A loss-of-function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa.

Dowling Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by acquired, slowly progressive reticulated pigmented lesions primarily involving flexural skin areas. Mutations in KRT5, POGLUT-1 and POFUT-1 genes have been associated with DDD, and loss-of-function mutations in PSENEN, a subunit of the gamma-secretase complex, were found in patients presenting with DDD or DDD comorbid with hidradenitis suppurativa (HS). A nonsense mutation in NCSTN, another subunit of the gamma-secretase, was already described in a patient suffering from HS and DDD but whether NCSTN could be considered a novel gene for DDD is still debated. Here, we enrolled a four-generation family with HS and DDD. Through Whole Exome Sequencing (WES) we identified a novel nonsense mutation in the NCSTN gene in all the affected family members. To study the impact of this variant, we isolated outer root sheath cells from patients' hair follicles. We showed that this variant leads to a premature stop codon, activates a nonsense-mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals. In fact, cells treated with gentamicin, a readthrough agent, had the NCSTN levels corrected. Moreover, we observed that this haploinsufficiency also affects other subunits of the gamma-secretase complex, possibly causing DDD. Our findings clearly support NCSTN as a novel DDD gene and suggest carefully investigating this co-occurrence in HS patients carrying a mutation in the NCSTN gene.

Proximal tubular dysfunction related to tenofovir in people living with HIV/AIDS: a pharmacogenetic study.

OBJECTIVES: The purpose of this case-control study was to verify the association between single nucleotide polymorphisms (SNPs) in genes encoding drug transporters related to tenofovir disoproxil fumarate (TDF) and proximal renal tubular dysfunction (PRTD), and the association between PRTD and clinical characteristics. METHODS: The 'cases' met the diagnostic criteria for PRTD, determined by the presence of two or more of the following abnormalities: non-diabetic glycosuria, metabolic acidosis, increased uric acid and phosphorus excretion, decreased tubular phosphorus reabsorption and ß2-microglobulinuria. We analyzed eight SNPs in ABCC2, ABCC4, ABCC10 and SLC28A2 genes. Genotyping was performed using real-time PCR. RESULTS: Of the 204 people living with HIV, 38 (18.6%) met the criteria for diagnosis of PRTD and 131 were male (64.2%), with a mean age of 49 years and a history of previous antiretroviral therapy for an average of 5 years. In the multivariate analysis, older individuals, TDF use, protease inhibitor, antihypertensives and anticonvulsants were associated with a risk of developing PRTD. Increased excretion of ß2microglobulin was associated with the A/G genotype of rsCC8187710 from ABCC2 ( P = 0.003) and the following genotypes of ABCC4 SNPs: A/G from rs1059751 ( P = 0.023), G/G from rs1059751 ( P = 0.030) and C/C of rs3742106 ( P = 0.041). The increase in the fraction of excreted phosphorus was associated with the C/T genotype of SNCC rsP40037 from ABCC2 ( P = 0.0041). CONCLUSIONS: The results indicate an important relationship between SNPs associated with these markers and changes in proximal renal tubule function, and thus support their use as biomarkers for the early detection of PRTD risk.

Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis.

The challenge of unravelling the molecular basis of multifactorial disorders nowadays cannot rely just on association studies searching for potential causative variants shared by groups of patients and not present in healthy individuals; indeed, association studies have as a main limitation the lack of information on the interactions between the disease-causing variants. Thus, new genomic analysis tools focusing on disrupted pathways rather than associated gene variants are required to better understand the complexity of a disease. Therefore, we developed the Variant Enrichment Analysis (VEA) workflow, a tool applicable for whole exome sequencing data, able to find differences between the numbers of genetic variants in a given pathway in comparison with a reference dataset. In this study, we applied VEA to discover novel pathways altered in patients with complex autoinflammatory skin disorders, namely PASH (n = 9), 3 of whom are overlapping with SAPHO) and PAPASH (n = 3). With this approach we have been able to identify pathways related to neutrophil and endothelial cells homeostasis/activations, as disrupted in our patients. We hypothesized that unregulated neutrophil transendothelial migration could elicit increased neutrophil infiltration and tissue damage. Based on our findings, VEA, in our experimental dataset, allowed us to predict novel pathways impaired in subjects with autoinflammatory skin disorders.

Multiomics Integration in Skin Diseases with Alterations in Notch Signaling Pathway: PlatOMICs Phase 1 Deployment.

