transformers safetensors deberta-v2 question-answering license:mit endpoints_compatible region:us
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- text: How many children were infected by HIV-1 in 2008-2009, worldwide?
  context: 'Functional Genetic Variants in DC-SIGNR Are Associated with Mother-to-Child
    Transmission of HIV-1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752805/ Boily-Larouche,
    Geneviève; Iscache, Anne-Laure; Zijenah, Lynn S.; Humphrey, Jean H.; Mouland,
    Andrew J.; Ward, Brian J.; Roger, Michel 2009-10-07 DOI:10.1371/journal.pone.0007211
    License:cc-by Abstract: BACKGROUND: Mother-to-child transmission (MTCT) is the
    main cause of HIV-1 infection in children worldwide. Given that the C-type lectin
    receptor, dendritic cell-specific ICAM-grabbing non-integrin-related (DC-SIGNR,
    also known as CD209L or liver/lymph node–specific ICAM-grabbing non-integrin (L-SIGN)),
    can interact with pathogens including HIV-1 and is expressed at the maternal-fetal
    interface, we hypothesized that it could influence MTCT of HIV-1. METHODS AND
    FINDINGS: To investigate the potential role of DC-SIGNR in MTCT of HIV-1, we carried
    out a genetic association study of DC-SIGNR in a well-characterized cohort of
    197 HIV-infected mothers and their infants recruited in Harare, Zimbabwe. Infants
    harbouring two copies of DC-SIGNR H1 and/or H3 haplotypes (H1-H1, H1-H3, H3-H3)
    had a 3.6-fold increased risk of in utero (IU) (P = 0.013) HIV-1 infection and
    a 5.7-fold increased risk of intrapartum (IP) (P = 0.025) HIV-1 infection after
    adjusting for a number of maternal factors. The implicated H1 and H3 haplotypes
    share two single nucleotide polymorphisms (SNPs) in promoter region (p-198A) and
    intron 2 (int2-180A) that were associated with increased risk of both IU (P =
    0.045 and P = 0.003, respectively) and IP (P = 0.025, for int2-180A) HIV-1 infection.
    The promoter variant reduced transcriptional activity in vitro. In homozygous
    H1 infants bearing both the p-198A and int2-180A mutations, we observed a 4-fold
    decrease in the level of placental DC-SIGNR transcripts, disproportionately affecting
    the expression of membrane-bound isoforms compared to infant noncarriers (P =
    0.011). CONCLUSION: These results suggest that DC-SIGNR plays a crucial role in
    MTCT of HIV-1 and that impaired placental DC-SIGNR expression increases risk of
    transmission. Text: Without specific interventions, the rate of HIV-1 mother-tochild
    transmission (MTCT) is approximately 15-45% [1] . UNAIDS estimates that last year
    alone, more than 400,000 children were infected worldwide, mostly through MTCT
    and 90% of them lived in sub-Saharan Africa. In the most heavilyaffected countries,
    such as Zimbabwe, HIV-1 is responsible for one third of all deaths among children
    under the age of five. MTCT of HIV-1 can occur during pregnancy (in utero, IU),
    delivery (intrapartum, IP) or breastfeeding (postpartum, PP). High maternal viral
    load, low CD4 cells count, vaginal delivery, low gestational age have all been
    identified as independent factors associated with MTCT of HIV-1 [1] . Although
    antiretrovirals can reduce MTCT to 2%, limited access to timely diagnostics and
    drugs in many developing world countries limits the potential impact of this strategy.
    A better understanding of the mechanisms acting at the maternal-fetal interface
    is crucial for the design of alternative interventions to antiretroviral therapy
    for transmission prevention. Dendritic cell-specific ICAM-grabbing non-integrin-related
    (DC-SIGNR, also known as CD209L or liver/lymph node-specific ICAM-grabbing non-integrin
    (L-SIGN)) can interact with a plethora of pathogens including HIV-1 and is expressed
    in placental capillary endothelial cells [2] . DC-SIGNR is organized in three
    distinct domains, an N-terminal cytoplasmic tail, a repeat region containing seven
    repeat of 23 amino acids and a C-terminal domain implicated in pathogen binding.
    Alternative splicing of DC-SIGNR gene leads to the production of a highly diversify
    isoforms repertoire which includes membrane-bound and soluble isoforms [3] . It
    has been proposed that interaction between DC-SIGNR and HIV-1 might enhance viral
    transfer to other susceptible cell types [2] but DC-SIGNR can also internalize
    and mediate proteasome-dependant degradation of viruses [4] that may differently
    affect the outcome of infection. Given the presence of DC-SIGNR at the maternal-fetal
    interface and its interaction with HIV-1, we hypothesized that it could influence
    MTCT of HIV-1. To investigate the potential role of DC-SIGNR in MTCT of HIV-1,
    we carried out a genetic association study of DC-SIGNR in a well-characterized
    cohort of HIV-infected mothers and their infants recruited in Zimbabwe, and identified
    specific DC-SIGNR variants associated with increased risks of HIV transmission.
