Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.
Elite controllers are a distinct group, even when compared to persons with low level viremia, but they exhibit marked genetic and immunologic heterogeneity. Even low-level viremia among HIV controllers was associated with measurable T cell dysfunction, which has implications for current prophylactic vaccine strategies.
Background
HIV-1 elite controllers are able to control virus replication to levels below the limits of detection by commercial assays, but the actual level of viremia in these individuals is not well defined. Here we quantify plasma HIV-1 RNA in elite controllers and correlate this with specific immunologic parameters.
Methods
Plasma HIV- 1 RNA levels were quantified in 90 elite controllers using a real time RT-PCR assay with a sensitivity of 0.2 copies/ml. HIV-specific immune responses and longitudinal CD4+ T cell counts were examined.
Results
Median plasma HIV-1 RNA was 2 copies/ml (IQR 0.2–14 copies/ml). Longitudinal analysis of 31 elite controllers showed 2–5 fold fluctuations in viremia in the majority of individuals; 6 had persistent levels below 1 copy/ml. Viremia correlated directly with HIV specific neutralizing antibodies and Western Blot reactivity, but not with CD8+ T cell responses. Absolute CD4+ T cell decline was more common among individuals with detectable viremia (p=0.04).
Conclusions
Low-level viremia is present in the majority of elite controllers and is associated with higher HIV specific antibody responses. Absolute CD4+ T cell loss is more common among viremic individuals, suggesting that even very low-level viremia has negative consequences over time.
BackgroundStudies throughout Northern Europe, the United States and Australia have found an association between childhood attention deficit hyperactivity disorder (ADHD) and family socioeconomic disadvantage. We report further evidence for the association and review potential causal pathways that might explain the link.MethodSecondary analysis of a UK birth cohort (the Millennium Cohort Study, N = 19,519) was used to model the association of ADHD with socioeconomic disadvantage and assess evidence for several potential explanatory pathways. The case definition of ADHD was a parent-report of whether ADHD had been identified by a medical doctor or health professional when children were 7 years old.ResultsADHD was associated with a range of indicators of social and economic disadvantage including poverty, housing tenure, maternal education, income, lone parenthood and younger motherhood. There was no evidence to suggest childhood ADHD was a causal factor of socioeconomic disadvantage: income did not decrease for parents of children with ADHD compared to controls over the 7-year study period. No clinical bias towards labelling ADHD in low SES groups was detected. There was evidence to suggest that parent attachment/family conflict mediated the relationship between ADHD and SES.ConclusionAlthough genetic and neurological determinants may be the primary predictors of difficulties with activity level and attention, aetiology appears to be influenced by socioeconomic situation.
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