ELMO2 biallelic pathogenic variants in a patient with gingival hypertrophy and cherubism phenotype: Case report and molecular review.

Ramon syndrome (OMIM #266270) was first described in a patient with cherubism, gingival fibromatosis, epilepsy, intellectual disability, hypertrichosis, and stunted growth. In 2018, Mehawej et al. described a patient with Ramon syndrome in whom a homozygous variant in ELMO2 was identified, suggesting that this gene may be the causative for this syndrome. ELMO2 biallelic pathogenic variants were also described in patients with a primary intraosseous vascular malformation (PIVM; OMIM #606893). These patients presented gingival bleeding and cherubism phenotype. Herein, a patient with gingival hypertrophy, neurodevelopmental delay, and cherubism phenotype with a novel homozygous predicted loss-of-function (LOF) variant in the ELMO2 gene and family recurrence was reported. A surgical approach to treat gingival bleeding and mandible vascular malformation was also described. Furthermore, this study includes a comprehensive literature review of molecular data regarding the ELMO2 gene. All the variants, except one described in the ELMO2, were predicted as LOF, including our patient's variant. There is an overlapping between PIVM, also caused by LOF biallelic variants in the ELMO2 gene, and Ramon syndrome, which can suggest that they are not different entities. However, due to a limited number of cases described with molecular evaluation, it is hard to establish a genotype-phenotype correlation. Our study supports that LOF pathogenic biallelic variants in the ELMO2 gene cause a phenotype that has cherubism and gingival hypertrophy as main characteristics.

Clinical-Epidemiological Characteristics and IFITM-3 (rs12252) Variant Involvement in HIV-1 Mother-to-Children Transmission Susceptibility in a Brazilian Population.

Mother-to-children transmission (MTCT) is the main infection route for HIV-1 in children, and may occur during pregnancy, delivery, and/or postpartum. It is a multifactorial phenomenon, where genetic variants play an important role. This study aims at analyzing the influence of clinical epidemiological characteristics and a variant (rs12252) in interferon-induced transmembrane protein 3 (IFITM-3), a gene encoding an important viral restriction factor, on the susceptibility to HIV-1 mother-to-children transmission (MTCT). A case-control study was performed on 209 HIV-1-infected mothers and their exposed infected (87) and uninfected (122) children from Pernambuco, Brazil. Clinical-epidemiological characteristics are significantly associated with MTCT susceptibility. Transmitter mothers have a significantly lower age at delivery, late diagnosis, deficiency in ART use (pregnancy and delivery), and detectable viral load in the third trimester of pregnancy compared with non-transmitter mothers. Infected children show late diagnosis, vaginal delivery frequency, and tend to breastfeed, differing significantly from uninfected children. The IFITM-3 rs12252-C allele and TC/CC genotypes (dominant model) are significantly more frequent among infected than uninfected children, but the statistical significance does not remain when adjusted for clinical factors. No significant differences are observed between transmitter and non-transmitter mothers in relation to the IFITM-3 variant.

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.

Gain-of-function STAT1 mutation and visceral leishmaniasis.

Gain-of-function mutations in the STAT1 gene have been initially associated with chronic mucocutaneous candidiasis. However, further research has shown that STAT1 GOF variants may increase susceptibility to infection by other intracellular pathogens. This report describes the first case of disseminated leishmaniasis associated with a STAT1 GOF mutation in a pediatric patient who did not have chronic mucocutaneous candidiasis. The patient was a four-year-old boy presenting with fever, severe asthenia, hepatosplenomegaly, pancytopenia, and liver failure. Bone marrow aspirate revealed hemophagocytosis and Leishmania parasites. Treatment consisted primarily of liposomal amphotericin B, as per the Hemophagocytic Lymphohistiocytosis 2004 protocol. After eight weeks of treatment, the patient did not improve and was submitted to diagnostic splenectomy. Activated macrophages and nodular spleen necrosis secondary to the visceral leishmaniasis were detected. Unfortunately, the patient died in the second week after splenectomy due to overwhelming systemic infection. DNA sequencing revealed a pathogenic (p. R274Q) GOF mutation in STAT1.

Genomic study of nonsyndromic hearing loss in unaffected individuals: Frequency of pathogenic and likely pathogenic variants in a Brazilian cohort of 2,097 genomes.

Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy-Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4-15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.

Inborn Errors of Immunity in Patients with Adverse Events Following BCG Vaccination in Brazil.

