Daiana Mir

Zika virus in the Americas: Early epidemiological and genetic findings

Zika virus genomes from Brazil The Zika virus outbreak is a major cause for concern in Brazil, where it has been linked with increased reports of otherwise rare birth defects and neuropathology. In a phylogenetic analysis, Faria et al. infer a single introduction of Zika to the Americas and estimated the introduction date to be about May to December 2013—some 12 months earlier than the virus was reported. This timing correlates with major events in the Brazilian cultural calendar associated with increased traveler numbers from areas where Zika virus has been circulating. A correlation was also observed between incidences of microcephaly and week 17 of pregnancy. Science, this issue p. 345 Virus sequencing indicates that Zika arrived in Brazil during the middle of 2013, coincident with a surge in air travelers. Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas.

Phylodynamics of Yellow Fever Virus in the Americas: new insights into the origin of the 2017 Brazilian outbreak

Yellow fever virus (YFV) strains circulating in the Americas belong to two distinct genotypes (I and II) that have diversified into several concurrent enzootic lineages. Since 1999, YFV genotype I has spread outside endemic regions and its recent (2017) reemergence in non-endemic Southeastern Brazilian states fuels one of the largest epizootic of jungle Yellow Fever registered in the country. To better understand this phenomenon, we reconstructed the phylodynamics of YFV American genotypes using sequences from nine countries sampled along 60 years, including strains from Brazilian 2017 outbreak. Our analyses reveals that YFV genotypes I and II follow roughly similar evolutionary and demographic dynamics until the early 1990s, when a dramatic change in the diversification process of the genotype I occurred associated with the emergence and dissemination of a new lineage (here called modern). Trinidad and Tobago was the most likely source of the YFV modern-lineage that spread to Brazil and Venezuela around the late 1980s, where it replaced all lineages previously circulating. The modern-lineage caused all major YFV outbreaks detected in non-endemic South American regions since 2000, including the 2017 Brazilian outbreak, and its dissemination was coupled to the accumulation of several amino acid substitutions particularly within non-structural viral proteins.

Spatiotemporal Dynamics of the HIV-1 Subtype G Epidemic in West and Central Africa

The human immunodeficiency virus type 1 (HIV-1) subtype G is the second most prevalent HIV-1 clade in West Africa, accounting for nearly 30% of infections in the region. There is no information about the spatiotemporal dynamics of dissemination of this HIV-1 clade in Africa. To this end, we analyzed a total of 305 HIV-1 subtype G pol sequences isolated from 11 different countries from West and Central Africa over a period of 20 years (1992 to 2011). Evolutionary, phylogeographic and demographic parameters were jointly estimated from sequence data using a Bayesian coalescent-based method. Our analyses indicate that subtype G most probably emerged in Central Africa in 1968 (1956–1976). From Central Africa, the virus was disseminated to West and West Central Africa at multiple times from the middle 1970s onwards. Two subtype G strains probably introduced into Nigeria and Togo between the middle and the late 1970s were disseminated locally and to neighboring countries, leading to the origin of two major western African clades (GWA-I and GWA-II). Subtype G clades circulating in western and central African regions displayed an initial phase of exponential growth followed by a decline in growth rate since the early/middle 1990s; but the mean epidemic growth rate of GWA-I (0.75 year−1) and GWA-II (0.95 year−1) clades was about two times higher than that estimated for central African lineages (0.47 year−1). Notably, the overall evolutionary and demographic history of GWA-I and GWA-II clades was very similar to that estimated for the CRF06_cpx clade circulating in the same region. These results support the notion that the spatiotemporal dissemination dynamics of major HIV-1 clades circulating in western Africa have probably been shaped by the same ecological factors.