    We further characterized the functional impact of these genetic variants on DC-SIGNR
    expression and show that they affect both the level and type of DC-SIGNR transcripts
    produced in the placenta. Samples consisted of stored DNA extracts obtained from
    197 mother-child pairs co-enrolled immediately postpartum in the ZVITAMBO Vitamin
    A supplementation trial (Harare, Zimbabwe) and followed at 6 weeks, and 3-monthly
    intervals up to 24 months. The ZVITAMBO project was a randomized placebocontrolled
    clinical trial that enrolled 14,110 mother-child pairs, between November 1997
    and January 2000, with the main objective of investigating the impact of immediate
    postpartum vitamin A supplementation on MTCT of HIV-1. The samples used in the
    present study were from mother-child pairs randomly assigned to the placebo group
    of the ZVITAMBO project. Antiretroviral prophylaxis for HIV-1-positive antenatal
    women was not available in the Harare public-sector during ZVITAMBO patient recruitment.
    The samples were consecutively drawn from two groups: 97 HIV-1-positive mother/HIV-1-positive
    child pairs and 100 HIV-1-positive mother/HIV-negative child pairs. Mother''s
    serological status was determined by ELISA and confirmed by Western Blot. Infants
    were considered to be infected if they were HIV-1 seropositive at 18 months or
    older and had two or more positive HIV-1-DNA polymerase chain reaction (PCR) results
    at earlier ages. 100 infants were considered to be uninfected as they were ELISA
    negative at 18 months or older and had two DNA PCR negative results from samples
    collected at a younger age. Of the 97 HIV-1-infected infants, 57 were infected
    IU, 11 were infected IP, and 17 were infected PP as determined by PCR analyses
    of blood samples collected at birth, 6 weeks, 3 and 6 months of age and according
    to the following definitions adapted from Bryson and colleagues [5] . Briefly,
    infants who were DNA PCR positive at birth were infected IU. Infants with negative
    PCR results from sample obtained at birth but who become positive by 6 weeks of
    age were infected IP. Infants with negative PCR results at birth and 6 weeks of
    age but who subsequently became DNA PCR positive were considered to be infected
    during the PP period. In the analysis comparing the 3 different modes of MTCT,
    12 HIV-1-infected infants were excluded because the PCR results were not available
    at 6 weeks of age. Full methods for recruitment, baseline characteristics collection,
    laboratory procedures have been described elsewhere [6] . The nucleotide sequence
    variation of the entire promoter, coding and part of 39-UTR regions of DC-SIGNR
    gene in the study population was determined previously [7] . Haplotype reconstruction
    was performed using Bayesian statistical method implemented in PHASE [8] , version
    2.1.1, using single nucleotide polymorphism (SNP) with a minimum allele frequency
    (MAF) of 2%. We applied the algorithm five times, using different randomly generated
    seeds, and consistent results were obtained across runs ( Figure 1 ). Fifteen
    haplotype-tagged SNPs (htSNPs) were identified by the HaploBlockFinder software
    [9] with a MAF $5%. These htSNPs were genotyped in the 197 infants by direct PCR
    sequencing analysis as we have described previously [7] . The DC-SIGNR exon 4
    repeat region genotype was determined by PCR amplification followed by migration
    in 1.5% agarose gels [10] . DNA sequences in the promoter region were analysed
    with the TESS interface (http//:www.cbil.upenn.edu/tess) for putative transcription
    factors binding sites using the TRANSFAC database. Luciferase reporter assays
    using pGL2-Basic vector were performed in order to investigate the functional
    effect of mutations on DC-SIGNR promoter activity. Genomic DNA from subjects homozygous
    for the promoter variants and WT was amplified from nucleotide position 2715 to
    21 and cloned between the BglII and HindIII multiple cloning sites in the pGL2-Basic
    vector which harbours a reporter firefly luciferase gene downstream (Invitrogen
    Canada inc, Burlington, Canada). All recombinants clones were verified by DNA
    sequencing. The firefly luciferase test reporter vector was co-transfected at
    a ratio of 10:1 with the constitutive expressor of Renilla luciferase, phRL-CMV
    (Promega, Madison, WI, USA). We cultured HeLa cells in 6 wells plates (2610 5
    cells) and transfected them the following day using lipofectamine (Invitrogen)
    according to the manufacturer. Cells were lysed and luciferase assays were performed
    using 20 mg of protein extract according to the manufacturer (Promega) at 44 h
    post-transfection. Firefly luciferase activity was normalized to Renilla luciferase
    activity. 0 mg, 0,5 mg or 1 mg CMV-Tat vector was transfected with LTR-Luc as
    a positive control in these experiments. We carried out lucierase assays in triplicate
    in three independent experiments. Results are expressed as mean6 standard error
    of the mean (S.E.M). First-term placental tissues were obtained from abortions
    following voluntary interruption of pregnancy at CHUM Hôpital Saint-Luc (Montreal,
    Canada). Tissues from 3 H1 (associated with MTCT of HIV-1) and 3 H15 (wild-type)
    homozygous haplotypes were used to analyse possible differences in isoform expression.
    Total placental RNAs were extracted by MasterPure DNA and RNA Extraction Kit (Epicentre
    Biotechnologies, Madison, WI, USA) according to the manufacturer. Fragments corresponding
    to the DC-SIGNR coding region were reversed transcribed (RT) and then amplified
    by nested PCR with the following primers; RT primers RR, first PCR RF and RR and
    second PCR RcF and RcR according to Liu and colleagues [11] . 1 mg of total RNA
    was reverse transcribed with Expand RT (Roche Applied Science, Indianapolis, IN,
    USA) according to the manufacturer and were PCR-amplified with DNA Platinum Taq
    Polymerase (Invitrogen). Major PCR products from the second PCR reaction were
    gel extracted with the Qiagen Gel Extraction Kit (Qiagen Canada inc, Mississauga,
    ON, Canada) and cloned using the TOPO TA Cloning Kit for sequencing (Invitrogen).