The high volume of information produced in the age of omics was and still is an important step to understanding several pathological processes, providing the enlightenment of complex molecular networks and the identification of molecular targets associated with many diseases. Despite these remarkable scientific advances, the majority of the results are disconnected and divergent, making their use limited. Skin diseases with alterations in the Notch signaling pathway were extensively studied during the omics era. In the GWAS Catalog, considering only studies on genomics association (GWAS), several works were deposited, some of which with divergent results. In addition, there are thousands of scientific articles available about these skin diseases. In our study, we focused our attention on skin diseases characterized by the impairment of Notch signaling, this pathway being of pivotal importance in the context of epithelial disorders. We considered the pathologies of five human skin diseases, Hidradenitis Suppurativa, Dowling Degos Disease, Adams-Oliver Syndrome, Psoriasis, and Atopic Dermatitis, in which the molecular alterations in the Notch signaling pathway have been reported. To this end, we started developing a new multiomics platform, PlatOMICs, to integrate and re-analyze omics information, searching for the molecular interactions involved in the pathogenesis of skin diseases with alterations in the Notch signaling pathway.

VDR polymorphisms influence immunological response in HIV-1+ individuals undergoing antiretroviral therapy.

Vitamin D exerts an immuno-modulatory activity on several immune system cells through the vitamin D receptor (VDR). Herein, we verified that age and a therapeutic regimen containing protease inhibitors are associated with failures in antiretroviral therapies (ARVs). In addition, we assessed whether a VDR SNP (rs11568820: C allele and CC genotype) and GC (rs2228570-rs11568820) allelic combinations are associated with immunological failure (p < 0.05). Our findings suggest a possible role of VDR SNPs on immunological failure in HIV-1+ individuals undergoing regular ARVs.

Dendritic Cell-Based Immunotherapies to Fight HIV: How Far from a Success Story? A Systematic Review and Meta-Analysis.

The scientific community still faces the challenge of developing strategies to cure HIV-1. One of these pursued strategies is the development of immunotherapeutic vaccines based on dendritic cells (DCs), pulsed with the virus, that aim to boost HIV-1 specific immune response. We aimed to review DCs-based therapeutic vaccines reports and critically assess evidence to gain insights for the improvement of these strategies. We performed a systematic review, followed by meta-analysis and meta-regression, of clinical trial reports. Twelve studies were selected for meta-analysis. The experimental vaccines had low efficiency, with an overall success rate around 38% (95% confidence interval = 26.7%-51.3%). Protocols differed according to antigen choice, DC culture method, and doses, although multivariate analysis did not show an influence of any of them on overall success rate. The DC-based vaccines elicited at least some immunogenicity, that was sometimes associated with plasmatic viral load transient control. The protocols included both naïve and antiretroviral therapy (ART)-experienced individuals, and used different criteria for assessing vaccine efficacy. Although the vaccines did not work as expected, they are proof of concept that immune responses can be boosted against HIV-1. Protocol standardization and use of auxiliary approaches, such as latent HIV-1 reservoir activation and patient genomics are paramount for fine-tuning future HIV-1 cure strategies.

Meta-analysis of Brazilian genetic admixture and comparison with other Latin America countries.

OBJECTIVES: This study aims at performing a systematic review and meta-analysis with the studies of genetic admixture inference of Brazilian population and to compare these results with the genetic admixture levels in other Latin American countries. METHODS: We searched for articles regarding the estimation of Brazilian genetic admixture published between 1980 and 2014 that used autosomal markers. Then, conducted meta-analyses at the whole-country and regional level. Finally, we compared the results of Brazil with other estimates from other South, Central and North American countries. RESULTS: We analyzed data from 25 studies in 38 different Brazilian populations. European (EUR) ancestry is the major contributor to the genetic background of Brazilians, followed by African (AFR), and Amerindian (AMR) ancestries. The pooled ancestry contributions were 0.62 EUR, 0.21 AFR, and 0.17AMR. The Southern region had a greater EUR contribution (0.77) than other regions. Individuals from the Northeast (NE) region had the highest AFR contribution (0.27) whereas individuals from the North regions had more AMR contribution (0.32). In the Latin America context, Brazil has the 5th high EUR contribution, the 12th for the AFR component and the 10th for the AMR ancestry. CONCLUSIONS: Admixture proportions vary greatly among Brazilian populations and also through Latin America. More studies in the Center-West, North and NE regions are needed to capture a more complete picture of the genomic ancestry of Brazil.

