Identification of IL7RA risk alleles for rapid progression during HIV-1 infection: a comprehensive study in the GRIV cohort

Interleukin 7 (IL7) is a critical factor for lymphocyte homeostasis. A dysfunction of the IL7/IL7R pathway has previously been described in HIV-1 infection, and promising results were observed in recent analyses of IL7 for therapeutic use in HIV infected individuals. However, further investigations are still warranted to understand the possible roles of this cytokine. Here, we explored whether the IL7 and IL7RA genetic polymorphisms were associated with the progression of HIV infection. We extensively genotyped the IL7 and IL7RA genes in the GRIV (Genomics of Resistance to Immunodeficiency Virus) cohort, composed of patients with extreme progression profiles - long-term non (LTNP) and rapid (RP) progressors--, and in a healthy control group (CTR). Statistical case-control analyses were performed using the Fisher's exact test, comparing either LTNP vs CTR or RP vs CTR. Three IL7RA SNPs (single nucleotide polymorphisms--rs7701176, rs987106 and rs10491434), but no IL7 SNPs, were significantly associated with rapid disease progression (P < 0.01). In a multi-marker analysis focusing on functional variants, a strong association between an IL7RA haplotype and rapid progression was observed (P = 5.59 x 10(-3)). In summary, our comprehensive genetic study revealed three SNPs and a risk of haplotype associated with rapid progression to AIDS in the IL7RA gene. Interestingly, the haplotype is composed of SNPs previously identified in other inflammatory diseases (e.g., multiple sclerosis) by GWAS and by functional studies. Our results contribute to the growing understanding of the role of IL7/IL7R in HIV disease progression, and more widely, in CD4+ T cell homeostasis.     

Molecular characterization of human B domain-specific anti-factor VIII monoclonal antibodies generated in transgenic mice

The development of antibodies directed against factor VIII (FVIII) represents a major hurdle in the treatment of hemophilia A. Most anti-FVIII antibodies are identified through their ability to inhibit the FVIII procoagulant activity. Many of them, however, do not interfere with the functional properties of FVIII. Antibodies directed against the B domain belong to this latter category. Here, we characterized B domain-specific human monoclonal Abs (mAbs) at the molecular level. A series of human mAbs directed against FVIII was produced upon immunization of transgenic XenoMouse mice with human recombinant FVIII (rFVIII). Selection of the hybridoma with epitope specificity for the B domain was performed by differential recognition of full-length and B domain-deleted rFVIII. None of the anti-B domain mAbs demonstrated inhibitory activity against FVIII. Three of the mAbs recognized linear epitopes: mAb 25H3 bound to the (1014)HIDGPSLLIEN(1024) sequence; mAbs 8E3 and 22B6 shared the same epitope, composed of residues (1534)KWNEANR(1540). The corresponding soluble peptides inhibited the binding of their respective mAbs to FVIII. mAbs 8E3 and 22B6 displaced the binding of FVIII to vonWillebrand factor. Moreover, some of them (in particular mAbs 4G6 and 8E3) were able to compete for binding to the B domain with the anti-FVIII Abs from hemophilia A patients without inhibitor or with low Bethesda titers. Further investigation will allow to better characterize their clinical relevance.     

Comparative study of meningitis dynamics across nine African countries: a global perspective

Background  

Meningococcal meningitis (MM) represents an important public health problem especially in the "meningitis belt" in Africa. Although seasonality of epidemics is well known with outbreaks usually starting in the dry season, pluri-annual cycles are still less understood and even studied. In this context, we aimed at study MM cases time series across 9 sahelo-sudanian countries to detect pluri-annual periodicity and determine or not synchrony between dynamics. This global and comparative approach allows a better understanding of MM evolution in time and space in the long-term.     

Unprecedented heat-related deaths during the 2003 heat wave in Paris: consequences on emergency departments

In August 2003, France sustained an unprecedented heat wave that resulted in 14,800 excess deaths. The consequences were maximal in the Paris area. The Assistance Publique–H?pitaux de Paris reported more than 2600 excess emergency department visits, 1900 excess hospital admissions, and 475 excess deaths despite a rapid organization. Indeed, simple preventice measures before hospital admissions are only able to reduce mortality which mostly occurred at home and in nursing homes.     

Prognostic value of the pulmonary dead-space fraction during the first 6 days of acute respiratory distress syndrome

BACKGROUND: The ratio of pulmonary dead space to tidal volume (VD/VT) in acute respiratory distress syndrome (ARDS) is reported to be between 0.35 and 0.55. However, VD/VT has seldom been measured with consideration to the evolving pathophysiology of ARDS. METHODS: We made serial VD/VT measurements with 59 patients who required mechanical ventilation for > or = 6 days. We measured VD/VT within 24 h of the point at which the patient met the American-European Consensus Conference criteria for ARDS, and we repeated the VD/VT measurement on ARDS days 2, 3, and 6 with a bedside metabolic monitor during volume-regulated ventilation. We analyzed the changes in VD/VT over the 6-day period to determine whether VD/VT has a significant association with mortality. RESULTS: VD/VT was significantly higher in nonsurvivors on day 1 (0.61 +/- 0.09 vs 0.54 +/- 0.08, p < 0.05), day 2 (0.63 +/- 0.09 vs 0.53 +/- 0.09, p < 0.001), day 3 (0.64 +/- 0.09 vs 0.53 +/- 0.09, p < 0.001), and day 6 (0.66 +/- 0.09 vs 0.51 +/- 0.08, p < 0.001). CONCLUSION: In ARDS a sustained VD/VT elevation is characteristic of nonsurvivors, so dead-space measurements made beyond the first 24 hours may have prognostic value.     

DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells

Dendritic cells (DCs) are essential for the early events of human immunodeficiency virus (HIV) infection. Model systems of HIV sexual transmission have shown that DCs expressing the DC-specific C-type lectin DC-SIGN capture and internalize HIV at mucosal surfaces and efficiently transfer HIV to CD4+ T cells in lymph nodes, where viral replication occurs. Upon DC-T cell clustering, internalized HIV accumulates on the DC side at the contact zone (infectious synapse), between DCs and T cells, whereas HIV receptors and coreceptors are enriched on the T cell side. Viral concentration at the infectious synapse may explain, at least in part, why DC transmission of HIV to T cells is so efficient.Here, we have investigated the role of DC-SIGN on primary DCs in X4 HIV-1 capture and transmission using small interfering RNA-expressing lentiviral vectors to specifically knockdown DC-SIGN. We demonstrate that DC-SIGN- DCs internalize X4 HIV-1 as well as DC-SIGN+ DCs, although binding of virions is reduced. Strikingly, DC-SIGN knockdown in DCs selectively impairs infectious synapse formation between DCs and resting CD4+ T cells, but does not prevent the formation of DC-T cells conjugates.Our results demonstrate that DC-SIGN is required downstream from viral capture for the formation of the infectious synapse between DCs and T cells. These findings provide a novel explanation for the role of DC-SIGN in the transfer and enhancement of HIV infection from DCs to T cells, a crucial step for HIV transmission and pathogenesis.