    For each placenta, 15 different clones were randomly selected and amplified with
    M13 primers and sequenced with ABI PRISM 3100 capillary automated sequencer (Applied
    Biosystems, Foster City, CA, USA). Sequences were analysed and aligned with GeneBank
    reference sequence NM_014257 using Lasergene software (DNA Stars, Madison, WI,
    USA). Quantitative expression of DC-SIGNR isoforms 1,5 mg of placental RNA was
    reverse transcribed using 2.5 mM of Oligo dT 20 and Expand RT in 20 ml volume
    according to the manufacturer (Roche Applied Science). 15 ng of total cDNA in
    a final volume of 20 ml was used to perform quantitative real-time PCR using Universal
    Express SYBR GreenER qPCR Supermix (Invitrogen) on a Rotor Gene Realtime Rotary
    Analyser (Corbett Life Science, Sydney, Australia). Samples from 2 subjects in
    each group were used because RNA quality of others was not suitable for a qRT-PCR
    analysis. Amplification of all DC-SIGNR isoforms was performed using an exon 5
    specific primer pair (Table S1 ). Membrane-bound isoforms were amplified using
    primers specific for exon 3, corresponding to the common trans-membrane domain
    of DC-SIGNR. Primers were targeted to the exon-exon junction and RNA extracts
    were treated with DNase (Fermantas International inc, Burlington, ON, Canada)
    to avoid amplification of contaminant DNA. Standard curves (50-500 000 copies
    per reaction) were generated using serial dilution of a full-length DC-SIGNR or
    commercial GAPDH (Invitrogen) plasmid DNA. All qPCR reactions had efficiencies
    ranging from 99% to 100%, even in the presence of 20 ng of non-specific nucleic
    acids, and therefore could be compared. The copy number of unknown samples was
    estimated by placing the measured PCR cycle number (crossing threshold) on the
    standard curve. To correct for differences in both RNA quality and quantity between
    samples, the expression levels of transcripts were normalised to the reference
    GAPDH gene transcripts. GAPDH primer sequences were kindly provided by A. Mes-Masson
    at the CHUM. The results are presented as target gene copy number per 10 5 copies
    of GAPDH. The ratio of membrane-bound isoforms was calculated as E3/E5. Soluble
    isoforms were calculated by subtracting membrane-bound from total isoforms. We
    carried out qPCR assays in triplicate in three independent experiments. Results
    are expressed as mean6S.E.M. Statistical analysis was performed using the GraphPad
    PRISM 5.0 for Windows (GraphPad Software inc, San Diego, CA, USA). Differences
    in baseline characteristics and genotypic frequencies of haplotypes or htSNPs
    were compared between groups using the x 2 analysis or Fisher''s exact test. Logistic
    regression analysis was used to estimate odds ratios (OR) for each genotype and
    baseline risk factors. Multiple logistic regression was used to define independent
    predictors identified as significant in the crude analysis. ORs and 95% confidence
    interval were calculated with the exact method. Comparisons of continuous variables
    between groups were assessed with the unpaired two-tailed Student''s t test when
    variables were normally distributed and with the Mann-Whitney U test when otherwise.
    Differences were considered significant at P,0.05. Written informed consent was
    obtained from all mothers who participated in the study and the ZVITAMBO trial
    and the investigation reported in this paper were approved by The We carried out
    an association study of DC-SIGNR polymorphism in 197 infants born to untreated
    HIV-1-infected mothers recruited in Harare, Zimbabwe. Among them, 97 infants were
    HIV-1-infected and 100 infants remained uninfected. Of the 97 HIV-1-infected infants,
    57 were infected IU, 11 were infected IP, and 17 were infected PP. Timing of infection
    was not determined for 12 HIV-1-infected infants. Baseline characteristics of
    mothers and infants are presented in Table 1 . Maternal age and CD4 cell count,
    child sex, mode of delivery, duration of membrane rupture and gestational age
    were similar among all groups. However, maternal viral load .29 000 copies/ml
    was associated with increased risk in both IU and PP with odds ratios (OR) of
    3.64 (95% CI = 1.82-7.31, P = 0.0002) and 4.45 (95% CI = 1.50-13.2, P = 0.0045)
    for HIV-1 transmission, respectively. Fifteen haplotype-tagged SNPs (htSNPs) corresponding
    to the 15 major DC-SIGNR haplotypes ( Figure 1 ) described among Zimbabweans [7]
    were genotyped in our study samples (Tables S2 and S3 ). H1 (31%) and H3 (11%)
    were the most frequent haplotypes observed (Figure 1 ). Being homozygous for the
    H1 haplotype was associated with increased risk of both IU (OR: 4.42, P = 0.022)
    and PP (OR: 7.31, P = 0.016) HIV-1 transmission ( Table 2) . Infants harbouring
    two copy combinations of H1 and/ or H3 haplotypes (H1-H1, H1-H3 or H3-H3) had
    increased risk of IU (OR: 3.42, P = 0.007) and IP (OR: 5.71, P = 0.025) but not
    PP (P = 0.098) HIV-1 infection compared to infant noncarriers ( Table 2 ). The
    latter associations remained significant after adjustment was made for the maternal
    viral load for both IU (OR: 3.57, 95% CI = 1.30-9.82, P = 0.013) and IP (OR: 5.71,
    95% CI = 1.40-23.3, P = 0.025) HIV-1 transmission. The H1 and H3 haplotypes share
    a cluster of mutations (p-198A, int2-391C, int2-180A, ex4RPT, int5+7C) ( Figure
    1 ). Of these, the p-198A and int2-180A variants were significantly associated
    with MTCT of HIV-1 (Table S2 ). In the unadjusted regression analysis, homozygous
    infants for the p-198A and int2-180A variants had increased risk of IU (OR: 2.07
    P = 0.045, OR: 3.78, P = 0.003, respectively) and IP (OR: 2.47, P = 0.17, O.R:
    5.71, P = 0.025, respectively) HIV-1 infection compared to heterozygote infants
    or noncarriers (Table 3) . When adjustment was made for maternal factors, only
    the association with the int2-180A variant remained significant for IU (OR: 3.83,
    95% CI = 1.42-10.4, P = 0.008) and IP (O.R: 5.71, 95% CI = 1.40-23.3, P = 0.025)
    HIV-1 transmission. Thus, infants homozygous for DC-SIGNR variant int2-180A contained
    in H1 and H3 haplotypes were 4-fold to 6-fold more likely to be infected by HIV-1
    during pregnancy or at delivery, respectively. Alternative splicing of the DC-SIGNR
    gene in the placenta produces both membrane-bound and soluble isoform repertoires
    [3] . The relative proportion of membrane bound and soluble DC-SIGNR could plausibly
    influence the susceptibility to HIV-1 infection [11] . We therefore hypothesized
    that the DC-SIGNR mutations associated with MTCT of HIV-1 would have an impact
    on both the level of DC-SIGNR expression and in the isoform repertoire produced.