NLRP3 polymorphism is associated with protection against human T-lymphotropic virus 1 infection.

Inter-individual heterogeneity in the response to human T-lymphotropic virus 1 (HTLV-1) infection has been partially attributed to host genetic background. The antiviral activity of the inflammasome cytoplasmic complex recognises viral molecular patterns and regulates immune responses via the activation of interleukin (IL)-1 family (IL-1, IL-18 and IL-33) members. The association between polymorphisms in the inflammasome receptors NLRP1 and NLRP3 and HTLV-1 infection was evaluated in a northeastern Brazilian population (84 HTLV-1 carriers and 155 healthy controls). NLRP3 rs10754558 G/G was associated with protection against HTLV-1 infection (p = 0.012; odds ratio = 0.37). rs10754558 affects NLRP3 mRNA stability; therefore, our results suggest that higher NLRP3 expression may augment first-line defences, leading to the effective protection against HTLV-1 infection.

Mannose binding lectin and mannose binding lectin-associated serine protease-2 genes polymorphisms in human T-lymphotropic virus infection.

Variations in genes involved in the immune response pathways may influence the interaction between viruses (such as Human T-lymphotropic virus, HTLV-1) and the host. The mannose binding lectin (MBL) and its associated serine protease type 2 (MASP-2) promote the activation of the lectin pathway of the complement system. As the interaction of complement system with HTLV-1 is not well understood, the MBL2 promoter/exon 1 polymorphisms and a MASP2 missense polymorphism were examined in a Northeast Brazilian population, looking for a possible relationship between these variations and the susceptibility to HTLV-1 infection. The present study describes an association between a polymorphism in the MASP2 gene and susceptibility to HTLV-1 infection, and provides further evidence of an association between the MBL2 gene and HTLV-1 infection. These findings suggest an important role of the complement system activation, via the lectin pathway, in the susceptibility to HTLV-1 infection.

An overview of Zika virus genotypes and their infectivity.

Zika virus (ZIKV) is an enveloped, single-stranded RNA arbovirus belonging to the genus Flavivirus. It was first isolated from a sentinel monkey in Uganda in 1947. More recently, ZIKV has undergone rapid geographic expansion and has been responsible for outbreaks in Southeast Asia, the Pacific Islands, and America. In this review, we have highlighted the influence of viral genetic variants on ZIKV pathogenesis. Two major ZIKV genotypes (African and Asian) have been identified. The Asian genotype is subdivided into Southwest Asia, Pacific Island, and American strains, and is responsible for most outbreaks. Non-synonymous mutations in ZIKV proteins C, prM, E, NS1, NS2A, NS2B, NS3, and NS4B were found to have a higher prevalence and association with virulent strains of the Asian genotype. Consequently, the Asian genotype appears to have acquired higher cellular permissiveness, tissue persistence, and viral tropism in human neural cells. Therefore, mutations in specific coding regions of the Asian genotype may enhance ZIKV infectivity. Considering that mutations in the genomes of emerging viruses may lead to new virulent variants in humans, there is a potential for the re-emergence of new ZIKV cases in the future.

HIV-1 Infection Transcriptomics: Meta-Analysis of CD4+ T Cells Gene Expression Profiles.

HIV-1 infection elicits a complex dynamic of the expression various host genes. High throughput sequencing added an expressive amount of information regarding HIV-1 infections and pathogenesis. RNA sequencing (RNA-Seq) is currently the tool of choice to investigate gene expression in a several range of experimental setting. This study aims at performing a meta-analysis of RNA-Seq expression profiles in samples of HIV-1 infected CD4+ T cells compared to uninfected cells to assess consistently differentially expressed genes in the context of HIV-1 infection. We selected two studies (22 samples: 15 experimentally infected and 7 mock-infected). We found 208 differentially expressed genes in infected cells when compared to uninfected/mock-infected cells. This result had moderate overlap when compared to previous studies of HIV-1 infection transcriptomics, but we identified 64 genes already known to interact with HIV-1 according to the HIV-1 Human Interaction Database. A gene ontology (GO) analysis revealed enrichment of several pathways involved in immune response, cell adhesion, cell migration, inflammation, apoptosis, Wnt, Notch and ERK/MAPK signaling.

