 21 areas, divided into Italian Regions and autonomous Provinces, showed a wide range in the frequency of cases at day 81 (58–921, median 258/100,000 persons) and total predicted cases (58–946, median 267/100,000 persons). Similarly, the predicted time for the end of the wave of the epidemic (considering as surrogate marker the time at which 99% of the total cases are predicted to occur) was highly variable, ranging from 64 to 136 (median 99) days. We analyzed the impact of local and interventional variables on the epidemic curve in each Region. The number of cases correlated inversely with the distance from the area in which first cases were detected and directly also with the gross domestic product pro capite (as a marker of industrial activity) of the Region. Moreover, an earlier start of the lockdown (i.e. in the presence of a lower number of cases) and wider testing were associated with a lower final number of total cases. In conclusion, this analysis shows that population-wide testing and early lockdown enforcement appear effective in limiting the spreading of the SARS-CoV-2 epidemic.

Primary human cytomegalovirus (HCMV) infections during pregnancy are associated with a high risk of virus transmission to the fetus. To identify correlates of intrauterine HCMV transmission, serial serum samples from HCMV transmitter and non-transmitter pregnant women with primary HCMV infection were analyzed for the presence of neutralizing antibodies against different glycoproteins and glycoprotein complexes, which are known to mediate entry into distinct types of host cells. Neutralizing activity was detected in the sera early after primary infection; absorption with a soluble pentameric complex formed by gH/gL/pUL128-131, but not with gH/gL dimer or with gB, abolished the capacity of sera to neutralize infection of epithelial cells. Importantly, an early, high antibody response to pentamer antigenic sites was associated with a significantly reduced risk of HCMV transmission to the fetus. This association is consistent with the high in vitro inhibition of HCMV infection of epithelial/endothelial cells as well as cell-to-cell spreading and virus transfer to leukocytes by anti-pentamer antibodies. Taken together, these findings indicate that the HCMV pentamer complex is a major target of the antibody-mediated maternal immunity.

Congenital cytomegalovirus (cCMV) might occur as a result of the human cytomegalovirus (HCMV) primary (PI) or nonprimary infection (NPI) in pregnant women. Immune correlates of protection against cCMV have been partly identified only for PI. Following either PI or NPI, HCMV strains undergo latency. From a diagnostic standpoint, while the serological criteria for the diagnosis of PI are well-established, those for the diagnosis of NPI are still incomplete. Thus far, a recombinant gB subunit vaccine has provided the best results in terms of partial protection. This partial efficacy was hypothetically attributed to the post-fusion instead of the pre-fusion conformation of the gB present in the vaccine. Future efforts should be addressed to verify whether a new recombinant gB pre-fusion vaccine would provide better results in terms of prevention of both PI and NPI. It is still a matter of debate whether human hyperimmune globulin are able to protect from HCMV vertical transmission. In conclusion, the development of an HCMV vaccine that would prevent a significant portion of PI would be a major step forward in the development of a vaccine for both PI and NPI.

Congenital cytomegalovirus infection (cCMV) may affect about 1% of all newborns all over the world as a result of either a primary or recurrent human cytomegalovirus (HCMV) infection. While about 90% of infants affected by cCMV are asymptomatic at birth, the remaining 10% are symptomatic often with neurodevelopmental impairment and sensorineural hearing loss. In view of identifying the best approach to vaccine prevention of cCMV, this review will examine the most important steps made in the study of the immune response to, and diagnosis of, HCMV infection. The maternal immune response and immune correlates of protection are being partially identified with a partial contribution given by our laboratory. The diagnosis of primary infection is often difficult to achieve in the first three months of pregnancy, which is the time primarily involved in virus transmission to the fetus in association with the most severe symptoms and sequelae. Prevention of cCMV is anticipated by prevention of primary infection in early pregnancy by means of different measures, such as (i) behavioral-educational measures, (ii) immunoglobulin administration, (iii) antiviral treatment with valaciclovir. However, the most promising approach to cCMV prevention appears to be the development of a non-living vaccine, including at least three viral antigens: gB, pentamer complex gHgLpUL128L, and pp65, which have been shown to be able to stimulate both the humoral and the cellular arms of the maternal immune response. Primary HCMV infection may be managed in pregnancy by counseling of the couples involved by a team of specialists that includes virologists, obstetricians, infectivologists and neonatologists.

Congenital human cytomegalovirus (HCMV) infection is the major cause of birth defects and a precise definition of the HCMV-specific T-cell response in primary infection may help define reliable correlates of immune protection during pregnancy. In this study, a high throughput method was used to define the frequency of CD4+ and CD8+ T cells specific for four HCMV proteins in the naïve compartment of seronegative subjects and the effector/memory compartments of subjects with primary/remote HCMV infection. The naïve repertoire displayed comparable frequencies of T cells that were reactive with HCMV structural (pp65, gB and the pentamer gHgLpUL128L) and non-structural (IE-1) proteins. Whereas, following natural infection, the majority of effector/memory CD4+ and CD8+ T cells recognized either gB or IE-1, respectively, and pp65. The pattern of T cell reactivity was comparable at early and late stages of infection and in pregnant women with primary HCMV infection transmitting or not transmitting the virus to the fetus. At an early stage of primary infection, about 50% of HCMV-reactive CD4+ T cells were long-term IL-7Rpos memory cells, while 6-12 months later, the frequency of these cells increased to 70%, approaching 100% in remote infections. In contrast, only 10-20% of HCMV-specific CD8+ T cells were long-term memory cells up to 12 months after infection onset, thereafter increasing to 70% in remote infections. Interestingly, a significantly higher frequency of HCMV-specific CD4+ T cells with a long-term IL-7Rpos memory phenotype was observed in non-transmitting compared to transmitting women. These findings indicate that immunodominance in HCMV infection is not predetermined in the naïve compartment, but is the result of virus-host interactions and suggest that prompt control of HCMV infection in pregnancy is associated with the rapid development of long-term IL-7Rpos memory HCMV-specific CD4+ T cells and a low risk of virus transmission to the fetus.