    We investigated DC-SIGNR transcript expression in first-term placentas obtained
    after elective abortion. We cloned DC-SIGNR from placental tissues by RT-PCR from
    3 homozygous H1 samples containing both the DC-SIGNR p-198AA and int2-180AA variants
    associated with HIV-1 transmission and 3 homozygous wild-type (WT) (p-198CC, int2-180GG)
    samples. Fifteen clones per sample were randomly selected for sequencing. As expected,
    we found an extensive repertoire of DC-SIGNR transcripts in all samples with 9
    to 16 different isoforms per individual. A total of 65 distinct transcripts were
    identified ( Figure S1 ), of which 3 were full-length transcripts. 64 of the sequenced
    clones contained a total of 69 amino acid substitutions with 3 new C termini and
    2 premature stop codons. However, the diversity was mostly attributable to the
    entire deletion of exon 2 or exon 3 or to variations in the length of the neck
    region (exon 4) of DC-SIGNR. The deletion of exon 3 eliminates the trans-membrane
    domain of the protein and leads to the expression of soluble DC-SIGNR isoforms
    [3] . Interestingly, the abundance of membrane-bound isoforms in placental tissues
    of the H1 homozygotes appears to be lower than that observed in samples from WT
    individuals ( Figure S1 ). The deletion of exon 3 was confirmed by sequencing
    and we hypothesize that the skipping of exon 3, could be due to the presence of
    the int2-180A mutation observed in infants with the H1 haplotype. In fact, this
    intron mutation is located 180 bp downstream from exon 3 and potentially modifies
    splicing events (Figure 2A ). We confirmed that the variation in transcript proportions
    seen between the two groups was also reflected at the level of mRNA expression
    in the placenta. To quantify membrane-bound vs soluble isoforms in placental samples
    from homozygous H1 and WT infants, we amplified the exon 5 (E5) sequence present
    in all DC-SIGNR isoforms (total transcripts). We then amplified exon 3 (E3) which
    is deleted in the soluble forms and then calculated the E3:E5 ratio. We found
    that placental tissues from homozygous H1 infants express a significantly lower
    proportion of membrane-bound DC-SIGNR (18%) compared to that in WT individuals
    (36%) (P = 0.004) ( Figure 2B ) suggesting that exon 3 skipping happens more frequently
    in presence of the DC-SIGNR int2-180A variant associated with MTCT of HIV-1. The
    DC-SIGNR int2-180A variant is always transmitted with the promoter mutation p-198A
    (Figure 1 ). In the unadjusted regression analysis, the p-198A variant was significantly
    associated with IU but not with IP and PP HIV-1 transmission (Table 3) . Computational
    transcription factor binding site analysis predicts Table 1 . Baseline characteristics
    of mother and infants risk factors for intrauterine (IU), intrapartum (IP) and
    postpartum (PP) mother-to-child HIV-1 transmission. Figure 3A ). The luciferase
    activity of the p-198A variant construct was significantly lower than that of
    the WT p-198C promoter construct (p-198C/A ratio = 2, P = 0.006) ( Figure 3B )
    suggesting that DC-SIGNR p-198A affects promoter activity. The other promoter
    mutants (p-577C and p-323A) observed in the Zimbabwean population did not affect
    DC-SIGNR transcription in this assay ( Figure S2 ). To determine the net impact
    of the DC-SIGNR p-198A mutation on DC-SIGNR expression in the placenta, we quantitated
    the absolute number of total and membrane-bound DC-SIGNR transcripts in the H1
    homozygote and wild-type placental samples as described earlier. The total number
    of DC-SIGNR transcripts was determined to be 6856213 (DC-SIGNR copies6S.E.M per
    10 5 GAPDH copies) in the placental samples from homozygous H1 infants and was
    4-fold lower compared to that found in placentas from WT individuals (27816638,
    P = 0.011) ( Figure 3C ). As suggested earlier, the int2-180A mutation might induce
    exon 3 skipping leading to a lower production of membrane-bound DC-SIGNR. Although,
    the decrease in the total number of DC-SIGNR transcripts in H1 homozygous placental
    samples containing both the p-198AA and int2-180AA variants affected the proportion
    of membrane-bound and soluble isoforms, the effect of these mutations was more
    pronounced on the membrane-bound isoforms with an 8-fold decrease (H1 = 117636.2
    vs WT = 9906220.6, P = 0.003) compared to a 3-fold decrease in total soluble isoforms
    (H1 = 5686181.9 vs WT = 19256495.3, P = 0.03) ( Figure 3C ). Therefore, DC-SIGNR
    p-198A and int2-180A mutations associated with MTCT of HIV-1 significantly decreased
    the level of total placental DC-SIGNR transcripts, disproportionately affecting
    the membrane-bound isoform production. Table 3 . Associations between infant DC-SIGNR
