Latent Persistent Infections Research Articles

Peripheral Blood Mononuclear Cells’ Proliferative Response to Human Parvovirus B19 Antigens in Patients with Rheumatoid Arthritis / Reimatoīdā Artrīta Slimnieku Perifēro Asiņu Mononukleāro Šūnu Proliferativā Atbilde Uz Cilvēka Parvovīrusa B19 Antigēniem

Abstract This study aimed to determine peripheral blood mononuclear cells’ (PBMC) proliferative response to parvovirus B19 (B19) antigens in rheumatoid arthritis (RA) patients and possible changes in proliferative response due to chemotherapy. Serum and blood samples of 52 RA patients and 25 sex and age matched healthy individuals were examined for the presence of anti-B19 IgG and IgM class antibodies and virus specific DNA sequence by the recomLine B19 test and nested polymerase chain reaction, respectively. The PBMC proliferative activity was estimated on the 3rd and 6th day of PBMC cultivation in the presence of virus and B19 VP1/VP2 peptide, using thymidine incorporation assay. On the 3rd day, PBMC response to B19 antigens was detected in 74.1% RA patients with active, in 44.8% - with remote and in 40% - with latent stage of persistent B19 infection, while in the control group the response was observed only in two individuals with active viral infection. On the 6th day, the response was found in 50% RA patients with active, 68.9% - with remote and in 80% - with latent stage of latent persistent infection as well as in 41.1% remotely infected control individuals. The highest PBMC mean stimulation indices were detected in the RA patients and control persons with active infection as well as in RA patients with latent stage of persistent viral infection. On the 3rd and 6th day, strong proliferative response was significantly more frequently observed in RA patients not receiving methotrexate treatment, compared to the patients receiving methotrexate treatment in different combinations with other drugs. RA patients had more frequent and faster response to B19 antigens than apparently healthy persons.

B Cell-Specific Biomarkers for Optimal Antibody Responses to Influenza Vaccination and Molecular Pathways That Reduce B Cell Function with Aging.

This review highlights recent findings on the effects of aging on influenza vaccine responses, with major emphasis on T and B cells, which are significantly impaired by aging. We discuss changes in T cell production and thymic output; T cell subsets; and TCR repertoire, function, and response to latent persistent infection. We also discuss changes in B cell subsets, repertoire, and function, and how function is impaired by increased intrinsic B cell inflammation and reduced signal transduction. This review presents age-related effects on antigen-presenting cells, summarizes recent studies, including our own, aimed at the identification of biomarkers of protective vaccine responses, and provides examples of recent technical advances and insights into human vaccine responses that are helping to define the features associated with successful vaccination and that may enable a more predictive vaccinology in the future.

Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories.

Until the mid-20th century, infectious diseases were the major cause of morbidity and mortality in humans. Massive vaccination campaigns, antibiotics, antivirals, and advanced public health measures drastically reduced sickness and death from infections in children and younger adults. However, older adults (>65 y of age) remain vulnerable to infections, and infectious diseases remain among the top 5-10 causes of death in this population. The aging of the immune system, often referred to as immune senescence, is the key phenomenon underlying this vulnerability. This review centers on age-related changes in T cells, which are dramatically and reproducibly altered with aging. I discuss changes in T cell production, maintenance, function, and response to latent persistent infection, particularly against CMV, which exerts a profound influence on the aging T cell pool, concluding with a brief list of measures to improve immune function in older adults.

Herpes simplex virus type 1 induces simultaneous activation of Toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes

Herpes simplex virus type 1 (HSV-1) is the most common pathogenic cause of sporadic acute encephalitis and it produces latent persistent infection lifelong in infected individuals. Brain inflammation is associated with activation of glial cells, which can detect pathogen-associated molecular patterns (PAMPs) through a variety of pattern-recognition receptors (PRR), including Toll-like receptors (TLRs). In this study, we evaluated the expression and activation of TLR2, TLR3, and TLR4 in HSV-1-infected astrocyte and neuronal primary cultures. Our results showed a clear induction in TLR2 and TLR4 expression in astrocytes as early as 1h after HSV-1 infection, whereas no significant change was observed in neurons. In addition, infected astrocytes showed increased levels of interferon regulatory factors IRF3 and IRF7, interferon β (INFβ), interleukin 6 (IL6), and serum amyloid A (SAA3) transcripts, as well as phospho-IRF3 protein. These effects seemed to be dependent on viral replication since previous treatment of the cells with acyclovir resulted in low levels of TLRs expression and activation even after 4h post-infection. These results suggest that reactivation of HSV-1 at the central nervous system (CNS) would likely induce and activate TLR2 and TLR4 receptors directly through interaction of astrocytes with the pathogen and also indirectly by endogenous ligands produced locally, such as serum amyloid protein, potentiating the neuroinflammatory response.

Functional CD8 T Cell Memory Responding to Persistent Latent Infection Is Maintained for Life

Aging is associated with depressed naive T cell responses, but it is less clear whether T cell memory established early in life also becomes impaired with age. This is particularly important for T cells responding to latent persistent infection, which need to remain functional and capable of controlling the infection over the lifetime; however, repeated stimulation over the lifetime may dysregulate their maintenance or function, potentially contributing to impaired immunity in the elderly. Systemic infection with HSV-1, a persistent latent virus, is associated with memory inflation of virus-specific CD8 T cells. We tested how these inflated memory cells are maintained from adulthood into old age. We found no significant differences in the numbers (i.e., blood, spleen), ex vivo Ag-specific IFN-γ production, and in vivo recall response to HSV-1 (i.e., proliferation, IFN-γ production, cytolysis) between adult and old memory T cells. There was a discrete shift from dominantly effector memory phenotype in the adults to a central memory-like phenotype in the old mice, with fewer old cells expressing the killer cell lectin-like receptor G1 (KLRG1). Adult and old KLRG1(+) memory CD8 T cells were functionally identical: both produced IFN-γ but could minimally proliferate in response to viral challenge. Interestingly, regardless of age, KLRG1(+) cells retained the ability to proliferate and survive in response to homeostatic signals, both in vitro (culture with IL-7 and IL-15) and in vivo (expansion following transfer into lymphopenic recipients). This finding demonstrates that functional effector memory T cells, including those expressing KLRG-1, are maintained and are functional for life, despite the presence of persistent viral infection.

