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Research Project
DESENVOLVIMENTO DE NOVOS MICROBICIDAS PARA PREVENIR A INFECÇÃO POR VIH
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Publications
Donor-Recipient identification in para- and poly-phyletic trees under alternative HIV-1 transmission hypotheses using approximate Bayesian computation
Publication . Romero-Severson, Ethan O.; Bulla, Ingo; Hengartner, Nick; Bártolo, Inês; Abecasis, Ana; Azevedo-Pereira, José M.; Taveira, Nuno; Leitner, Thomas
Diversity of the founding population of Human Immunodeficiency Virus Type 1 (HIV-1) transmissions raises many important biological, clinical, and epidemiological issues. In up to 40% of sexual infections, there is clear evidence for multiple founding variants, which can influence the efficacy of putative prevention methods, and the reconstruction of epidemiologic histories. To infer who-infected-whom, and to compute the probability of alternative transmission scenarios while explicitly taking phylogenetic uncertainty into account, we created an approximate Bayesian computation (ABC) method based on a set of statistics measuring phylogenetic topology, branch lengths, and genetic diversity. We applied our method to a suspected heterosexual transmission case involving three individuals, showing a complex monophyletic-paraphyletic-polyphyletic phylogenetic topology. We detected that seven phylogenetic lineages had been transmitted between two of the individuals based on the available samples, implying that many more unsampled lineages had also been transmitted. Testing whether the lineages had been transmitted at one time or over some length of time suggested that an ongoing superinfection process over several years was most likely. While one individual was found unlinked to the other two, surprisingly, when evaluating two competing epidemiological priors, the donor of the two that did infect each other was not identified by the host root-label, and was also not the primary suspect in that transmission. This highlights that it is important to take epidemiological information into account when analyzing support for one transmission hypothesis over another, as results may be nonintuitive and sensitive to details about sampling dates relative to possible infection dates. Our study provides a formal inference framework to include information on infection and sampling times, and to investigate ancestral node-label states, transmission direction, transmitted genetic diversity, and frequency of transmission.
HIV-1 Diversity, Transmission Dynamics and Primary Drug Resistance in Angola
Publication . Bártolo, Inês; Zakovic, Susana; Martin, Francisco; Palladino, Claudia; Carvalho, Patrícia; Camacho, Ricardo; Thamm, Sven; Clemente, Sofia; Taveira, Nuno
"Objectives: To assess HIV-1 diversity, transmission dynamics and prevalence of
transmitted drug resistance (TDR) in Angola, five years after ART scale-up.
Methods: Population sequencing of the pol gene was performed on 139 plasma
samples collected in 2009 from drug-naive HIV-1 infected individuals living in
Luanda. HIV-1 subtypes were determined using phylogenetic analysis. Drug
resistance mutations were identified using the Calibrated Population Resistance
Tool (CPR). Transmission networks were determined using phylogenetic analysis
of all Angolan sequences present in the databases. Evolutionary trends were
determined by comparison with a similar survey performed in 2001.
Results: 47.1% of the viruses were pure subtypes (all except B), 47.1% were
recombinants and 5.8% were untypable. The prevalence of subtype A decreased
significantly from 2001 to 2009 (40.0% to 10.8%, P50.0019) while the prevalence
of unique recombinant forms (URFs) increased.2-fold (40.0% to 83.1%,
P,0.0001). The most frequent URFs comprised untypable sequences with
subtypes H (U/H, n57, 10.8%), A (U/A, n56, 9.2%) and G (G/U, n54, 6.2%). Newly
identified U/H recombinants formed a highly supported monophyletic cluster
suggesting a local and common origin. TDR mutation K103N was found in one
(0.7%) patient (1.6% in 2001). Out of the 364 sequences sampled for transmission
network analysis, 130 (35.7%) were part of a transmission network. Forty eight
transmission clusters were identified; the majority (56.3%) comprised sequences
sampled in 2008–2010 in Luanda which is consistent with a locally fuelled
epidemic. Very low genetic distance was found in 27 transmission pairs sampled in
the same year, suggesting recent transmission events.
Conclusions: Transmission of drug resistant strains was still negligible in Luanda
in 2009, five years after the scale-up of ART. The dominance of small and recent
transmission clusters and the emergence of new URFs are consistent with a rising
HIV-1 epidemics mainly driven by heterosexual transmission."
