RESUMEN
BACKGROUND: Lymph nodes serve as reservoirs for the replication of human immunodeficiency virus (HIV) type 1. Comparison of serial measurements of virus burden in lymph nodes and peripheral blood after a change in antiretroviral therapy may provide insights into pathogenic mechanisms and permit a more accurate assessment of a therapeutic response. STUDY DESIGN: Nevirapine was added to the drug regiment of eight children with HIV infection treated with the combination of zidovudine and didanosine who had increasing levels of serum p24 antigen. Lymph node biopsies were performed at entry and after 12 weeks of therapy. RESULTS: Neither CD4 counts nor p24 antigen level correlated with the degree of viremia as measured by ribonucleic acid copy numbers in plasma. Correlations were found between HIV DNA copy number in peripheral blood mononuclear cells and HIV DNA copy number in lymph nodes (p = 0.02), as well as between peripheral blood CD4 counts and lymph node architecture. The HIV signals in the lymph nodes conformed to the anatomic organization of apical light zones in the germinal centers; however, in more advanced disease stages, organized germinal centers disappeared as evidence by a decline in the extent of the follicular dendritic network. CONCLUSIONS: Lymph node biopsies in this small number of HIV-infected children revealed a progressive loss of an organized architecture, especially of the follicular dendritic network. This correlated with a progressive loss of CD4+ cells but not with other measures of disease stage, including viral load, as measured by ribonucleic acid copy numbers.
Asunto(s)
Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Ganglios Linfáticos/virología , Antivirales/uso terapéutico , Biopsia , Recuento de Linfocito CD4 , Niño , Preescolar , ADN Viral/análisis , Didanosina/administración & dosificación , Quimioterapia Combinada , Femenino , Proteína p24 del Núcleo del VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Hibridación in Situ , Lactante , Ganglios Linfáticos/patología , Masculino , Nevirapina , Piridinas/administración & dosificación , Viremia , Zidovudina/administración & dosificaciónRESUMEN
We used a quantitative human immunodeficiency virus, type 1 (HIV-1) culture method to determine whether there is a relationship between the amount of replicating virus in the blood of vertically infected children and the relatively short latency period before development of symptomatic disease in these children. HIV-1 titers were determined by end point dilution in the peripheral blood mononuclear cells and the plasma of 30 infected (CDC class P1 and P2), 36 indeterminate (CDC class PO), and 19 uninfected (CDC class P3) infants and children born to HIV-1 seropositive mothers. HIV-1 was recovered from 35 (90%) of 39 PBMC cultures and 23 (60%) of 38 plasma cultures of infected patients not receiving antiretroviral therapy. The mean HIV-1 titers tended to be higher in patients with more advanced disease (P2, D, E, or F: 1760 TCID/10(6) PBMC, 460 TCID/ml plasma) than in asymptomatic or mildly symptomatic patients (P1; P2, A or C: 90 TCID/10(6) PBMC; 60 TCID/ml plasma). A poor correlation between HIV-1 titers and serum p24 antigen levels was found. No correlation was observed between viral titers and relative or absolute numbers of CD4 lymphocytes. Plasma virus titers were lower in 9 patients receiving zidovudine (ZDV) therapy (mean 2 TCID/ml) than in untreated patients of similar clinical status. The viral titers measured in the blood of vertically infected infants and children were on the same order of magnitude as the viral titers measured in HIV-infected adults. We conclude that the relatively rapid progression to symptomatic disease of the majority of vertically infected patients is not due to a higher load of replicating virus in blood.
Asunto(s)
Infecciones por VIH/microbiología , Seropositividad para VIH/microbiología , VIH-1/aislamiento & purificación , Complejo Relacionado con el SIDA/sangre , Complejo Relacionado con el SIDA/microbiología , Complejo Relacionado con el SIDA/transmisión , Síndrome de Inmunodeficiencia Adquirida/sangre , Síndrome de Inmunodeficiencia Adquirida/microbiología , Síndrome de Inmunodeficiencia Adquirida/transmisión , Técnicas Bacteriológicas , Linfocitos T CD4-Positivos , Niño , Preescolar , Productos del Gen gag/sangre , Antígenos VIH/sangre , Proteína p24 del Núcleo del VIH , Infecciones por VIH/sangre , Infecciones por VIH/transmisión , Seropositividad para VIH/sangre , Seropositividad para VIH/transmisión , VIH-1/inmunología , Humanos , Lactante , Recuento de Leucocitos , Sepsis/sangre , Sepsis/microbiología , Sepsis/transmisión , Proteínas del Núcleo Viral/sangreRESUMEN
Cytotoxic T lymphocyte (CTL) responses to human immunodeficiency virus type 1 (HIV-1) gag proteins were studied prospectively in 17 children (12 infected) born of mothers with HIV-1 seropositivity and in five pediatric patients with hemophilia infected by transfusion of HIV-1-contaminated factor VIII concentrate. B lymphoblastoid cells infected with vaccinia virus vectors expressing HIV-1 gag gene products were combined with autologous peripheral blood mononuclear cells to detect circulating CTLs. Effector cells were defined by monoclonal antibody-mediated, complement-dependent cytolysis. Circulating HIV-1 gag-specific cytotoxic responses were detectable in 4 of 5 HIV-1-infected pediatric hemophilic patients, and were similar in magnitude to those previously described in adults. In contrast, circulating HIV-1 gag-specific cytolysis was detectible in only 3 of 12 vertically infected children. Depletion data revealed that the majority of detectible gag-specific cytolysis was CD8 T cell-mediated. No apparent relationships between CD4 T cell counts, CD8 T cells counts, or serum p24 antigen levels and CTL responses were seen. Deficient CTL development may, in part, explain the more rapid onset of symptomatic disease following vertical HIV infection.