OBJECTIVE: The Bacille Calmette-Guérin (BCG) vaccine is routinely applied in Brazil. Adverse events (AE) may occur in patients with inborn or acquired immunodeficiencies, varying between local (BCGitis) or disseminated (BCGosis) reactions. We evaluated 53 individuals with local or disseminated adverse events to BCG vaccination to assess if they had inborn errors of immunity (IEI). METHODS: Patients diagnosed with an adverse event following BCG vaccination between 2014 and 2017 were included in the study. We collected clinical data, immunophenotyped T and B lymphocytes, and natural killer cells (NK), assessed oxidative function of neutrophils through dihydrorhodamine (DHR) 123 testing, and genotyped 361 genes related to IEI through targeted (panel) sequencing. RESULTS: The median age of the 53 individuals was four months (IQ 1.5-12), and 52.8% were male. Forty-eight (90.6%) individuals presented only locoregional AE and five (9.4%) presented both locoregional and disseminated AE. Nine (16.9%) patients were diagnosed with an IEI. Four of them presented BCGitis and five presented BCGosis after BCG vaccination. Clinically, four presented chronic granulomatous disease (CGD), three Mendelian susceptibility to mycobacterial disease (MSMD), and two severe combined immunodeficiency (SCID). Patients with IEI had a higher frequency of systemic symptomatology (p = 0.002), history of other infections (p < 0.001), parental consanguinity (p = 0.01), familial history of sick siblings (p < 0.001), or early deaths in the family (p < 0.01). CONCLUSION: There is a high frequency of IEI in patients with locoregional and disseminated adverse events to BCG vaccination, revealing the need for the investigation of IEI accompanied by clinical and familial inquiry.

The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.

Hereditary cancer risk syndromes are caused by germline variants, commonly in tumor suppressor genes. Most studies on hereditary cancer have been conducted in white populations. We report the largest study in Brazilian individuals with multiple ethnicities. We genotyped 1682 individuals from all country regions with Next-generation sequencing (NGS) panels. Most were women with a personal/family history of cancer, mostly breast and ovarian. We identified 321 pathogenic/likely pathogenic (P/LP) variants in 305 people (18.1%) distributed among 32 genes. Most were on BRCA1 and BRCA2 (129 patients, 26.2% and 14.3% of all P/LP, respectively), MUTYH (42 monoallelic patients, 13.1%), PALB2 (25, 7.8%), Lynch syndrome genes (17, 5.3%), and TP53 (17, 5.3%). Transheterozygosity prevalence in our sample was 0.89% (15/1682). BRCA1/BRCA2 double heterozygosity rate was 0.78% (1/129) for BRCA variants carriers and 0.06% (1/1682) overall. We evaluated the performance of the genetic testing criteria by NCCN and the Brazilian National Health Agency (ANS). The inclusion criteria currently used in Brazil fail to identify 17%-25% of carriers of P/LP variants in hereditary cancer genes. Our results add knowledge on the Brazilian spectrum of cancer risk germline variants, demonstrate that large multigene panels have high positivity rates, and indicate that Brazilian inclusion criteria for genetic testing should be improved.

The Brazilian Rare Genomes Project: Validation of Whole Genome Sequencing for Rare Diseases Diagnosis.

Rare diseases affect up to 13.2 million individuals in Brazil. The Brazilian Rare Genomes Project is envisioned to further the implementation of genomic medicine into the Brazilian public healthcare system. Here we report the validation results of a whole genome sequencing (WGS) procedure for implementation in clinical laboratories. In addition, we report data quality for the first 1,200 real-world patients sequenced. We sequenced a well-characterized group of 76 samples, including seven gold standard genomes, using a PCR-free WGS protocol on Illumina Novaseq 6,000 equipment. We compared the observed variant calls with their expected calls, observing good concordance for single nucleotide variants (SNVs; mean F-measure = 99.82%) and indels (mean F-measure = 99.57%). Copy number variants and structural variants events detection performances were as expected (F-measures 96.6% and 90.3%, respectively). Our WGS protocol presented excellent intra-assay reproducibility (coefficients of variation ranging between 0.03% and 0.20%) and inter-assay reproducibility (coefficients of variation ranging between 0.02% and 0.09%). Limitations of the WGS protocol include the inability to confidently detect variants such as uniparental disomy, balanced translocations, repeat expansion variants, and low-level mosaicism. In summary, the observed performance of the WGS protocol was in accordance with that seen in the best centers worldwide. The Rare Genomes Project is an important initiative to bring pivotal improvements to the quality of life of the affected individuals.