In silico analysis of molecular interactions between HIV-1 glycoprotein gp120 and TNF receptors.

Proinflammatory microenvironmental is crucial for the Human Immunodeficiency Virus Type 1 (HIV-1) pathogenesis. The viral glycoprotein 120 (gp120) must interact with the CD4+ T cell chemokine receptor (CCR5) and a co-receptor C-X-C chemokine receptor type 4 (CXCR4) to let the virus entry into the host cells. However, the interaction of the viral particle with other cell surface receptors is mandatory for its attachment and subsequently entry. Tumor Necrosis Factor receptor type I (TNFR1), type II (TNFR2) and Fas are a superfamily of transmembrane proteins involved in canonical inflammatory pathway and cell death by apoptosis as responses against viral pathogens. In our study, we performed an in silico evaluation of the molecular interactions between viral protein gp120 and TNF receptors (TNFR1, TNFR2 and Fas). Protein structures were retrieved from Protein Databank (PDB), and Molecular Docking and dynamics were performed using ClusPro 2.0 server and GROMACS software, respectively. We observed that gp120 is able to bind TNFR1, TNFR2 and Fas receptors, although only the TNFR2-gp120 complex demonstrated to produce a stable and durable binding. Our findings suggest that gp120 may act as an agonist to TNF-α and also function as an attachment factor in HIV-1 entry process. These molecular interaction by gp120 may be the key to HIV-1 immunopathogenesis. In conclusion, gp120 may stimulate pro-inflammatory and apoptotic signaling transduction pathways mediated by TNFR2 and may act as an attachment factor retaining HIV-1 viral particles on the host cell surface.

Increased risk of dizziness in human immunodeficiency virus-infected patients taking zidovudine and efavirenz combination: a Brazilian cohort study.

OBJECTIVES: Neuropsychiatric adverse effects (NPAE) related to efavirenz, mainly dizziness, is detrimental to human immunodeficiency virus (HIV) treatment. Our study aims at evaluating if zidovudine use potentiates the risk of dizziness related to efavirenz when used together and whether there are significant differences in over time distribution of this NPAE and others relatively frequents regarding efavirenz regimen without zidovudine. METHODS: Human immunodeficiency virus-infected patients under efavirenz-containing different therapy were enrolled. A retrospective analysis of official medical records was accomplished to collect clinical data regarding NPAE occurrence and severity. Univariate statistic and statistical model based on survival analyses were performed. KEY FINDINGS: One hundred sixty-two patients were included, of these seventy-seven (47.5%) had NPAE reported, such as dizziness (more frequent), depression and insomnia. Univariate statistical analysis demonstrated that the combined use of efavirenz with zidovudine increased the NPAE risk (OR: 2.5; P-value: 0.008), mainly dizziness risk (OR: 3.5; P-value: 0.009) and survival analysis showed that such combination is associated with dizziness occurrence faster (HR: 2.9; P-value: 0.02). CONCLUSIONS: The results may contribute to clarify the dizziness occurrence dynamics in therapy with efavirenz and zidovudine by identifying susceptibilities and assisting in the choice of combined antiretroviral therapy.

Principles and applications of polymerase chain reaction in medical diagnostic fields: a review.

Recent developments in molecular methods have revolutionized the detection and characterization of microorganisms in a broad range of medical diagnostic fields, including virology, mycology, parasitology, microbiology and dentistry. Among these methods, Polymerase Chain Reaction (PCR) has generated great benefits and allowed scientific advancements. PCR is an excellent technique for the rapid detection of pathogens, including those difficult to culture. Along with conventional PCR techniques, Real-Time PCR has emerged as a technological innovation and is playing an ever-increasing role in clinical diagnostics and research laboratories. Due to its capacity to generate both qualitative and quantitative results, Real-Time PCR is considered a fast and accurate platform. The aim of the present literature review is to explore the clinical usefulness and potential of both conventional PCR and Real-Time PCR assays in diverse medical fields, addressing its main uses and advances.

ZIKA virus entry mechanisms in human cells.

