acyclovir and Severe-Combined-Immunodeficiency

Twenty-six cases of B cell lymphoproliferative disorder (BLPD) were identified among 2395 patients following hematopoietic stem cell transplants (HSCT) for which an overall incidence of BLPD was 1.2%. The true incidence was probably higher, since 9/26 of the diagnoses were made at autopsy. No BLPD was observed following autologous HSCT, so risk factor analyses were confined to the 1542 allogeneic HSCT. Factors assessed were HLA-mismatching (> or = 1 antigen), T cell depletion (TCD), presence of acute GvHD (grades II-IV), donor type (related vs unrelated), age of recipient and donor, and underlying disease. Factors found to be statistically significant included patients transplanted for immune deficiency and CML, donor age > or = 18 years, TCD, and HLA-mismatching, with recipients of combined TCD and HLA-mismatched grafts having the highest incidence. Factors found to be statistically significant in a multiple regression analysis were TCD, donor age and immune deficiency, although 7/8 of the patients with immunodeficiencies and BLPD received a TCD graft from a haploidentical parent. The overall mortality was 92% (24/26). One patient had a spontaneous remission, but subsequently died >1 year later of chronic GVHD. Thirteen patients received therapy for BLPD. Three patients received lymphocyte infusions without response. The only patients with responses and longterm survival received alpha interferon (alphaIFN). Of seven patients treated with alphaIFN there were four responses (one partial and three complete). These data demonstrate that alphaIFN can be an effective agent against BLPD following HSCT, if a timely diagnosis is made.

Topics: Acyclovir; Adjuvants, Immunologic; Adolescent; Adult; Antiviral Agents; B-Lymphocytes; Blood Donors; Child; Epstein-Barr Virus Infections; Female; Genetic Diseases, Inborn; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Histocompatibility; Humans; Immunocompromised Host; Immunoglobulins, Intravenous; Immunophenotyping; Immunosuppression Therapy; Incidence; Infant; Interferon-alpha; Leukemia; Life Tables; Lymphoproliferative Disorders; Male; Middle Aged; Nuclear Family; Parents; Remission, Spontaneous; Retrospective Studies; Risk Factors; Severe Combined Immunodeficiency; T-Lymphocytes, Cytotoxic; Transplantation, Homologous; Treatment Outcome

Herpes simplex virus 1 can cause severe infections in individuals who are immunocompromised. In these patients, emergence of drug resistance mutations causes difficulties in infection management.. Seventeen herpes simplex virus 1 isolates were obtained from orofacial/anogenital lesions in a patient with leaky severe combined immunodeficiency over 7 years, before and after stem cell transplantation. Spatial/temporal evolution of drug resistance was characterized genotypically-with Sanger and next-generation sequencing of viral thymidine kinase (TK) and DNA polymerase (DP)-and phenotypically. CRISPR/Cas9 was used to introduce the novel DP Q727R mutation, and dual infection-competition assays were performed to assess viral fitness.. Isolates had identical genetic backgrounds, suggesting that orofacial/anogenital infections derived from the same virus lineage. Eleven isolates proved heterogeneous TK virus populations by next-generation sequencing, undetectable by Sanger sequencing. Thirteen isolates were acyclovir resistant due to TK mutations, and the Q727R isolate additionally exhibited foscarnet/adefovir resistance. Recombinant Q727R mutant virus showed multidrug resistance and increased fitness under antiviral pressure.. Long-term follow-up of a patient with severe combined immunodeficiency revealed virus evolution and frequent reactivation of wild-type and TK mutant strains, mostly as heterogeneous populations. The DP Q727R resistance phenotype was confirmed with CRISPR/Cas9, a useful tool to validate novel drug resistance mutations.

Topics: Acyclovir; Antiviral Agents; DNA-Directed DNA Polymerase; Drug Resistance, Multiple; Drug Resistance, Viral; Gene Editing; Herpes Simplex; Herpesvirus 1, Human; Humans; Immunologic Deficiency Syndromes; Mutation; Severe Combined Immunodeficiency; Thymidine Kinase