Asunto(s)
Infecciones por VIH/inmunología , VIH-1/inmunología , Linfocitos T Citotóxicos/inmunología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/microbiología , Síndrome de Inmunodeficiencia Adquirida/transmisión , Adolescente , Antígenos CD/sangre , Antígenos de Diferenciación de Linfocitos T/sangre , Antígenos CD4/sangre , Antígenos CD8 , Niño , Preescolar , Pruebas Inmunológicas de Citotoxicidad/métodos , Productos del Gen gag/sangre , Productos del Gen gag/inmunología , Antígenos VIH/sangre , Proteína p24 del Núcleo del VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/microbiología , Infecciones por VIH/transmisión , VIH-1/aislamiento & purificación , Hemofilia A/complicaciones , Hemofilia A/inmunología , Hemofilia A/microbiología , Humanos , Lactante , Proteínas del Núcleo Viral/sangre , Cultivo de VirusRESUMEN
As part of a prospective study of human immunodeficiency virus (HIV) infection in hemophilia, peripheral blood mononuclear cells (PBMs) from 72 individuals without acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) were cultured for virus. HIV was isolated from PBMs from 16 (24%) of 66 patients with hemophilia who were seropositive for HIV and from none of six seronegative patients. Cells from five of six patients from which HIV was isolated were again successfully cultured for virus 3 to 12 months later. HIV core P24 antigen was detected in serum from seven of 15 patients with HIV-positive cells and from eight of 50 with HIV-negative cells. Patients with hemophilia with isolation-positive cells had significantly fewer T helper cells and significantly lower T helper/T suppressor ratios, pokeweed mitogen responsiveness, and total platelet counts than did those whose cells did not yield HIV on cultivation. HIV neutralizing antibody titers did not differ between hemophiliacs with or without HIV-positive PBMs. Three of the 16 patients with virus-positive cells developed AIDS, and two ARC, within 18 months of the study, compared with three of 50 seropositive hemophiliacs whose cells did not yield virus, who developed ARC during the same period. The significant decrease in the number of T helper cells, decreased platelet counts, and higher rate of progression to AIDS in the group with HIV isolation may reflect a heavier virus load, indicating that the ability to culture HIV may be an early marker of more significant disease.
Asunto(s)
VIH/aislamiento & purificación , Hemofilia A/microbiología , Adolescente , Adulto , Anciano , Anticuerpos Antivirales/análisis , Antígenos Virales/análisis , Células Sanguíneas/microbiología , Células Cultivadas , Niño , VIH/inmunología , Hemofilia A/inmunología , Hemofilia B/microbiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Enfermedades de von Willebrand/microbiologíaRESUMEN
The relationship between hemophiliac immunodeficiency and exposures to factor VIII concentrate, LAV/HTLV-III retrovirus, and infection with Epstein-Barr virus and cytomegalovirus was examined. Exposure to factor VIII concentrate was significantly correlated with decreased percentages of T helper/inducer cells, decreased T helper/suppressor cell ratios, and decreased proliferative responses to plant mitogens. LAV/HTLV-III seropositivity was the primary predictor of increased percentages of HLA-DR-bearing mononuclear cells and decreased proliferative responses to pokeweed mitogen. Epstein-Barr virus and cytomegalovirus infections acted in a synergistic manner with LAV/HTLV-III to produce immunoregulatory defects. Increased percentages of T suppressor cells and decreased delayed cutaneous hypersensitivity skin test responses were observed in LAV/HTLV-III seropositive hemophiliacs infected with Epstein-Barr or cytomegalovirus. We conclude that hemophiliacs receiving commercial factor VIII concentrate experience several stepwise incremental insults to the immune system: alloantigens in factor VIII concentrate, LAV/HTLV-III infections, and herpesvirus infections.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/transmisión , Factor VIII/inmunología , Hemofilia A/inmunología , Infecciones por Herpesviridae/transmisión , Tolerancia Inmunológica , Adolescente , Adulto , Anciano , Niño , Preescolar , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/transmisión , Deltaretrovirus/inmunología , Contaminación de Medicamentos , Factor VIII/efectos adversos , Herpesvirus Humano 4/inmunología , Humanos , Hipersensibilidad Tardía/inmunología , Recuento de Leucocitos , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Pruebas Cutáneas , Linfocitos T Colaboradores-Inductores , Linfocitos T ReguladoresRESUMEN
Immune deficiency, especially to the Epstein-Barr virus, and increased susceptibility to fatal infectious mononucleosis, acquired agammoglobulinemia, and lymphoma are the cardinal features of the X-linked lymphoproliferative syndrome. Since the establishment of the XLP Registry in September, 1978, 59 affected males in seven unrelated kindreds were comprehensively studied. A spectrum of lymphoproliferative phenotypes was observed. Thirty-four patients (57%) died from infectious mononucleosis, eight (14%) had fatal infectious mononucleosis with lymphoma (immunoblastic sarcoma), nine (15%) had depressed immunity following EBV infection, and eight (14%) developed lymphoma. Several patients with XLP lacked EBV antibodies despite infection by EBV. The results of this study suggest that EBV can be an oncogenic agent in patients who are immune deficient with XLP.