Gain-of-function STAT1 mutation and visceral leishmaniasis

ABSTRACT Gain-of-function mutations in the STAT1 gene have been initially associated with chronic mucocutaneous candidiasis. However, further research has shown that STAT1 GOF variants may increase susceptibility to infection by other intracellular pathogens. This report describes the first case of disseminated leishmaniasis associated with a STAT1 GOF mutation in a pediatric patient who did not have chronic mucocutaneous candidiasis. The patient was a four-year-old boy presenting with fever, severe asthenia, hepatosplenomegaly, pancytopenia, and liver failure. Bone marrow aspirate revealed hemophagocytosis and Leishmania parasites. Treatment consisted primarily of liposomal amphotericin B, as per the Hemophagocytic Lymphohistiocytosis 2004 protocol. After eight weeks of treatment, the patient did not improve and was submitted to diagnostic splenectomy. Activated macrophages and nodular spleen necrosis secondary to the visceral leishmaniasis were detected. Unfortunately, the patient died in the second week after splenectomy due to overwhelming systemic infection. DNA sequencing revealed a pathogenic (p. R274Q) GOF mutation in STAT1.

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.

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.

Immunological recovery failure in cART-treated HIV-positive patients is associated with reduced thymic output and RTE CD4+ T cell death by pyroptosis.

Despite more than three decades of studies and advances in combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV), the mechanisms that precisely determine immune reconstitution failure have not been completely elucidated yet. Thus, this study aimed to investigate the thymic function, immune activation, and cell death by pyroptosis and apoptosis in virologically suppressed HIV-positive patients receiving cART. Immunophenotyping analyses were performed in 57 cART-treated HIV-infected patients with undetectable plasma viral load, who were classified as immunological nonresponders (INR = 29) and immunologic responders (IR = 28). Sociodemographic and clinical data were also assessed from medical records. Twelve healthy volunteers were also included in this study. The INR showed lower pretreatment CD4+ T cell count that remained low even after 1 yr of treatment, lower CD4/CD8 ratio, lower percentage of recent thymic emigrant (RTE) CD4+ T cell (CD45RA+CD31+) and naïve CD4+ T cell (CD45RA+CD62L+), higher levels of effector memory CD4+ T cells (CD45RA-CD62L-), and higher pyroptosis levels of RTE CD4+ T cells (CD31+FLICA-Caspase1+) when compared with IR. Our findings indicate that reduced thymic function and RTE CD4+ T cell death by pyroptosis are the major mechanisms of immunological recovery failure in HIV-infected patients receiving cART.

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.

HIV-1 mother-to-child transmission in Brazil (1994-2016): a time series modeling

Abstract HIV-1 mother-to-child transmission (HIV-1 MTCT), is an important cause of children mortality worldwide. Brazil has been traditionally praised by its HIV/Aids program, which provides free-of-charge care for people living with HIV-1. Using public epidemiology and demographic databases, we aimed at modeling HIV-1 MTCT prevalence in Brazil through the years (1994-2016) and elaborate a statistical model for forecasting, contributing to HIV-1 epidemiologic surveillance and healthcare decision-making. We downloaded sets of live births and mothers' data alongside HIV-1 cases notification in children one year old or less. Through time series modeling, we estimated prevalence along the years in Brazil, and observed a remarkable decrease of HIV-1 MTCT between 1994 (10 cases per 100,000 live births) and 2016 (five cases per 100,000 live births), a reduction of 50%. Using our model, we elaborated a prognosis for each Brazilian state to help HIV-1 surveillance decision making, indicating which states are in theory in risk of experiencing a rise in HIV-1 MTCT prevalence. Ten states had good (37%), nine had mild (33%), and eight had poor prognostics (30%). Stratifying the prognostics by Brazilian region, we observed that the Northeast region had more states with poor prognosis, followed by North and Midwest, Southeast and South with one state of poor prognosis each. Brazil undoubtedly advanced in the fight against HIV-1 MTCT in the past two decades. We hope our model will help indicating where HIV-1 MTCT prevalence may rise in the future and support government decision makers regarding HIV-1 surveillance and prevention.

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.

Prevalence of Guillain-Barré syndrome among Zika virus infected cases: a systematic review and meta-analysis.