    promoter p-198 and intron 2 (int2)-180 variants and intrauterine (IU), intrapartum
    (IP) and postpartum (PP) mother-to-child HIV-1 transmission. Our genetic results,
    supported by expression assay in placenta, suggest the involvement of DC-SIGNR
    in MTCT of HIV-1. Homozygosity for the haplotype H1 was associated with IU transmission
    in the unadjusted regression analysis. However, the association disappeared after
    adjustment was made for the maternal factors presumably because of the small number
    of H1 homozygote infants analysed in each groups. H1 and H3 were the most frequent
    haplotypes observed in the study population and they share a cluster of mutations
    (Figure 1 ). Grouping haplotypes H1 and H3 increased the power of the study and
    permitted the identification of specific DC-SIGNR mutations associated with MTCT
    of HIV-1. Indeed, two mutations shared by haplotypes H1 and H3 were associated
    with vertical transmission of HIV-1. The int2-180A was associated with a 4-fold
    increased risk of IU and 6fold increased risk of IP after adjustment for the maternal
    factors. Although the p-198A variant was associated with IU transmission, the
    association disappeared after adjustment was made for the maternal viral load.
    Nevertheless, we showed that this mutation reduces DC-SIGNR transcriptional activity
    in vitro and produces lower level of DC-SIGNR transcripts in placental tissues
    in combination with the int2-180A variant. Since int2-180A is always transmitted
    with p-198A on the MTCT associated combined haplotypes H1/H3, whereas p-198A is
    carried on other nonassociated haplotypes (Figure 1) , we can speculate that the
    p-198A mutation alone may have a minor effect in vivo whereas in combination with
    the int2-180A variant, they both act to reduce the level of placental DC-SIGNR
    expression resulting in an increased risk of MTCT of HIV-1. The majority of IU
    transmission occurs during the last trimester of pregnancy (reviewed in [12] ).
    Full-term placenta samples were not available for the current study and the expression
    assays were performed on first-term placental tissues. A previous study looking
    at DC-SIGNR placental isoforms repertoire in full-term placenta samples demonstrated
    similar diversity of DC-SIGNR transcripts as in the first-term placental tissues
    studied herein [3] . However, since levels of DC-SIGNR expression have never been
    compared between the different terms of pregnancy, it is not known whether DC-SIGNR
    expression varies during the course of pregnancy. Nevertheless, it is reasonable
    to assume that the inter-individual differences in both DC-SIGNR isoform repertoire
    and transcript levels observed between the H1 and WT homozygous infants would
    be reflected throughout the pregnancy. To date, most studies have focused on the
    potential role of DC-SIGNR in trans infection of HIV-1 in vitro [2, 10] . However,
    the multiple mechanisms involved in trans infection and redundancy among C-type
    lectin functions make it difficult to determine the actual participation of DC-SIGNR
    in this mode of infection in vivo [13, 14] . The strong correlation we observed
    between MTCT of HIV-1 and DC-SIGNR genetic variants producing low levels of DC-SIGNR
    in the placenta suggested that mechanisms other than DC-SIGNR-mediated trans infection
    might operate during vertical transmission of HIV-1. For example, DC-SIGNR has
    also been shown to function as a HIV-1 antigen-capturing receptor [15] . Chan
    and colleagues recently demonstrated that DC-SIGNR transfected CHO cells diminish
    SARS-CoV titers by enhanced capture and degradation of the virus in a proteasome-dependent
    manner [4] . Since endothelial cells express MHC-I and II, degraded viral antigens
    could then be presented to immune cells to elicit an adaptive immune response
    [16, 17] . The HIV-1 coreceptor CCR5, but not CD4, is co-expressed with DC-SIGNR
    on placental and blood-brain barrier (BBB) endothelial cells [18, 19] . HIV-1
    gp120 binding to CCR5 receptor on endothelial cells compromises BBB integrity
    and enhances monocytes adhesion and transmigration across the BBB [20, 21] . It
    is thus possible that reduced expression of DC-SIGNR, particularly the membranebound
    isoforms, on placental capillary endothelial cells might favour HIV-1 binding
    to CCR5 receptor, instead of DC-SIGNR receptor, facilitating the migration of
    maternal HIV-1-infected cells across the placental barrier resulting in IU transmission
    of HIV-1. The int2-180A variant contained in the H1 and H3 haplotypes was associated
    with IP transmission suggesting that DC-SIGNR also affect transmission of HIV-1
