Cellular senescence meets infection: highlights from the 10th annual International Cell Senescence Association (ICSA) conference, Rome 2025.

A light in the darkness: Predicting outcomes for congenital cytomegalovirus infections

Hearing Loss, Congenital HIV, and Medulloblastoma: A Case Report

Cytomegalovirus Identification and Quantification from the Saliva of Human Immunodeficiency Virus Seropositive and Seronegative Patients Using Real Time Polymerase Chain Reaction

We have been studying the role of human cytomegalovirus (HCMV) as a potential cofactor in human immunodeficiency virus (HIV)-related disease. The clinical relevance of HCMV is highlighted by the fact that it is a principal viral pathogen in patients with AIDS and is known to infect the same cells as HIV. In this study, we focused on the molecular interactions between HIV and HCMV in human fibroblasts and in the human glioblastoma/astrocytoma-derived cell line U373 MG, cells which can be productively infected by both viruses. Because these cells are CD4-, we used HIV pseudotyped with a murine amphotropic retrovirus as described previously (D. H. Spector, E. Wade, D. A. Wright, V. Koval, C. Clark, D. Jaquish, and S. A. Spector, J. Virol. 64:2298-2308, 1990). Initial studies showed that when cells were preinfected with HIV (Ampho-1B) for 5 days and then superinfected with HCMV, HIV antigen production dropped significantly in the coinfected cells but continued to rise in cells infected with HIV (Ampho-1B) alone. HCMV production, however, was unaffected by the presence of HIV. Further analysis showed that HIV steady-state RNA levels and gag and env protein production were also inhibited in the presence of HCMV. The transcriptional inhibition of HIV was particularly surprising in view of the previous results of several other laboratories as well as our own that HCMV infection stimulates HIV long terminal repeat-chloramphenicol acetyltransferase (LTR-CAT) expression in transient expression assays. To investigate this further, we transfected the HIV LTR-CAT construct into either uninfected cells or cells which had been preinfected with HIV. The cells were infected with HCMV 24 h posttransfection and assayed for CAT gene expression at 48 h after HCMV infection. Although there was some stimulation of the LTR-CAT in cells that were dually infected by HIV and HCMV, it was 16-fold less than that in the cells infected only with HCMV. This suggests that in the presence of the HIV infection, the stimulation of the HIV LTR-CAT gene by HCMV is significantly reduced. Experiments with UV-irradiated HCMV and the HCMV DNA polymerase inhibitor ganciclovir showed that HCMV transcription is necessary for the reduction in HIV production to occur; however, replication of the HCMV genome or any events which take place after DNA replication are not necessary. These results, coupled with the observation that inhibition is usually first seen between 8 and 24 h after HCMV infection, suggest that an HCMV early protein is involved in repression of HIV.

Human Immunodeficiency Virus: The Initial Physician-Patient Encounter

Gastrointestinal Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques Is Characterized by Proinflammatory Dysregulation of the Interleukin-6-Janus Kinase/Signal Transducer and Activator of Transcription3 Pathway

There are several reports of thrombocytopenia temporally associated with cytomegalovirus (CMV) infection in both immunocompetent and immunosuppressed patients (Crapnell et al, 2000; Yenicesu et al, 2002). While these anecdotal and brief reports raise the question of CMV causing immune thrombocytopenic purpura (ITP), the role of CMV infection in typical acute, self-limited or persistent ITP in children and adults remains unclear. There are several theoretical reasons why CMV infection may cause thrombocytopenia: direct cytotoxicity of CMV to haematopoietic cells; immune-mediated destruction of infected cells; or impairment of bone marrow stromal function by CMV (Crapnell et al, 2000). It is also possible that CMV infection induces non-specific autoantibodies that somehow result in antibody-mediated destruction of platelets (Toyoda et al, 1999). It has been shown that human CMV can infect megakaryocytes and their precursors in vitro, suggesting that infection of haematopoietic progenitor cells in vivo may contribute to thrombocytopenia in patients with CMV infection (Crapnell et al, 2000). In a study of CMV infection in a primate model, one of eight subjects exhibited marked thrombocytopenia that was also associated with transient leucocytosis (Lockridge et al, 1999). To investigate the association between CMV infection and thrombocytopenia, we screened a series of 80 adult and 28 paediatric patients who presented to the Platelet Disorders Center of the New York Presbyterian Hospital–Weill Medical College of Cornell University for the management and evaluation of thrombocytopenia. All patients attending the centre with a diagnosis of ITP were screened during a 6-month period in 1999. Urine was tested for CMV by shell vial assay. Of the 28 paediatric patients presenting with thrombocytopenia, three (11%) were positive for CMV in the urine by shell vial assay. Of these, two patients were diagnosed as having ‘routine’ ITP and one patient had Evan's syndrome. All were human immunodeficiency virus (HIV) negative. Of the 80 adult patients, three (4%) were CMV positive in the urine. Two of these patients were HIV positive with ITP. One patient had chronic ITP and an abnormally decreased lymphoproliferative response to phytohaemagglutinin. The mean nadir platelet count for patients who tested positive for CMV at any time was 12·4 × 109/l compared with 14·7 × 109/l for patients that were never positive for CMV (P = 0·799). There were no statistically significant differences in other blood cell indices between CMV-positive and -negative patients. There was no statistically significant difference between clinical course based on CMV status. We screened a total of 108 patients who presented to clinic with thrombocytopenia for CMV infection by performing shell vial assays on urine samples. Shell vial assay for the detection of CMV has been shown to be more reliable than serological testing in immunocompromised subjects and neonates (Weber et al, 1992), and more sensitive in asymptomatic patients and patients receiving antiviral therapy (Manez et al, 1994). Based on our findings, CMV infection does not appear to be involved with routine ITP. Of 108 patients, only six had CMV-positive urine results. While HIV+ patients with thrombocytopenia have improved platelet counts when HIV viral load is controlled, there were no similar findings with regard to CMV. There was no apparent correlation between CMV clearance and resolution of thrombocytopenia. The patients who did not receive anti-viral therapy still cleared the CMV. While we did not have a control group of patients who were screened for CMV, based on the historical understanding of CMV infection and detection, it seems unlikely that CMV infection is a common cause of profound thrombocytopenia. It does not, therefore, seem merited to routinely test patients with otherwise typical ITP for CMV infection. However, screening of highly refractory patients still remains as a possible strategy, and exploration of immune function of patients infected with CMV may be appropriate.