In solid-organ transplant recipients (SOTR) the protective role of human cytomegalovirus (HCMV)-specific CD4+, CD8+ and γδ T-cells vs. HCMV reactivation requires better definition. The aim of this study was to investigate the relevant role of HCMV-specific CD4+, CD8+ and γδ T-cells in different clinical presentations during the post-transplant period. Thirty-nine SOTR underwent virologic and immunologic follow-up for about 1 year after transplantation. Viral load was determined by real-time PCR, while immunologic monitoring was performed by measuring HCMV-specific CD4+ and CD8+ T cells (following stimulation with autologous HCMV-infected dendritic cells) and γδ T-cells by flow cytometry. Seven patients had no infection and 14 had a controlled infection, while both groups maintained CD4+ T-cell numbers above the established cut-off (0.4 cell/µL blood). Of the remaining patients, 9 controlled the infection temporarily in the presence of HCMV-specific CD8+ only, until CD4+ T-cell appearance; while 9 had to be treated preemptively due to a viral load greater than the established cut-off (3×10(5) DNA copies/mL blood) in the absence of specific CD4+ T-cells. Polyfunctional CD8+ T-cells as well as Vδ2- γδ T-cells were not associated with control of infection. In conclusion, in the absence of HCMV-specific CD4+ T-cells, no long-term protection is conferred to SOTR by either HCMV-specific CD8+ T-cells alone or Vδ2- γδ T-cell expansion.

Human respiratory syncytial virus (RSV) is the leading cause of respiratory tract infections in children globally, with nearly all children experiencing at least one infection by the age of two. Partial sequencing of the attachment glycoprotein gene is conducted routinely for genotyping, but relatively few whole genome sequences are available for RSV. The goal of our study was to sequence the genomes of RSV strains collected from multiple countries to further understand the global diversity of RSV at a whole-genome level. We collected RSV samples and isolates from Mexico, Argentina, Belgium, Italy, Germany, Australia, South Africa, and the USA from the years 1998-2010. Both Sanger and next-generation sequencing with the Illumina and 454 platforms were used to sequence the whole genomes of RSV A and B. Phylogenetic analyses were performed using the Bayesian and maximum likelihood methods of phylogenetic inference. We sequenced the genomes of 34 RSVA and 23 RSVB viruses. Phylogenetic analysis showed that the RSVA genome evolves at an estimated rate of 6.72 × 10(-4) substitutions/site/year (95% HPD 5.61 × 10(-4) to 7.6 × 10(-4)) and for RSVB the evolutionary rate was 7.69 × 10(-4) substitutions/site/year (95% HPD 6.81 × 10(-4) to 8.62 × 10(-4)). We found multiple clades co-circulating globally for both RSV A and B. The predominant clades were GA2 and GA5 for RSVA and BA for RSVB. Our analyses showed that RSV circulates on a global scale with the same predominant clades of viruses being found in countries around the world. However, the distribution of clades can change rapidly as new strains emerge. We did not observe a strong spatial structure in our trees, with the same three main clades of RSV co-circulating globally, suggesting that the evolution of RSV is not strongly regionalized.

In allogeneic hematopoietic stem-cell transplantation (HSCT) recipients, outcome of human cytomegalovirus (HCMV) infection results from balance between viral load/replication and pathogen-specific T-cell response. Using a cut-off of 30,000 HCMV DNA copies/ml blood for pre-emptive therapy and cut-offs of 1 and 3 virus-specific CD4(+) and CD8(+) T cells/µl blood for T-cell protection, we conducted in 131 young patients a prospective 3-year study aimed at verifying whether achievement of such immunological cut-offs protects from HCMV disease. In the first three months after transplantation, 55/89 (62%) HCMV-seropositive patients had infection and 36/55 (65%) were treated pre-emptively, whereas only 7/42 (17%) HCMV-seronegative patients developed infection and 3/7 (43%) were treated. After 12 months, 76 HCMV-seropositive and 9 HCMV-seronegative patients (cumulative incidence: 90% and 21%, respectively) displayed protective HCMV-specific immunity. Eighty of these 85 (95%) patients showed spontaneous control of HCMV infection without additional treatment. Five patients after reaching protective T-cell levels needed pre-emptive therapy, because they developed graft-versus-host disease (GvHD). HSCT recipients reconstituting protective levels of HCMV-specific T-cells in the absence of GvHD are no longer at risk for HCMV disease, at least within 3 years after transplantation. The decision to treat HCMV infection in young HSCT recipients may be taken by combining virological and immunological findings.