    during delivery. Little is known about the mechanisms underlying transmission
    of HIV-1 during delivery. Passage through the birth canal could potentially expose
    infants through a mucosal portal entry (presumably ophthalmic, skin, or gastrointestinal),
    whereas placental insult during delivery (physical or inflammatory) may enhance
    transplacental passage of maternal HIV-1-infected cells into foetal circulation
    [22, 23] . Such process called microtransfusion has been proposed in regards to
    the results obtain in a Malawian cohort. Kweik and colleagues found a significant
    association between levels of maternal DNA in umbilical cord blood and IP transmission
    of HIV-1 suggesting that passage of maternal infected cells through the placenta
    is likely to occur during delivery [22] . Thus, in a similar fashion as suggested
    earlier for IU transmission, the relatively lower level of DC-SIGNR in the placenta
    of homozygous infants harbouring the int2-180A variant could promote HIV-1 binding
    to CCR5 receptor on endothelial cells affecting the placental barrier integrity
    and facilitating the passage of maternal infected cells in foetal circulation
    during delivery. Beside DC-SIGNR, other HIV-1 receptors are known to influence
    MTCT of HIV-1 (reviewed in [24] ). Genetic variants in CCR5 have been shown to
    influence vertical transmission of HIV-1. CCR5 promoter variants resulting in
    higher expression of the receptor were associated with increased risk of MTCT
    of HIV-1 among sub-Saharan Africans [25, 26] . The 32-pb deletion polymorphism
    in CCR5 has be shown to protect from vertical transmission of HIV-1 [27] , but
    this variant is virtually absent among African populations [28] . High copy numbers
    of CCL3L1, a potent HIV-1 suppressive ligand for CCR5, are associated with higher
    chemokine production and lower risk of MTCT of HIV-1 among South African infants
    [29, 30] . Mannose-binding lectin (MBL) is an innate immune receptor synthesised
    in the liver and secreted in the bloodstream in response to inflammation signal.
    MBL promotes pathogen elimination by opsonization and phagocytosis, and reduced
    expression of MBL resulting from polymorphism in coding and non-coding regions
    has been associated with an increased risk of MTCT of HIV-1 [31, 32] . In this
    study, we demonstrate for the first time, the potential functional impact of DC-SIGNR
    mutations on its expression in the placenta and in vertical transmission of HIV-1.
    We believe that the presence of DC-SIGNR at the placental endothelial cell surface
    may protect infants from HIV-1 infection by capturing virus and promoting its
    degradation/presentation. However, in placenta containing low levels of DC-SIGNR,
    HIV-1 would preferentially binds CCR5 on endothelial cells resulting in a loss
    of placental barrier integrity and enhanced passage of maternal HIV-1-infected
    cells in foetal circulation leading to MTCT of HIV-1. This mechanism may also
    apply to other vertically-transmitted pathogens known to interact with DC-SIGNR
    such as HIV-2, hepatitis C and dengue viruses and warrant further investigation.
    Associations between child DC-SIGNR exon 4 repeated region genotypes and mother-to-child
    HIV-1 transmission.CI, Confidence interval; N, number; NA; not applicable; OR,
    odds ratio a P-value as determined by the Chi-square test. b Comparison between
    genotype and all others. Found at: doi:10.1371/journal.pone.0007211.s003 (0.05
    MB DOC) Figure S1 DC-SIGNR transcripts repertoire in placenta. Major RT-PCR products
    from RNA extract from 3 homozygous H1 and 3 homozygous WT placenta samples were
    purified, cloned and sequenced. Sequenced were analysed according to NCBI reference
    sequence NM_014257. CT; cytoplasmic tail, TM; trans-membrane domain; WT; wild-type
    Found at: doi:10.1371/journal.pone.0007211.s004 (0.11 MB DOC) Figure S2 Effect
    of DC-SIGNR promoter variant on transcriptional activity in luciferase reporter
    assay in vitro in transfected HeLa cells. Relative luciferase expression from
    pGL2-Basic, parental vector without promoter. Expression DC-SIGNR promoter constructs,
    spanning p-577C variant or p-323A variant were calculated relatively to this value.
    Data are presented in mean values6S.E.M of three independent experiments performed
    in triplicate. One-way ANOVA test followed by the Dunnett test for multiple comparison
    was used to compare the relative luciferase expression of the p-557C and p-323A
    variant reporters against the wild-type (WT) construct (not significant). 0 mg,
    0,5 mg or 1 mg CMV-Tat vector was transfected with LTR-Luc as a positive control
    in these experiments.'
- text: Approximately how many people died during the 1918-1919 influenza pandemic?