The tropism of herpes simplex virus (HSV-1) for human sensory neurons infected in vivo was examined using dorsal root ganglion (DRG) xenografts maintained in mice with severe combined immunodeficiency (SCID). In contrast to the HSV-1 lytic infectious cycle in vitro, replication of the HSV-1 F strain was restricted in human DRG neurons despite the absence of adaptive immune responses in SCID mice, allowing the establishment of neuronal latency. At 12 days after DRG inoculation, 26.2% of human neurons expressed HSV-1 protein and 13.1% expressed latency-associated transcripts (LAT). Some infected neurons showed cytopathic changes, but HSV-1, unlike varicella-zoster virus (VZV), only rarely infected satellite cells and did not induce fusion of neuronal and satellite cell plasma membranes. Cell-free enveloped HSV-1 virions were observed, indicating productive infection. A recombinant HSV-1-expressing luciferase exhibited less virulence than HSV-1 F in the SCID mouse host, enabling analysis of infection in human DRG xenografts for a 61-day interval. At 12 days after inoculation, 4.2% of neurons expressed HSV-1 proteins; frequencies increased to 32.1% at 33 days but declined to 20.8% by 61 days. Frequencies of LAT-positive neurons were 1.2% at 12 days and increased to 40.2% at 33 days. LAT expression remained at 37% at 61 days, in contrast to the decline in neurons expressing viral proteins. These observations show that the progression of HSV-1 infection is highly restricted in human DRG, and HSV-1 genome silencing occurs in human neurons infected in vivo as a consequence of virus-host cell interactions and does not require adaptive immune control.

Topics: Acyclovir; Animals; Ganglia, Spinal; Gene Expression; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 3, Human; Humans; Luciferases; Mice; Mice, SCID; Satellite Cells, Perineuronal; Severe Combined Immunodeficiency; Transplantation, Heterologous; Valacyclovir; Valine; Viral Proteins; Viral Tropism; Virus Latency; Virus Replication

To assess the etiology, prognosis, and appropriate treatment of hemophagocytic lymphohistiocytosis (HLH) in neonates.. We collected information on neonates in whom HLH was diagnosed between 1997 and 2007 from participating members of the Japanese Society of Pediatric Hematology.. HLH was diagnosed in 20 patients within 4 weeks after birth. Of the diagnostic criteria for HLH-2004, the incidence of fever was quite low in preterm infants, and hypertriglyceridemia and neutropenia were uncommon. Familial HLH (n = 6) or severe combined immunodeficiency-associated HLH (n = 1) was diagnosed in 7 patients, and 2 of them have survived. Herpes simplex virus-associated HLH was diagnosed in 6 patients, and 2 of them have survived. The overall survival rate for the 20 patients was 40%.. HLH is rare in neonates and has a poor prognosis. Early diagnosis and immediate treatment are required when considering the possibility of herpes simplex virus-associated or familial HLH.

Topics: Acyclovir; Adrenal Cortex Hormones; Antineoplastic Agents, Phytogenic; Antiviral Agents; beta 2-Microglobulin; Consciousness Disorders; Cyclosporine; Erythema; Etoposide; Exanthema; Female; Fetal Distress; Fever; gamma-Globulins; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans; Immunologic Factors; Immunosuppressive Agents; Infant, Newborn; Infant, Premature; Japan; L-Lactate Dehydrogenase; Leukocytosis; Lymphohistiocytosis, Hemophagocytic; Male; Ocular Motility Disorders; Plasma Exchange; Prognosis; Respiratory Distress Syndrome, Newborn; Seizures; Severe Combined Immunodeficiency

Patients with primary or secondary immunodeficiency are at high risk for B cell lymphoproliferative syndromes (LPS) that are generally Epstein-Barr virus (EBV)-associated. We established a cell line, termed JuWa, from an immunoblastic lymphoma that developed in a child with severe combined immunodeficiency. JuWa cells were representative of the original lymph node as shown by a similar IgH gene rearrangement pattern. The cell line exhibited the typical features of a lymphoblastoid cell line (LCL): (1) growth pattern in large clumps, (2) lack of structural chromosome abnormalities, (3) type III latency with expression of EBV-associated EBNA2 and LMP, as well as B cell activation markers CD23 and CD30, thereby showing characteristics of an EBV producer cell line, i.e. a latent infection with a small subpopulation of cells spontaneously entering the lytic cycle, (4) inducibility of the lytic cycle by IdU and TPA, leading to an increase of early antigen and viral capsid antigen-positive cells from 1 to 15-20%, and (5) elimination of the linear viral genomes by treatment with acyclovir (ACV), without affecting the circular episomal genomes. After withdrawal of ACV, viral replication resumed within 7 days. Thus, JuWa cells support the concept of the LCL-like features of LPS and lymphomas occurring in the setting of immunodeficiency. In our in vitro model, ACV treatment could effectively suppress the viral replication but not cure EBV infection of B cells.

Topics: Acyclovir; Antigens, Viral; Antiviral Agents; Cells, Cultured; DNA, Viral; Female; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunophenotyping; In Situ Hybridization; Infant; Lymph Nodes; Lymphocytes; Lymphoproliferative Disorders; Severe Combined Immunodeficiency; Syndrome