The clinical course of HIV-1 infection is highly variable among individuals, at least in part as a result of genetic polymorphisms in the host. Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these receptors have been associated with increased or decreased susceptibility to infections. To determine whether single-nucleotide polymorphisms (SNPs) in TLR2–4 and TLR7–9 influenced the natural course of HIV-1 infection. Twenty-eight SNPs in TLRs were analysed in HAART-naive HIV-positive patients from the Swiss HIV Cohort Study. The SNPs were detected using Sequenom technology. Haplotypes were inferred using an expectation–maximization algorithm. The CD4 T cell decline was calculated using a least-squares regression. Patients with a rapid CD4 cell decline, less than the 15th percentile, were defined as rapid progressors. The risk of rapid progression associated with SNPs was estimated using a logistic regression model. Other candidate risk factors included age, sex and risk groups (heterosexual, homosexual and intravenous drug use). Two SNPs in TLR9 (1635A/G and +1174G/A) in linkage disequilibrium were associated with the rapid progressor phenotype: for 1635A/G, odds ratio (OR), 3.9 [95% confidence interval (CI),1.7–9.2] for GA versus AA and OR, 4.7 (95% CI,1.9–12.0) for GG versus AA (P = 0.0008). Rapid progression of HIV-1 infection was associated with TLR9 polymorphisms. Because of its potential implications for intervention strategies and vaccine developments, additional epidemiological and experimental studies are needed to confirm this association.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFα) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p<10⁻³) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal α = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFα p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFα p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system.

Purpose: In this study, the authors determined adolescent speech, language, and literacy outcomes of individuals with histories of early childhood speech sound disorders (SSD) with and without comorbid language impairment (LI) and examined factors associated with these outcomes. Method: This study used a prospective longitudinal design. Participants with SSD ( n = 170), enrolled at early childhood (4–6 years) were followed at adolescence (11–18 years) and were compared to individuals with no histories of speech or language impairment (no SSD; n = 146) on measures of speech, language, and literacy. Comparisons were made between adolescents with early childhood histories of no SSD, SSD only, and SSD plus LI as well as between adolescents with no SSD, resolved SSD, and persistent SSD. Results: Individuals with early childhood SSD with comorbid LI had poorer outcomes than those with histories of SSD only or no SSD. Poorer language and literacy outcomes in adolescence were associated with multiple factors, including persistent speech sound problems, lower nonverbal intelligence, and lower socioeconomic status. Adolescents with persistent SSD had higher rates of comorbid LI and reading disability than the no SSD and resolved SSD groups. Conclusion: Risk factors for language and literacy problems in adolescence include an early history of LI, persistent SSD, lower nonverbal cognitive ability, and social disadvantage.