  context: 'It is Unlikely That Influenza Viruses Will Cause a Pandemic Again Like
    What Happened in 1918 and 1919 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019839/
    Song, Liting 2014-05-07 DOI:10.3389/fpubh.2014.00039 License:cc-by Abstract: nan
    Text: Influenza and influenza viruses are wellknown popular topics to medical
    professionals and the general public. Influenza viruses had caused a pandemic
    globally during 1918 and 1919, and that influenza pandemic had taken away more
    than 20 million people''s lives in the world. However, in my opinion, it is unlikely
    that influenza viruses will again cause a pandemic on a level (both of the morbidity
    rate and the mortality rate) comparable to what happened in 1918 and 1919. Influenza
    viruses very easily reassort, recombine, and point mutate in nature due to their
    segmented RNA genome structures, however, unlike highly pathogenic (virulent)
    viruses like rabies virus, Lassa fever virus, smallpox virus, eastern equine encephalitis
    virus, Ebola virus, Marburg virus, and human immunodeficiency virus 1 (HIV-1);
    most influenza viruses (wild types and mutants) are moderately pathogenic. The
    case fatality rates of some highly virulent viruses and related references are
    listed in Table 1 . On November 11, 1918 , the fighting of World War I was stopped,
    and World War I was officially ended on June 28, 1919 with the signing of the
    Versailles Treaty. It is estimated that around 8.5-10 million soldiers lost their
    lives in World War I due to battle. The war also directly caused more than 6 million
    civilian deaths. Millions of people suffered from hunger and malnutrition during
    the war. Malnutrition weakened the human immune system and made a person more
    vulnerable to infectious diseases like tuberculosis and influenza, therefore,
    hunger and malnutrition were indirectly responsible for millions of deaths in
    the world in that period of time. For example, about 700,000 Germans died from
    malnutrition-related diseases in the years of 1914-1918. During the 1918-1919
    influenza pandemic, between 21 and 25 million people died of influenza worldwide.
    Those people were killed both directly and indirectly by influenza virus infections.
    Many families were too poor to buy food and coal, and to afford health care expenses
    when their family members were ill. Influenza virus could infect all members of
    a family, and this could result in no one left to feed the fires, and to prepare
    food for the whole family, even if they had firewood, coal, and food left in their
    homes. Sadly, a large number of people died of influenza virus infections along
    with starvation, cold, and poor living conditions (8) . In recent years, while
    hunger and malnutrition are not major and serious problems in some developed countries
    anymore, they are still very difficult to overcome in many developing countries.
    In these less-developed countries, there were approximately 925 million people
    who suffered from hunger; 125 million children were underweight; and 195 million
    children were stunted each year (9) . Nevertheless, in comparison to 1918 and
    1919, currently, we have much better social and economic conditions and public
    health systems globally; and generally speaking, the majority of people in the
    world have better nutritional and educational statuses; better living and working
    conditions; therefore, better general health and immunity. Furthermore, in 1918
    and 1919, physicians and nurses almost had nothing in their hands to help individuals
    who were infected by influenza viruses. Today, although we still do not have very
    effective, powerful, and practical anti-influenza drugs available, we at least
    have some improved, useful, and helpful anti-viral drugs like zanamivir, and effective,
    convenient anti-cold medicines like Tylenol or Advil. We do not have a universal
    vaccine to prevent all influenza virus infections, but we can make effective vaccines
    to a specific influenza virus strain in a short time. Actually, in the United
    States of America, the influenza classed mortality rate declined from 10.2/100,000
    in the 1940s to 0.56/100,000 in the 1990s; and the classed mortality rates of
    1957-1958 and 1968-1969 influenza pandemics were not remarkably different from
    the non-pandemic seasons (10) . Because of the above reasons, we can optimistically
    assume that even the same strain of influenza virus, which caused pandemic in
    1918 and 1919, would not be able to kill millions of people and cause a pandemic
    comparable to the 1918-1919 pandemic again in the future. Additionally, a significant
    number of viruses can cause influenza-like syndromes, such as rhinovirus, parainfluenza
    virus, adenovirus, coronavirus, respiratory syncytial virus, Coxsackie B virus,
    echovirus, and metapneumovirus (11, 12) . Some of the above-mentioned viruses
    like adenovirus and mutated coronavirus could cause problems that are comparable
    to influenza viruses (13, 14) . The World Health Organization (WHO) mistakenly
    raised the level of influenza pandemic alert from phase 5 to the highest phase
    6 on June 11, 2009 (15) . However, the truth was that most cases of H1N1 influenza
    A virus infections were mild, the symptomatic case fatality rate was only 0.005%
    in New Zealand (16) ; and in New York City, the case fatality rate was 0.0094-0.0147%
    for persons ≥65 years old, and for those of 0-17 years old, the case fatality
    rate was 0.0008-0.0012% (17) . Some researchers argued that it should not have
    been called an influenza pandemic in the first place if the clinical severity
    was considered (15, (18) (19) (20) . I believe it was unwise that we had paid
    too much www.frontiersin.org 23) . Not surprisingly, every year there would be
    some influenza patients and a few of them would die from the infections, as it
    is almost impossible to eliminate influenza viruses from the natural environment
    in many years. The severity of a viral infection is determined by both of the
    viral virulence (pathogenicity) and the host immunity. Some researchers'' opinions
    on H7N9 avian influenza virus were incorrect and/or inadequate. They mainly focused
    on influenza viruses and worried about viral mutations, viral pathogenicity, viral
    adaptation, and transmission. They overestimated the negative part of socio-economic
    factors of the present east China: overcrowded population in the epidemic region;
    very busy national and international transportation and travel; a large number
    of live poultry markets . . . but they underestimated the currently changed, developed,
    and improved positive part of socio-economic factors in China. The following factors
    might be used to explain why that H7N9 influenza A virus epidemic was limited
    and controlled in China, and only a few immunocompromised patients were killed
    by H7N9 influenza A virus. First, China has a relatively organized and effective
    public health system, there are four levels of (national, provincial, prefectural-level
    city, and county) centers for disease control and prevention all over China (24)
    . Second, physicians and nurses in China were prepared and knowledgeable of influenza
    virus infections. Third, samples from patients with suspected influenza virus
    infections were collected and sent to the local and national centers for disease
    control and prevention promptly. H7N9 influenza A viruses were isolated and identified
    very quickly. Thereby, they were able to diagnose, confirm, and report three cases
    of H7N9 influenza patients in the early stage of the epidemic (24, 25) . Fourth,
    health care and public health workers were protected properly. Consequently, none
    of the health professionals was infected by H7N9 influenza A virus in 2013. However,
    a surgeon died of H7N9 influenza in Shanghai, China in January of 2014 (26) .
