Reduced mortality and CD4 cell loss among carriers of the interleukin-10 -1082G allele in a Zimbabwean cohort of HIV-1-infected adults.

OBJECTIVES: To evaluate the effect on HIV progression of single nucleotide polymorphisms in promoters of the genes for tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 and known to influence cytokine production. METHODS: Survival was documented for 4.3 years after baseline for 198 HIV-1-infected and 180 HIV-uninfected individuals from the Mupfure Schistosomiasis and HIV Cohort in rural Zimbabwe. Polymorphisms determined were -592C>A and -1082A>G for IL-10 and -238G>A and -308G>A for TNF-alpha. CD4 cell counts, plasma HIV RNA, soluble TNF receptor II (sTNF-rII), IL-8 and IL-10 were also measured. RESULTS: Mortality was lower in carriers of the IL-10 -1082G high-producer allele (hazard ratio, 0.47; P < 0.01). CD4 cell count decrease in participants reporting for the follow-up at 3 years was attenuated in carriers of this allele (P < 0.01). In univariate analysis, plasma IL-10, IL-8, and sTNF-rII correlated negatively with CD4 cell count, positively with HIV RNA, and higher levels predicted mortality. In multivariate analysis only sTNF-rII was an independent predictor of HIV progression markers and mortality. Indeed, sTNF-rII predicted mortality (P < 0.01) at a level of significance comparable to HIV RNA (P < 0.01) and CD4 cell count (P < 0.05). CONCLUSIONS: In carriers of IL-10 -1082G, an allele linked to increased IL-10 production, survival was doubled and CD4 cell decrease was attenuated compared with noncarriers. Only sTNF-rII and not plasma IL-10 was an independent predictor of HIV progression markers and mortality. This study supports immune activation as a driving force in HIV pathogenesis and indicates a protective role of IL-10 -1082G that should be evaluated in other cohorts.

HIV-1 Vertical Transmission in Zimbabwe in 622 Mother and Infant Pairs: Rethinking the Contribution of Mannose Binding Lectin Deficiency in Africa.

Vertical transmission of human immunodeficiency virus (HIV) remains a major global health problem. We assessed the association of mannose binding lectin (MBL) deficiency and vertical transmission of HIV. Novel diagnostics would be a major breakthrough in this regard. MBL is a liver-derived protein and a key component of the innate immune system. MBL levels may be classified as normal, intermediate, or deficient in the plasma and can use MBL2 haplotypes as a proxy. These haplotypes comprise polymorphisms in the MBL2 gene and promoter region and are known to result in varying levels of MBL deficiency. MBL deficiency can be defined as presence of A/O and O/O genotypes in the mothers and their children. MBL deficiency leads to defective opsonization activities of the innate immune system and increased susceptibility to several infections, including HIV-1. We determined the prevalence of MBL deficiency, using MBL2 haplotypes among 622 HIV-positive Zimbabwean mothers and their children aged 9-18 months old, in relation to the HIV-1 vertical transmission risk. The median age of the mothers was 30 (26-34, interquartile range [IQR]) years, and the babies' median age was 13 (11-15, IQR) months old at the time of enrollment. From the sample of 622 mothers who were HIV-1 infected, 574 babies were HIV negative and 48 were HIV-1-positive babies, giving a transmission rate of 7.7%. MBL2 normal structural allele A and variants B (codon 5 A>G), C (codon 57 A>G), and promoter region SNPs -550(H/L) and -221(X/Y) were detected. Prevalence of haplotype-predicted MBL deficiency was 34% among the mothers and 32% among the children. We found no association between maternal MBL2 deficiency and HIV-1 transmission to their children. We found no difference in the distribution of HIV-1 infected and uninfected children between the MBL2 genotypes of the mothers and those of the children. Taken together, the present study in a large sample of mother-infant pairs in Zimbabwe adds to the emerging literature and the hypothesis that MBL2 variation as predicted by haplotypes does not influence the vertical transmission risk for HIV. Research from other populations from the African continent is called for to test this hypothesis further.

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.

HIV-1 Disease Progression and Survival in an Adult Population in Zimbabwe: Is There an Effect of the Mannose Binding Lectin Deficiency?