Zika virus (ZIKV) is an enveloped, mosquito-borne Flavivirus, which infects cells through clathrin-mediated endocytosis and fusion employing acidic endosomes. Cell entry is mostly mediated by the viral glycoprotein E, although incomplete particle maturation enables viral protein prM and anionic lipids present in the viral membrane to mediate this process. Incomplete proteolytic maturation results in a set of highly heterogeneous particles. These heterogeneous and dynamic infectious particles offer a variety of possible receptor interaction sites on their surfaces, thus contributing to the wide range of cells susceptible to ZIKV as well as to variation in tissue tropism. This review addresses recent advances in the understanding of ZIKV entry process into cells and put together fundamental questions about viral replication, maturation and host-cell interactions.

Mutational landscape of Zika virus strains worldwide and its structural impact on proteins.

Zika virus (ZIKV) has spread globally and has been linked to the onset of microcephaly and other brain abnormalities. The ZIKV genome consists of an ~10.7 kb positive-stranded RNA molecule that encodes three structural (C, prM and E) and seven nonstructural (5'-NS1-NS2A-NS2B-NS3- NS4A/2K-NS4B-NS5-3') proteins. In this work, we looked for genetic variants in 485 ZIKV complete genomes from GenBank (NCBI) and performed a computational systematic approach using MAESTROweb server to assess the impact of nonsynonymous mutations in ZIKV proteins (C, M, E, NS1, NS2A, NS2B-NS3 protease, NS3 helicase and NS5). Then, we merged the data and correlated it with the phenotypic reports of ZIKV circulating strains. The sensitivity profile of the proteins showed 96 mutational hotspots. We found 22 relevant mutations in proteins C (I80T), NS2A (I34M/T/V, I45V, I80T/V, L113F, A117V, I118V, L128P, V143A, T151A, M199I/V, R207K and L208I) and NS3 helicase (D436G, Y498H, R525K, Q528R and R583K) of the circulating strains. Our analysis exploited the impact of nonsynonymous mutations on ZIKV proteins, their structural and functional insights. The results presented here could advance our current understanding on ZIKV proteins functions and pathogenesis.

IL18 gene polymorphism and its influence on CD4+ T-cell recovery in HIV-positive patients receiving antiretroviral therapy.

BACKGROUND: Pyroptosis has been reported to be critical in human immunodeficiency virus type 1 (HIV-1) pathogenesis and acquired immunodeficiency syndrome (AIDS) progression. Even after achieving viral suppression to undetectable levels during antiretroviral therapy (ART), exacerbated CD4+ T-cell death by pyroptosis has been suggested as one of the main causes of immunological non-response. Thus, variants in genes of pyroptosis pathway were studied in individuals with poor CD4+ T-cell reconstitution under antiretroviral therapy against HIV-1. METHODS: 248 virologically suppressed ART-treated patients, 126 immunological non-responders (INR) and 122 immunological responders (IR) were recruited. Genotyping was performed using TaqMan probe-based realtime PCR platform. Genotype-guided flow cytometry analysis with general and recent thymic emigrant (RTE) CD4+ T-cells in pyroptosis was performed based on associated polymorphisms. RESULTS: Both IL18 rs187238 G allele and GG genotype were associated as protection factors against poor CD4+ T-cell recovery (OR = 0.22; 95%CI = 0.50-0.77; P = .010 and OR = 0.58; 95%CI = 0.36-0.93; P = .022, respectively). It was demonstrated a statistical association between IL18 rs187238 genotypes of ART-treated patients and death by Caspase-1 levels (P = .020). The GG genotype showed lower pyroptotic RTE CD4+ T-lymphocytes levels in the ART-treated groups comparing with CC (P = .029) and CG (P = .018) genotypes, suggesting that the G allele presence may be related to a lower IL-18 production and thus reduced dead CD4+ T-cells levels by Caspase-1. CONCLUSION: We observed that IL18 G variant allele and genotype were associated with a better immunological response, which may influence on immunological recovery of HIV-positive patients receiving antiretroviral therapy, and low Caspase-1 activity levels was observed on GG genotype when compared CC genotypes.

HLA-C Single Nucleotide Polymorphism Associated with Increased Viral Load Level in HIV-1 Infected Individuals from Northeast Brazil.