    Fifth, they detected H7N9 influenza A viruses from the samples of chickens, pigeons,
    and the environment of live poultry markets in Shanghai (27) ; and closed the
    live poultry markets of the involved epidemic region quickly. Sixth, patients
    were isolated and treated timely in hospitals, 74% (1251/1689) of those close
    contacts of H7N9 influenza patients were monitored and observed. Thus, H7N9 influenza
    A virus could not spread to a bigger population (24) . Last but not least, we
    are connected to the Internet now, and it seems that our planet is much smaller
    today than the earlier days when we did not have the Internet, because communication
    and information exchange have become so fast, easy, and convenient presently.
    During that avian influenza epidemic, some influenza experts in the world shared/exchanged
    H7N9 influenza A virus information and provided professional consultations and
    suggestions efficiently and rapidly. All these public health routine practices
    and measures resulted in that H7N9 influenza epidemic being controlled and stopped
    in China (24) . I have to point out that the cases of diagnosed H7N9 avian influenza
    A virus infection might only be the tip of the iceberg. Aside from one laboratory
    confirmed asymptotic case of H7N9 influenza A virus infection in Beijing (22),
    there were probably many undetected mild or asymptotic cases of influenza A H7N9
    infection. The reason is that most people usually think a common cold is a very
    common and normal occurrence, and they don''t take flu-like illnesses seriously.
    In most situations, they would just stay home and take some medicines. Only those
    who have very severe flu-like symptoms would see doctors, and thereby be detected
    and diagnosed, accordingly the real case fatality rate should be much lower than
    the detected 32.14% (45/140, one case from Taiwan, and one case from Hong Kong)
    (22, 23). Nowadays, we travel faster, and we travel more frequently and globally,
    and we have more complicated social activities and lifestyles, thereby increasing
    the chances of viral mutation; and we realize that influenza viruses are even
    easier to reassort, recombine, and mutate in nature than many other RNA viruses.
    However, we are now living in a technologically, economically, and socially much
    better and advanced society. I believe influenza virus infections are controllable
    and preventable, with the increased population health and immunity, with the WHO
    Global Influenza Surveillance and Response System, and with standard/routine epidemiological
    practices, and with new effective anti-viral agents and vaccines in production
    in the future. Now, I first predict that influenza viruses will unlikely again
    cause a pandemic on a level comparable to what happened in 1918 and 1919. Hopefully,
    one day we could consider a strategy to produce a universal vaccine that can prevent
    people from infections of all influenza virus strains, or we could produce some
    very effective anti-influenza virus drugs; then influenza would not be a problem
    anymore. We should learn lessons from the mistakes we made in the past. It is
    reasonable and necessary to be cautious about influenza viruses, but overreactions
    or catastrophic reactions should be avoided in the future. My opinion is anti-traditional;
    the purpose of this article is to influence public health policy, and to save
    some of the limited resources and money for more important diseases like heart
    diseases, cancer, diabetes, AIDS, hepatitises, and tuberculosis (15) . Liting
    Song: conception of manuscript, drafting of manuscript, critical revision of manuscript,
    and final approval of manuscript. The author would like to recognize the contributions
    of the reviewers and editors of this manuscript for their corrections and editing,
    and Dr. Emanuel Goldman for correcting errors related to grammar and syntax of
    the final manuscript.'
---

# Model Card for Model longluu/Medical-QA-deberta-MRQA-COVID-QA
The model is an extractive Question Answering algorithm that can find an answer to a question by finding a segment in a text. 

## Model Details

### Model Description
The base pretrained model is DeBERTa-v3-Large-MRQA (https://huggingface.co/VMware/deberta-v3-large-mrqa) which was fine-tuned on a large QA dataset, MRQA (https://huggingface.co/datasets/mrqa). 
Then using the COVID-QA dataset (https://huggingface.co/datasets/covid_qa_deepset), I fine-tuned the model for an extractive Question Answering algorithm that can answer
a question by finding it within a text.

### Model Sources [optional]
The github code associated with the model can be found here: https://github.com/longluu/Medical-QA-extractive.

## Training Details

### Training Data

This dataset contains 2,019 question/answer pairs annotated by volunteer biomedical experts on scientific articles regarding COVID-19 and other medical issues.
The dataset can be found here: https://github.com/deepset-ai/COVID-QA. The preprocessed data can be found here https://huggingface.co/datasets/covid_qa_deepset.

#### Training Hyperparameters

The hyperparameters are   --per_device_train_batch_size 2 \
                          --learning_rate 3e-5 \
                          --num_train_epochs 2 \
                          --max_seq_length 512 \
                          --doc_stride 250 \
                          --max_answer_length 200 \

## Evaluation
### Testing Data, Factors & Metrics
#### Testing Data
The model was trained and validated on train and validation sets.

#### Metrics
Here we use 2 metrics for QA tasks exact match and F-1.

### Results
{'exact_match': 34.653465, 'f1': 58.858354}

## Model Card Contact
Feel free to reach out to me at thelong20.4@gmail.com if you have any question or suggestion.