In vitro evaluation of novel reverse transcriptase inhibitors TAF (tenofovir alafenamide) and OBP-601 (2,3-didehydro-3-deoxy-4-ethynylthymidine) against multi-drug resistant primary isolates of HIV-2
Publication . Bártolo, Inês; Borrego, Pedro; Gomes, Perpétua; Gonçalves, Fátima; Caixas, Umbelina; Pinto, Inês V.; Taveira, Nuno
New antiretroviral drugs are needed to treat HIV-2 infected patients failing therapy. Herein, we evaluate the activity of novel reverse transcriptase inhibitors tenofovir alafenamide (TAF) and OBP-601(2,3-didehydro-3-deoxy-4-ethynylthymidine) against primary isolates from HIV-2 infected patients experiencing virologic failure. TAF and OBP-601 were tested against twelve primary isolates obtained from nine drug-experienced patients failing therapy and three drug naïve patients using a single-round infectivity assay in TZM-bl cells. The RT-coding region of pol was sequenced and the GRADE algorithm was used to identify resistance profiles and mutations. TAF and OBP-601 inhibited the replication of almost all isolates at a median EC50 of 0.27 nM and 6.83 nM, respectively. Two isolates showed moderate-level resistance to OBP-601 or TAF and two other isolates showed high-level resistance to OBP-601 or to both drugs. With one exception, all resistant viruses had canonical nucleoside reverse transcriptase inhibitors (NRTIs)-associated resistance mutations (K65R, N69S, V111I, Y115F, Q151M and M184V). Our results show that TAF has potent activity against most multi-drug resistant HIV-2 isolates and should be considered for the treatment of HIV-2 infected patients failing therapy.
Rare HIV-1 subtype J genomes and a new H/U/CRF02_AG recombinant genome suggests an ancient origin of HIV-1 in Angola
Publication . Bártolo, Inês; Calado, Rita; Borrego, Pedro; Thomas, Leitner; Taveira, Nuno
"Angola has an extremely diverse HIV-1 epidemic fueled in part by the frequent interchange of people with the Democratic Republic of Congo (DRC) and Republic of Congo (RC). Characterization of HIV-1 strains circulating in Angola should help to better understand the origin of HIV-1 subtypes and recombinant forms and their transmission dynamics. In this study we characterize the first near full-length HIV-1 genomic sequences from HIV-1 infected individuals from Angola. Samples were obtained in 1993 from three HIV-1 infected patients living in Cabinda, Angola. Near full-length genomic sequences were obtained from virus isolates. Maximum likelihood phylogenetic tree inference and analyses of potential recombination patterns were performed to evaluate the sequence classifications and origins. Phylogenetic and recombination analyses revealed that one virus was a pure subtype J, another mostly subtype J with a small uncertain region, and the final virus was classified as a H/U/CRF02_AG recombinant. Consistent with their epidemiological data, the subtype J sequences were more closely related to each other than to other J sequences previously published. Based on the env gene, taxa from Angola occur throughout the global subtype J phylogeny. HIV-1 subtypes J and H are present in Angola at low levels since at least 1993. Low transmission efficiency and/or high recombination potential may explain their limited epidemic success in Angola and worldwide. The high diversity of rare subtypes in Angola suggests that Angola was part of the early establishment of the HIV-1 pandemic."
The contribution of Angola to the early spread of the HIV-1 epidemic
Publication . Pineda-Peña, Andrea-Clemencia; Varanda, Jorge; Theys, Kristof; Bártolo, Inês; Leitner, Thomas; Taveira, Nuno; Vandamme, Anne-Mieke; Abecasis, Ana B.
"Understanding how, when and why the HIV-1 virus adapted to the human population and become pandemic is crucial to prevent its propagation and the establishment of other potential future viral pandemics. It is known that the HIV-1 group M epidemic started in Kinshasa, Democratic Republic of Congo (DRC), and soon spread across the Congo river to Brazzaville located in Republic of Congo (RC), and further to Lubumbashi and Mbuji-Mayi (DRC), around 1930s (~1937 [95% Bayesian Credible Interval: 1919-1957]).
Angola borders and has long-term links with DRC and RC as well as high levels of HIV-1 genetic diversity 2. Therefore, we aimed to investigate the role of this country in the initial spread of the HIV-1 pandemic."
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Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
Funding Award Number
SFRH/BPD/76225/2011