Role of Mannose-Binding Lectin Deficiency in HIV-1 and Schistosoma Infections in a Rural Adult Population in Zimbabwe

Background

Polymorphism in the MBL2 gene lead to MBL deficiency, which has been shown to increase susceptibility to various bacterial, viral and parasitic infections. We assessed role of MBL deficiency in HIV-1 and schistosoma infections in Zimbabwean adults enrolled in the Mupfure Schistosomiasis and HIV Cohort (MUSH Cohort).

Methods

HIV-1, S. haematobium and S. mansoni infections were determined at baseline. Plasma MBL concentration was measured by ELISA and MBL2 genotypes determined by PCR. We calculated and compared the proportions of plasma MBL deficiency, MBL2 structural variant alleles B (codon 54A>G), C (codon 57A>G), and D (codon 52T>C) as well as MBL2 promoter variants -550(H/L), -221(X/Y) and +4(P/Q) between HIV-1 and schistosoma co-infection and control groups using Chi Square test.

Results

We assessed 379 adults, 80% females, median age (IQR) 30 (17–41) years. HIV-1, S. haematobium and S. mansoni prevalence were 26%, 43% and 18% respectively in the MUSH baseline survey. Median (IQR) plasma MBL concentration was 800μg/L (192-1936μg/L). Prevalence of plasma MBL deficiency was 18% with high frequency of the C (codon 57G>A) mutant allele (20%). There was no significant difference in median plasma MBL levels between HIV negative (912μg/L) and HIV positive (688μg/L), p = 0.066. However plasma MBL levels at the assay detection limit of 20μg/L were more frequent among the HIV-1 infected (p = 0.007). S. haematobium and S. mansoni infected participants had significantly higher MBL levels than uninfected. All MBL2 variants were not associated with HIV-1 infection but promoter variants LY and LL were significantly associated with S. haematobium infection.

Conclusion

Our data indicate high prevalence of MBL deficiency, no evidence of association between MBL deficiency and HIV-1 infection. However, lower plasma MBL levels were protective against both S. haematobium and S. mansoni infections and MBL2 promoter and variants LY and LL increased susceptibility to S. haematobium infection.     

Longitudinal Analysis of CCR5 and CXCR4 Usage in a Cohort of Antiretroviral Therapy-Na?ve Subjects with Progressive HIV-1 Subtype C Infection

HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naïve subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an “Ile-Gly” insertion in the gp120 V3 loop and replacement of the V3 “Gly-Pro-Gly” crown with a “Gly-Arg-Gly” motif, but that the accumulation of additional gp120 “scaffold” mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage.     

Post Diagnosis Diet Quality and Colorectal Cancer Survival in Women

Background

Dietary factors are known to influence colorectal cancer (CRC) risk, however, their association with CRC survival is unclear. Therefore, we prospectively examined the association between diet quality scores, dietary patterns and colorectal cancer (CRC) survival.

Methods

1201 women diagnosed with stage I–III CRC between 1986 and 2008, were followed through 2010. Diet was assessed via a food frequency questionnaire administered at least 6 months after diagnosis. We computed the Alternate Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean Diet score (aMED) and Dietary Approaches to Stop Hypertension score (DASH) and derived two dietary patterns, Western (unhealthy) and prudent (healthy), by principal component analysis for each woman.

Results

During follow-up, we documented 435 deaths, including 162 from CRC. After adjusting for potential confounders, only a higher AHEI-2010 score was significantly associated with lower overall mortality (HR comparing extreme quintiles = 0.71, 95% CI 0.52–0.98, p trend = 0.01) as well as borderline significantly with lower risk of CRC mortality by the trend test (HR Q5 vs Q1 = 0.72, 95% CI = 0.43–1.21, p trend = 0.07). When AHEI-2010 components were examined separately, inverse associations for overall mortality were primarily accounted for by moderate alcohol intake (HR comparing abstainers vs 5–15 g/d = 1.30, 95%CI = 1.05–1.61) and lower intake of sugar sweetened beverages and fruit juices combined (HR for each additional serving = 1.11, 95% CI = 1.01–1.23). No other diet quality score or dietary pattern was associated with overall or CRC-specific mortality.

Conclusion

Higher AHEI-2010 score may be associated with lower overall mortality, moderate alcohol consumption and lower consumption of sugar sweetened beverages and juices combined appeared to account for most of the observed associations.     

Multi-Donor Longitudinal Antibody Repertoire Sequencing Reveals the Existence of Public Antibody Clonotypes in HIV-1 Infection

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