The Aging of the Adaptive Immune System

Adaptive immune responses are severely affected by the aging process as reflected by an increased morbidity and mortality from infectious diseases and a low efficacy of vaccination in elderly persons. Age-related changes within the bone marrow and thymus lead to an impaired generation of new T and B cells severely compromising the maintenance of a diverse and balanced T and B cell repertoire in old age. The maintenance of a balanced T cell repertoire is further challenged by latent persistent infections, such as Cytomegalovirus. Understanding the mechanisms of age-related alterations of the adaptive immune response may help to facilitate the development of more efficient vaccines for elderly persons and to envisage strategies to overcome immunosenescence.

Tick-borne Encephalitis Virus in Wild Rodents in Winter, Finland, 2008–2009

Rodents might maintain tick-borne encephalitis virus (TBEV) in nature through latent persistent infections. During 2 subsequent winters, 2008 and 2009, in Finland, we detected RNA of European and Siberian subtypes of TBEV in Microtus agrestis and Myodes glareolus voles, respectively. Persistence in rodent reservoirs may contribute to virus overwintering.

Elevada seroprevalencia de citomegalovirus, virus herpes simplex tipo 1 y virus Epstein Barr en adultos con virus de la inmunodeficiencia humana

Cytomegalovirus (CMV), herpes simplex type I (HSV-1) and Epstein Barr virus (EBV) are latent persistent infections. Their reactivation may cause illnesses and death in human immunodeficiency virus-infected (HIV) people. World wide seroprevalence of these viruses is over 50%. In Chile, information is not available. To determine the seroprevalence of CMV HSV-1 and EBV in Chilean HIV-infected adults. A total of 400 HIV-infected adults aged 17 to 67 years (340 males) were studied during 2005 and 2006 CMV HSV-1 and EBV serum antibodies were measured by enzyme-linked immunoabsorbent assay. The mean lapse from the diagnosis of HIV and serum testing was 67 months and 69.5% patients received antiretroviral therapy. Sixty seven percent of the sample were men who had sex with men (MSM). The seroprevalence for CM, HSV-1 and EBV were 98.5, 92.2 and 99.7%, respectively. No patient had negative antibodies for all three viruses. Male patients that were negative for HSV-1 had a lower frequency of MSM than the rest of males (26% vs. 62%, p < 0.01). There is a high prevalence of positive antibodies against CMV HSV-1 and EBV in Chilean adults infected with HIV Specific diagnostic tests and antiviral therapy should be available for these patients.

Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections

A diverse and well-balanced repertoire of T cells is thought to be crucial for the efficacious defence against infection with new or re-emerging pathogens throughout life. In the last third of the mammalian lifespan, the maintenance of a balanced T-cell repertoire becomes highly challenging because of the changes in T-cell production and consumption. In this Review, I question whether latent persistent pathogens might be key factors that drive this imbalance and whether they determine the extent of age-associated immune deficiency.

Depletion of CD4(+) T cells causes reactivation of murine persistent tuberculosis despite continued expression of interferon gamma and nitric oxide synthase 2.

Tuberculosis is a major cause of death in much of the world. Current estimates are that one-third of the world's population is infected with Mycobacterium tuberculosis. Most infected persons control the infection but in many cases may not eliminate the organism. Reactivation of this clinically latent infection is responsible for a large proportion of active tuberculosis cases. A major risk factor for reactivation of latent tuberculosis is HIV infection, suggesting a role for the CD4(+) T cell subset in maintaining the latent persistent infection. In this study, we tested the requirement for CD4(+) T cells in preventing reactivation in a murine model of latent tuberculosis. Antibody-mediated depletion of CD4(+) T cells resulted in rapid reactivation of a persistent infection, with dramatically increased bacterial numbers in the organs, increased pathology in the lungs, and decreased survival. Although CD4(+) T cells are believed to be a major source of interferon (IFN)-gamma, expression of the gene for IFN-gamma in the lungs of CD4(+) T cell-depleted mice was similar to that in control mice. In addition, inducible nitric oxide synthase production and activity was unimpaired after CD4(+) T cell depletion, indicating that macrophage activation was present even during CD4(+) T cell deficiency. These data indicate that CD4(+) T cells are necessary to prevent reactivation but may have roles in addition to IFN-gamma production and macrophage activation in controlling a persistent tuberculous infection.

Prevention of Infections Transmissible by Blood Derivatives

Agents that are transmissible by blood or its derivatives typically have long incubation periods, may often be asymptomatic for several years and can set up carrier or latent persistent infections. Examples are hepatitis B virus (HBV), hepatitis C virus (HCV), the human immunodeficiency viruses (HIV 1 and 2) and cytomegalovirus. The prevention of transfusion-transmitted infection (TTI) is based on the exclusion of potential blood donors who are not fit and well, the education of donors to exclude themselves if they are at risk of contracting TTIs, the laboratory screening of all blood donations for evidence of infection with a range of potential TTIs, physical removal of white cells in those cases where the agent is cell associated, viral inactivation procedures for pooled plasma derivatives, detection of viral genomes in plasma pools and the avoidance of unnecessary transfusions.