Spatiotemporal Dynamics of DENV-2 Asian-American Genotype Lineages in the Americas

The Asian/American (AS/AM) genotype of dengue virus type 2 (DENV-2) has been evolving in the Americas over the last 30 years, leading to several waves of dengue epidemics and to the emergence of different viral lineages in the region. In this study, we investigate the spatiotemporal dissemination pattern of the DENV-2 lineages at a regional level. We applied phylogenetic and phylogeographic analytical methods to a comprehensive data set of 582 DENV-2 E gene sequences of the AS/AM genotype isolated from 29 different American countries over a period of 30 years (1983 to 2012). Our study reveals that genetic diversity of DENV-2 AS/AM genotype circulating in the Americas mainly resulted from one single founder event and can be organized in at least four major lineages (I to IV), which emerged in the Caribbean region at the early 1980s and then spread and die out with different dynamics. Lineages I and II dominate the epidemics in the Caribbean region during the 1980s and early 1990s, lineage III becomes the prevalent DENV-2 one in the Caribbean and South America during the 1990s, whereas lineage IV dominates the epidemics in South and Central America during the 2000s. Suriname and Guyana seem to represent important entry points for DENV-2 from the Lesser Antilles to South America, whereas Venezuela, Brazil and Nicaragua were pointed as the main secondary hubs of dissemination to other mainland countries. Our study also indicates that DENV-2 AS/AM genotype was disseminated within South America following two main routes. The first route hits Venezuela and the western side of the Andes, while the second route mainly hits Brazil and the eastern side of the Andes. The phenomenon of DENV-2 lineage replacement across successive epidemic outbreaks was a common characteristic in all American countries, although the timing of lineage replacements greatly vary across locations.

Genomic and structural features of the yellow fever virus from the 2016–2017 Brazilian outbreak

Southeastern Brazil has been suffering a rapid expansion of a severe sylvatic yellow fever virus (YFV) outbreak since late 2016, which has reached one of the most populated zones in Brazil and South America, heretofore a yellow fever-free zone for more than 70 years. In the current study, we describe the complete genome of 12 YFV samples from mosquitoes, humans and non-human primates from the Brazilian 2017 epidemic. All of the YFV sequences belong to the modern lineage (sub-lineage 1E) of South American genotype I, having been circulating for several months prior to the December 2016 detection. Our data confirm that viral strains associated with the most severe YF epidemic in South America in the last 70 years display unique amino acid substitutions that are mainly located in highly conserved positions in non-structural proteins. Our data also corroborate that YFV has spread southward into Rio de Janeiro state following two main sylvatic dispersion routes that converged at the border of the great metropolitan area comprising nearly 12 million unvaccinated inhabitants. Our original results can help public health authorities to guide the surveillance, prophylaxis and control measures required to face such a severe epidemiological problem. Finally, it will also inspire other workers to further investigate the epidemiological and biological significance of the amino acid polymorphisms detected in the Brazilian 2017 YFV strains.

In-depth phylogenetic analysis of hepatitis C virus subtype 1a and occurrence of 80K and associated polymorphisms in the NS3 protease.

HCV genetic diversity is high and impacts disease progression, treatment and drug resistance. HCV subtype 1a is divided in two clades (I and II), and the 80 K natural polymorphism in the viral NS3 protease is prevalent in clade I. Paradoxically, countries dominated by this clade have contrasting frequencies of 80 K. Over 2,000 HCV 1a NS3 sequences were retrieved from public databases representing Europe, Oceania and the Americas. Sequences were aligned with HCV reference sequences and subjected to phylogenetic analysis to investigate the relative presence of different subtype 1a clades and NS3 protease mutations. HCV-1a sequences split into clades I and II. Clade I was further structured into three subclades, IA to C. Sub-clade IA prevailed in the U.S., while subclade IC was major in Brazil. The NS3 80 K polymorphism was associated with subclade IA, but nearly absent in subclades IB and IC, a pattern similarly seen for the 91S/T compensatory mutation. Three HCV-1a-I sub-clades have been identified, with different frequencies in distinct regions. The 80 K and 91A/S mutations were associated with subclade IA, which provide an explanation for the disparities seen in simeprevir resistance profiles of countries dominated by HCV 1a-I, like the U.S. and Brazil.

