ABSTRACT
OBJECTIVE: To determine the influences on pediatric AIDS of a heterozygous 32 base pair deletion in the CC-chemokine receptor 5 gene (CCR5 wt/Delta 32) and a common polymorphism in the 3' untranslated region of stromal cell-derived factor-1 beta gene transcript (SDF1-3'A). DESIGN: The rate of HIV-1 disease progression and viral burden were compared according to the CCR5 and SDF-1 genotypes in 127 (58 Caucasians, 60 African-Americans and nine Hispanics) perinatally HIV-1-infected children. RESULTS: Regardless of ethnic background, the CCR5 wt/Delta 32 genotype was associated with a delayed onset of AIDS-defining infectious complications during the first 5 years of infection [relative hazard (RH) = 0.22; 95% confidence interval (CI), 0.012--1.02; P = 0.053]. Similarly, CCR5 wt/Delta 32 conferred an early protection against severe immune suppression and HIV-1 encephalopathy, but only in those without SDF1-3'A (RH = 0; 95% CI, 0--0.70; P = 0.020, and RH = 0; 95% CI, 0--0.71; P = 0.021, respectively). When examined before 5 years of age (n = 81), the children with CCR5 wt/Delta 32 had significantly lower levels of cell-associated HIV-1 DNA than wild-type homozygotes (P = 0.016, adjusted by race), while SDF1-3'A carriers had relatively higher levels (P = 0.047, adjusted by race). Although the disease-retarding effect of CCR5 wt/Delta 32 subsequently disappeared, time to death was still significantly delayed in the CCR5 Delta 32 heterozygotes without SDF1-3'A (RH = 0; 95% CI, 0--0.53; P = 0.008). CONCLUSION: In pediatric AIDS, the protective effect of CCR5 wt/Delta 32 is more pronounced in early years of infection and appears to be abrogated by the SDF1-3'A genotype.
Subject(s)
Chemokines, CXC/genetics , HIV Infections/genetics , HIV-1 , Receptors, CCR5/genetics , Adolescent , Alleles , Base Sequence , Chemokine CXCL12 , Child , Child, Preschool , DNA, Viral/blood , Disease Progression , Genotype , HIV Infections/epidemiology , HIV Infections/pathology , Heterozygote , Humans , Infant , Proportional Hazards Models , Sequence Deletion , Survival AnalysisABSTRACT
A common polymorphism in the 3' untranslated region of the stromal cell-derived factor 1 (also called pre-B-cell-stimulating factor) beta gene transcript, termed SDF1-3'A, has been associated with an increased risk of non-Hodgkin's lymphoma (NHL) in HIV-1-infected, but not in uninfected, individuals. Because the gene variation is located within the 3' untranslated region, the SDF1-3'A may influence the abundance of SDF-1 mRNA, possibly up-regulating the chemokine expression especially in the presence of HIV-1. In the current study, we investigated the levels of SDF-1 mRNA in peripheral blood mononuclear cells and HIV-1 viral load in 84 HIV-1-infected children (0.7 to 18 years of age; median, 5.8), including 12 children who developed NHL during their illnesses (AIDS-NHL group; 8 with SDF1-3'A, 4 with SDF1-wild-type). High level SDF-1 expression was observed in 15 of 34 children with SDF1-3'A as compared with 10 of 50 with wild type (P < 0.03). More notably, the children with AIDS-NHL had significantly elevated levels of SDF-1 mRNA in peripheral blood mononuclear cells, obtained at the time of presentation in 10 children and 8.5 to 19.4 months before (median, 15 months) in 7 children, as compared with the children in the non-NHL group (P < 0.00001). The amounts of cell-associated HIV-1 DNA and singly spliced HIV-1 mRNA were significantly greater in children with AIDS-NHL than those with non-NHL AIDS (P = 0.0052 and 0.011, respectively; stratified by antiretroviral treatment regimen), whereas their serum HIV-1 RNA levels were comparable. Overexpression of SDF-1 and aberrant HIV-1 expression in circulating lymphocytes appear to be linked to the development of AIDS-lymphoma. Additional studies are required to determine whether excessive SDF-1, together with virally encoded factors, is directly involved in the pathogenesis of AIDS-lymphoma.
Subject(s)
Chemokines, CXC/genetics , HIV Infections/blood , HIV-1 , Lymphoma, AIDS-Related/blood , Lymphoma, Non-Hodgkin/blood , RNA, Messenger/blood , Adolescent , Chemokine CXCL12 , Chemokines, CXC/biosynthesis , Child , Child, Preschool , DNA, Viral/blood , Female , HIV Infections/complications , HIV Infections/genetics , Herpesvirus 4, Human/genetics , Humans , Infant , Lymphoid Tissue/metabolism , Lymphoma, AIDS-Related/genetics , Lymphoma, Non-Hodgkin/genetics , Lymphoma, Non-Hodgkin/virology , Male , RNA, Messenger/metabolism , Viral LoadSubject(s)
Acquired Immunodeficiency Syndrome/complications , Antiretroviral Therapy, Highly Active , Lung Diseases, Interstitial/physiopathology , Lymphoproliferative Disorders/physiopathology , Acquired Immunodeficiency Syndrome/drug therapy , Acquired Immunodeficiency Syndrome/physiopathology , Anti-HIV Agents/therapeutic use , Child , Disease Progression , Humans , Lung Diseases, Interstitial/etiology , Lymphoproliferative Disorders/etiologyABSTRACT
Lower respiratory tract infections in children are common and vary from relatively self-limited courses to life-threatening presentations. Recognition of disease patterns as they relate to age, sex, race, season, geography, environmental, and socioeconomic conditions is crucial in determining appropriate differential diagnosis and treatment strategies. The majority of children with respiratory infections will present to the primary care provider in an office setting and less frequently may require immediate referral from home or the outpatient setting to an emergency department. For children with recurrent or chronic respiratory infections, referral to a subspecialist may also be necessary. Primary providers are key in determining the extent of diagnostic effort, interventions, referrals, repeat evaluations, and in reinforcing treatment plans with children and their families.