Human Cytomegalovirus-Mediated Enhancement of Human Immunodeficiency Virus Type-1 Production in Monocyte-Derived Macrophages

A wide array of pathogens has the potential to injure the fetus and induce teratogenesis, the process by which mutations in fetal somatic cells lead to congenital malformations. Rubella virus was the first infectious disease to be linked to congenital malformations due to an infection in pregnancy, which can include congenital cataracts, microcephaly, hearing impairment and congenital heart disease. Currently, human cytomegalovirus (HCMV) is the leading infectious cause of congenital malformations globally, affecting 1 in every 200 infants. However, our knowledge of teratogenic viruses and pathogens is far from complete. New emerging infectious diseases may induce teratogenesis, similar to Zika virus (ZIKV) that caused a global pandemic in 2016–2017; thousands of neonates were born with congenital microcephaly due to ZIKV exposure in utero, which also included a spectrum of injuries to the brain, eyes and spinal cord. In addition to congenital anomalies, permanent injury to fetal and neonatal organs, preterm birth, stillbirth and spontaneous abortion are known consequences of a broader group of infectious diseases including group B streptococcus (GBS), Listeria monocytogenes, Influenza A virus (IAV), and Human Immunodeficiency Virus (HIV). Animal models are crucial for determining the mechanism of how these various infectious diseases induce teratogenesis or organ injury, as well as testing novel therapeutics for fetal or neonatal protection. Other mammalian models differ in many respects from human pregnancy including placentation, labor physiology, reproductive tract anatomy, timeline of fetal development and reproductive toxicology. In contrast, non-human primates (NHP) most closely resemble human pregnancy and exhibit key similarities that make them ideal for research to discover the mechanisms of injury and for testing vaccines and therapeutics to prevent teratogenesis, fetal and neonatal injury and adverse pregnancy outcomes (e.g., stillbirth or spontaneous abortion). In this review, we emphasize key contributions of the NHP model pre-clinical research for ZIKV, HCMV, HIV, IAV, L. monocytogenes, Ureaplasma species, and GBS. This work represents the foundation for development and testing of preventative and therapeutic strategies to inhibit infectious injury of human fetuses and neonates.

Cytomegalovirus is highly prevalent worldwide and an important opportunistic pathogen in human immunodeficiency virus (HIV)-infected individuals. The effects of cytomegalovirus infection on HIV-exposed infants are poorly understood. We conducted a systematic review to assess the relationship between cytomegalovirus and HIV infections among HIV-exposed infants. Limited evidence suggests that HIV-induced immunosuppression in the mother increases the rate of congenital cytomegalovirus infection, while maternal antiretroviral therapy may reduce it. Limited information exists on the direction of the relationship between cytomegalovirus and HIV transmission among HIV-exposed infants. Only 2 studies have addressed this temporal sequence of events, and they suggest that cytomegalovirus can lead to subsequent HIV infection in HIV-exposed infants. Most evidence suggests that early cytomegalovirus infection accelerates HIV disease progression in infants. Gaps remain in understanding the role that cytomegalovirus infection plays in HIV-exposed infants. Decreasing cytomegalovirus transmission prenatally and in infancy might further decrease HIV transmission and lead to better health among HIV-exposed infants.