HIV infection remains a major global health burden since its discovery in 1983. Sub-Saharan Africa is the region hardest hit by the HIV/AIDS pandemic where 63% of the 33 million infected people live. While there is marked person-to-person variability in susceptibility, progression, and survival with HIV infection, there is a paucity of predictive diagnostics associated with these clinical endpoints. In this regard, the deficiency in plasma Mannose Binding Lectin (MBL) is a common opsonic defect reported to increase susceptibility infections, including HIV. To the best of our knowledge, we report here the first study on the putative role of MBL deficiency on HIV progression and survival in an African adult population. We hypothesized that MBL deficiency has a role to play in HIV infection by increasing HIV disease progression and decreasing survival. We assessed the role of MBL deficiency on HIV disease progression and survival in a Zimbabwean adult population enrolled in the Mupfure Schistosomiasis and HIV (MUSH) cohort. We analyzed blood samples for MBL levels, MBL2 genotypes, HIV-1 status, viral load, and CD4(+) T cell counts. Participants were followed for 3 years wherein the endpoints were measured at baseline, 6 weeks, and 3, 6, 12, 24, and 36 months. Disease progression was measured as the rate of decline in CD4(+) T cell counts and the rate of increase in HIV viral load. We assessed 197 HIV positive adults where 83% (164) were women with a median age of 31 years. Prevalence of plasma MBL deficiency (less than 100 µg/L) and MBL2 deficient genetic variants (A/O and O/O genotypes) was 21% (42 out of 197) and 39% (74 out of 190), respectively. We did not observe a significant role to explain individual variation in mortality, change of CD4(+) T cell count, and viral load by MBL plasma deficiency or MBL2 genetic variants from baseline to 3 years follow up period in this adult population. We suggest the need for global OMICS research and that the present findings attest to the large between-population variability in a host of factors that can predispose individuals susceptible to HIV progression and mortality. We therefore cannot recommend at this time the use of plasma MBL levels or MBL2 genetic variants as a prognostic marker in HIV infection, disease progression, and survival in this adult population in Africa.

p24 as a predictor of mortality in a cohort of HIV-1-infected adults in rural Africa.

BACKGROUND: Implementation of antiretroviral treatment in sub-Saharan Africa requires efficient tools to monitor HIV patients. p24 measurements have been proposed as an alternative to HIV-RNA because of the low cost of reagents and equipment needed. Here, we evaluate p24 as a prognostic marker in a cohort of HIV-1-infected individuals in Zimbabwe. METHODS: Treatment-naive HIV-1-infected individuals (n=198) from the Mupfure Schistosomiasis and HIV Cohort were followed until death or censoring (3-4.3 years). At baseline, p24, HIV-RNA, CD4 cell counts, and clinical staging (Centers for Disease Control and Prevention classification) were assessed. RESULTS: p24 correlated with HIV-RNA (P<0.0001, R: 0.44). Ten percent of p24 but only 1% of HIV-RNA measurements was undetectable. p24 predicted Centers for Disease Control and Prevention category (P<0.001) stronger than CD4 count (P=0.34) in multivariate logistic regression. p24 predicted mortality in univariate Cox analysis (P<0.0001) and in multivariate analysis, but it was inferior to HIV-RNA and CD4 count. CONCLUSIONS: This is the first study to evaluate the prognostic strength of p24 in an area with a predominance of HIV subtype C infections. p24 correlated with HIV-RNA and predicted clinical stage better than CD4 count. It predicted mortality in both univariate and multivariate analysis, but in multivariate analysis, it was inferior to HIV-RNA and CD4 count.

Schistosomiasis and infection with human immunodeficiency virus 1 in rural Zimbabwe: systemic inflammation during co-infection and after treatment for schistosomiasis.

We previously reported that treatment for schistosomiasis in persons infected with human immunodeficiency virus 1 (HIV-1) attenuated HIV replication as measured by plasma HIV RNA. We investigated systemic inflammation as measured by plasma levels of soluble tumor necrosis factor-alpha receptor II (sTNF-rII), interleukin-8, (IL-8), and IL-10 during schistosomiasis and HIV co-infection and after schistosomiasis treatment. The cohort was composed of 378 persons who were or were not infected with HIV-1, Schistosoma haematobium, or S. mansoni. Schistosomiasis-infected persons were randomized to receive praziquantel (40 mg/kg) at baseline or at the three-month follow-up. sTNF-rII and IL-8 were positively associated with schistosomiasis intensity as measured by circulating anodic antigen (CAA), regardless of HIV status. Interleukin-10 was positively associated with CAA in HIV-negative participants. IL-8 levels were higher in S. mansoni-infected individuals. Treatment for schistosomiasis caused a decrease in levels of sTNF-rII (P < 0.05) and IL-10 (P < 0.001). Our results indicate that schistosomiasis treatment may attenuate HIV replication by decreasing systemic inflammation.