BACKGROUND: Genetic variations in Human leukocyte antigen C (HLA-C), Zinc ribbon domain containing 1 (ZNRD1) and its antisense RNA (ZNRD1-AS1) genes are known to influence the HIV-1 replication and disease progression. OBJECTIVE AND METHOD: We evaluated the distribution of HLA-C (rs10484554, rs9264942) and ZNRD1 (rs8321) and ZNRD1-AS1 (rs3869068), single nucleotide polymorphisms (SNPs) in 266 HIV-1-infected and 223 unexposed-uninfected individuals from Northeast Brazil and their relation to HIV-1 infection, CD4 T cells count and viral load pre-treatment. RESULTS: HLA-C SNPs were in Linkage Disequilibrium (D'=0.84), constituting four possible haplotypes. Our results showed that HLA-C, ZNRD1 and ZNRD1-AS1 SNPs as well as HLA-C haplotypes frequencies were not significantly different between HIV-1-infected and unexposed-uninfected individuals. In addition, we analyzed HLA-C and ZNRD-1 and ZNRD1-AS1 SNPs considering CD4+ T cell counts and viral load before the antiretroviral treatment. Individuals carrying HLA-C rs9264942 TT genotype showed a significant increased level of HIV-1 viral load pre-treatment, in comparison with individuals carrying the CC genotype (p-value = 0.0092). Finally, we stratified our findings according to CCR5Δ32 allele presence along with the studied SNPs: no statistically significant influence over viral load pre-treatment has been found. CONCLUSION: The association between HLA-C rs9264942 SNP and viral load prior treatment in an admixed population from North East Brazil was in agreement with findings from previous studies obtained on different ethnic groups; however more studies should be conducted in order to clarify how HLA-C impair the HIV-1 replication.

CUL5 and APOBEC3G Polymorphisms are Partially Implicated in HIV-1 Infection and Antiretroviral Therapy in a Brazilian Population.

BACKGROUND: Host restriction factors are cellular proteins able to diminish or block viral replication in a cell-specific way. OBJECTIVE AND METHOD: We evaluated the distribution of single nucleotide polymorphisms (SNPs) in APOBEC3G (rs3736685, rs2294367) and CUL5 (rs7117111, rs7103534, rs11212495) genes, among 264 HIV-1 infected (HIV-1+) and 259 unexposed- uninfected individuals from Northeast Brazil, looking for a possible association with susceptibility to HIV-1 infection, viral load during treatment, CD4+ T cell count and therapeutic success of the antiretroviral treatment. RESULTS: The rs11212495 CUL5 G allele and the CUL5 rs7103534-rs7117111 CG haplotype were more frequent among unexposed-uninfected than in HIV-1+ individuals, suggesting an association with a lower HIV-1 infection susceptibility. The APOBEC3G rs2294367 G/C genotype correlated with delayed viral load suppression. Our results showed a great heterogeneity in relation to the literature findings, possibly due to ethnic differences among the studied populations, sample size used in the studies and, also, to the type of controls, i.e. in our study used unexposed-uninfected rather than exposed-uninfected individuals (rare and considered gold standard for susceptibility studies). CONCLUSION: Our findings report genetic variants possibly associated with susceptibility to HIV-1 infection (CUL5 rs11212495, rs7103534, rs7117111) and partial viral load control (APOBEC3G rs2294367). Replica studies performed on higher number of subjects are envisaged to confirm our results.

An overview of Zika virus genotypes and their infectivity

ABSTRACT Zika virus (ZIKV) is an enveloped, single-stranded RNA arbovirus belonging to the genus Flavivirus. It was first isolated from a sentinel monkey in Uganda in 1947. More recently, ZIKV has undergone rapid geographic expansion and has been responsible for outbreaks in Southeast Asia, the Pacific Islands, and America. In this review, we have highlighted the influence of viral genetic variants on ZIKV pathogenesis. Two major ZIKV genotypes (African and Asian) have been identified. The Asian genotype is subdivided into Southwest Asia, Pacific Island, and American strains, and is responsible for most outbreaks. Non-synonymous mutations in ZIKV proteins C, prM, E, NS1, NS2A, NS2B, NS3, and NS4B were found to have a higher prevalence and association with virulent strains of the Asian genotype. Consequently, the Asian genotype appears to have acquired higher cellular permissiveness, tissue persistence, and viral tropism in human neural cells. Therefore, mutations in specific coding regions of the Asian genotype may enhance ZIKV infectivity. Considering that mutations in the genomes of emerging viruses may lead to new virulent variants in humans, there is a potential for the re-emergence of new ZIKV cases in the future.