Zika virus (ZIKV) is an emergent flavivirus transmitted mainly through Aedes spp. mosquitoes that is posing challenge to healthcare services in countries experiencing an outbreak. Usually ZIKV infection is mild, but in some cases it has been reported to progress into neurological diseases such as microcephaly in infants and Guillain-Barré syndrome (GBS) in adults. GBS is a debilitating autoimmune disorder that affects peripheral nerves. Since ZIKV caused massive outbreaks in South America in the past few years, we aimed to systematically review the literature and perform a meta-analysis to estimate the prevalence of GBS among ZIKV-infected individuals. We searched PubMed and Cochrane databases and selected three studies for a meta-analysis. We estimated the prevalence of ZIKV-associated GBS to be 1.23% (95% CI=1.17-1.29%). Limitations include paucity of data regarding previous flavivirus infections and ZIKV-infection confirmation issues. Our estimate seems to be low, but cannot be ignored, since ZIKV outbreaks affects an overwhelming number of individuals and GBS is a life-threatening debilitating condition, especially in pregnant women. ZIKV infection cases must be closely followed to assure prompt care to reduce the impact of GBS associated-sequelae on the quality of life of those affected.

Prevalence of Guillain-Barré syndrome among Zika virus infected cases: a systematic review and meta-analysis

ABSTRACT Zika virus (ZIKV) is an emergent flavivirus transmitted mainly through Aedes spp. mosquitoes that is posing challenge to healthcare services in countries experiencing an outbreak. Usually ZIKV infection is mild, but in some cases it has been reported to progress into neurological diseases such as microcephaly in infants and Guillain-Barré syndrome (GBS) in adults. GBS is a debilitating autoimmune disorder that affects peripheral nerves. Since ZIKV caused massive outbreaks in South America in the past few years, we aimed to systematically review the literature and perform a meta-analysis to estimate the prevalence of GBS among ZIKV-infected individuals. We searched PubMed and Cochrane databases and selected three studies for a meta-analysis. We estimated the prevalence of ZIKV-associated GBS to be 1.23% (95% CI = 1.17-1.29%). Limitations include paucity of data regarding previous flavivirus infections and ZIKV-infection confirmation issues. Our estimate seems to be low, but cannot be ignored, since ZIKV outbreaks affects an overwhelming number of individuals and GBS is a life-threatening debilitating condition, especially in pregnant women. ZIKV infection cases must be closely followed to assure prompt care to reduce the impact of GBS associated-sequelae on the quality of life of those affected.

Microcephaly Prevalence in Infants Born to Zika Virus-Infected Women: A Systematic Review and Meta-Analysis.

Zika virus is an emergent flavivirus transmitted by Aedes genus mosquitoes that recently reached the Americas and was soon implicated in an increase of microcephaly incidence. The objective of the present study is to systematically review the published data and perform a meta-analysis to estimate the prevalence of microcephaly in babies born to Zika virus-infected women during pregnancy. We searched PubMed and Cochrane databases, included cohort studies, and excluded case reports and case series publications. We extracted sample sizes and the number of microcephaly cases from eight studies, which permitted a calculation of prevalence rates that are pooled in a random-effects model meta-analysis. We estimated the prevalence of microcephaly of 2.3% (95% CI = 1.0-5.3%) among all pregnancies. Limitations include mixed samples of women infected at different pregnancy times, since it is known that infection at the first trimester is associated with higher risk to congenital anomalies. The estimates are deceptively low, given the devastating impact the infection causes over children and their families. We hope our study contributes to public health knowledge to fight Zika virus epidemics to protect mothers and their newborns.

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.

Antiretroviral Treatment in HIV-1-Positive Mothers: Neurological Implications in Virus-Free Children.

Since the worldwide introduction of antiretroviral therapy (ART) in human immunodeficiency virus type 1, HIV-1-positive mothers, together with HIV-1 testing prior to pregnancy, caesarian birth and breastfeeding cessation with replacement feeding, a reduction of HIV-1 mother-to-child transmission (MTCT) has been observed in the last few years. As such, an increasing number of children are being exposed in utero to ART. Several questions have arisen concerning the neurological effects of ART exposure in utero, considering the potential effect of antiretroviral drugs on the central nervous system, a structure which is in continuous development in the fetus and characterized by great plasticity. This review aims at discussing the possible neurological impairment of children exposed to ART in utero, focusing attention on the drugs commonly used for HIV-1 MTCT prevention, clinical reports of ART neurotoxicity in children born to HIV-1-positive mothers, and neurologic effects of protease inhibitors (PIs), especially ritonavir-"boosted" lopinavir (LPV/r) in cell and animal central nervous system models evaluating the potential neurotoxic effect of ART. Finally, we present the findings of a meta-analysis to assess the effects on the neurodevelopment of children exposed to ART in utero.