New insights into the hepatitis E virus genotype 3 phylodynamics and evolutionary history

Hepatitis E virus (HEV) is an emergent hepatotropic virus endemic mainly in Asia and other developing areas. However, in the last decade it has been increasingly reported in high-income countries. Human infecting HEV strains are currently classified into four genotypes (1-4). Genotype 3 (HEV-3) is the prevalent virus genotype and the mostly associated with autochthonous and sporadic cases of HEV in developed areas. The evolutionary history of HEV worldwide remains largely unknown. In this study we reconstructed the spatiotemporal and population dynamics of HEV-3 at global scale, but with particular emphasis in South America, where case reports have increased dramatically in the last years. To achieve this, we applied a Bayesian coalescent-based approach to a comprehensive data set comprising 97 GenBank HEV-3 sequences for which the location and sampling date was documented. Our phylogenetic analyses suggest that the worldwide genetic diversity of HEV-3 can be grouped into two main Clades (I and II) with a Ƭmrca dated in approximately 320years ago (95% HPD: 420-236years) and that a unique independent introduction of HEV-3 seems to have occurred in Uruguay, where most of the human HEV cases in South America have been described. The phylodynamic inference indicates that the population size of this virus suffered substantial temporal variations after the second half of the 20th century. In this sense and conversely to what is postulated to date, we suggest that the worldwide effective population size of HEV-3 is not decreasing and that frequently sources of error in its estimates stem from assumptions that the analyzed sequences are derived from a single panmictic population. Novel insights on the global population dynamics of HEV are given. Additionally, this work constitutes an attempt to further describe in a Bayesian coalescent framework, the phylodynamics and evolutionary history of HEV-3 in the South American region.

Tracing the origin of the NS1 A188V substitution responsible for recent enhancement of Zika virus Asian genotype infectivity

A recent study showed that infectivity of Zika virus (ZIKV) Asian genotype was enhanced by an alanine-to-valine amino acid substitution at residue 188 of the NS1 protein, but the precise time and location of origin of this mutation were not formally estimated. Here, we applied a Bayesian coalescent-based framework to estimate the age and location of the ancestral viral strain carrying the A188V substitution. Our results support that the ancestral ZIKV strain carrying the A188V substitution arose in Southeastern Asia at the early 2000s and circulated in that region for some time (5-10 years) before being disseminated to Southern Pacific islands and the Americas.

Phylodynamics of major HIV-1 subtype B pandemic clades circulating in Latin America.

Objective:To obtain a comprehensive description of the evolutionary and demographic history of major HIV-1 subtype B pandemic (BPANDEMIC) clades circulating in Latin America. Design:A total of 6789 HIV-1 subtype B pol sequences collected from seven different Latin American countries between 1990 and 2011 were combined with BPANDEMIC reference sequences (n = 500) from the United States and France. Methods:Major BPANDEMIC clades were identified by maximum likelihood phylogenetic analysis with sequential pruning of ambiguously positioned taxa. Time scale and demographic reconstructions were performed using a Bayesian coalescent-based method. Results:We identified 12 major BPANDEMIC monophyletic lineages mainly composed by Latin American sequences and that together comprise 36% of all subtype B sequences from the region here included. Four clades belong to two major regional lineages that comprise sequences from at least two neighboring countries, whereas the other eight clades were country-specific. The median age of major Latin American BPANDEMIC clades encompass a period of two decades (1968–1988), although most of them probably arose before the early 1980s. All major clades seem to have experienced an initial period of exponential growth, with median epidemic growth rates that range from 0.50 year−1to 0.94 year−1, followed by a recent decline in growth rate. Conclusion:About one-third of HIV-1 subtype B infections in Latin America originated from the spread of a few BPANDEMIC founder strains probably introduced in the region since the late 1960s. Despite their initial successful dissemination, all major BPANDEMIC clades showed signs of subsequent epidemic stabilization.

Detection and molecular characterization of emergent GII.P17/GII.17 Norovirus in Brazil, 2015

A newly GII.17 Kawazaki_2014 variant strain was detected recently in Brazil. Phylogenetic analysis reveals at least four independent introduction events of this lineage into this country that took place throughout 2014, coinciding with FIFA World Cup in Brazil, 2014, and Hong Kong has been identified as the most likely source of introduction. This variant emerged in Asia causing outbreaks and replacing prevalent GII.4. Emergence of GII.P17/GII.17 variant emphasizes the need for active laboratory surveillance for NoV including molecular epidemiology and studies on virus evolution.