Cytomegalovirus antigen-specific T cell immune responses in patients with autoimmune diseases under different cytomegalovirus infection status.

Cytomegalovirus (CMV) infection is a frequent transplant complication. Anti-CMV responses in allograft recipients have been extensively studied, only few reports addressing γδ T lymphocytes role (1, 2). γδ T cells may play a natural antiviral role (3), and kidney allograft recipients during CMV infection undergo a massive expansion of circulating γδ T cells (4). The occurrence of a primary CMV infection in a highly immunosuppressed patient may represent a model about the role of innate immunity in this setting. We analyzed a 41-year-old human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patient undergoing primary CMV infection after orthotopic liver transplantation (OLT). The donor was negative for antibodies to HIV-1/2 or HCV, but positive for CMV IgG. At day 42 after OLT, the patient suffered from fever (>38°C for more than 2 days), leukopenia (<4×109 leukocytes/L in >2 consecutive samples) and malaise. CMV infection resolved within day 60. No CMV prophylaxis or treatment were performed and CMV infection was retrospectively diagnosed. Thus, resolution was only dependent on the host-response. At day 45, CMV-DNA was transiently positive; anti-CMV IgM and IgG were observed at days 99 and 112, respectively. As Vδ1 T lymphocytes are specifically expanded by both chronic HIV (5, 6) or acute CMV infections (1, 2), the distribution of this γδ T cell subset was compared to the kinetics of CMV- and HIV-specific CD8 T cell responses (Fig. 1). Lymphocytes showed a transient decrease at CMV viremia and disease onset (day 45, Fig. 1A). Vδ1 T cells increased at day 2, decreased at the time of clinical disease at day 45 and dropped at day 72, suggesting a γδ-specific T cell exhaustion and/or tissue migration. A subsequent increase of Vδ1 T cells was observed at day 112. As shown in Figure 1B, during the preOLT period Vδ1 T cells were composed mostly of terminally differentiated effector memory Temra (CD27-CD45RA+) cells (7); 2 days after OLT, both Vδ1 naïve (CD27+CD45RA+) and Temra cells increased. Differently, the peak of naïve Vδ1 T cells that follows the resolution of CMV infection (at day 112) may represent a homeostatic response.FIGURE 1.: Vδ1 T lymphocytes and CMV- and HIV-specific CD8 responses in an HIV/HCV coinfected patient undergoing acute CMV infection after OLT. (A) Circulating total lymphocyte number and Vδ1 T cells number are shown. (B) Vδ1 differentiation subsets are shown as determined by flow cytometry. In particular, Vδ1 Naïve CD27+CD45RA+ and terminally differentiated effector memory CD27-CD45RA+ cells (Temra) numbers are shown. (C) CMV-specific CD8 response to CMV antigens, measured as IFN-γ production, is shown. (D) HIV-specific CD8 response to Nef, Gag, and Tat HIV-1 proteins, measured as IFN-γ production by flow cytometry, are shown. In both panels C and D, IFN-γ producing cell numbers among 105 CD8 T cells are shown.Before OLT, no CD8 response to CMV was found (Fig. 1C). CMV-specific CD8 T cells appeared at day 2, were stable up to day 72, with a peak at day 112 (Fig. 1C). When HIV Gag-, Nef- and Tat-specific CD8 responses were monitored (Fig. 1D), a slight increase of responding cells was found at day 2 after OLT, but dropped at day 72. γδ T cells are more resistant to immunosuppressive drugs than αβ T cells (8), and they are numerous in the mucosal epithelium, which is a preferred site of CMV replication (9). Moreover, Vδ2-negative T cell clones from kidney transplant recipients display strong reactivity against CMV-infected cells, being able to kill CMV-infected targets (10). Accordingly, this study shows for the first time that Vδ1 Temra effector cells increased before the onset of CMV acute symptoms, indicating that gamma/delta T cells may play a relevant antiviral role also in transplanted HIV/HCV immunocompromised host; their monitoring may be indicative of subclinical infections and ability to control CMV infection. Gianpiero D'Offizi Cristiana Gioia Federico Martini Ilaria Volpi Mariacarmela Solmone Fabrizio Poccia Pasquale Narciso National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS Rome, Italy Giovanni Vennarecci Giuseppe Maria Ettore Mario Antonini Eugenio Santoro Department of Surgical Oncology Division of Digestive Surgery and Liver Transplantation Regina Elena Cancer Institute Rome, Italy Giampiero Carosi Department of Infectious and Tropical Diseases University of Brescia Brescia, Italy

Activation of nuclear factor-κB pathway is responsible for tumor necrosis factor-α-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro

The Antiviral Effector IFITM3 Disrupts Intracellular Cholesterol Homeostasis to Block Viral Entry

Human cytomegalovirus infection of cells of hematopoietic origin: HCMV-induced immunosuppression, immune evasion, and latency