Percorrer por autor "Leitner, Thomas"
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- Accidental father-to-son HIV-1 transmission during the seroconversion periodPublication . Ezeonwumelu, Ifeanyi; Bártolo, Inês; Martin, Francisco; Abecasis, Ana; Campos, Teresa; Romero-Severson, Ethan O.; Leitner, Thomas; Taveira, NunoA 4-year-old child born to an HIV-1 seronegative mother was diagnosed with HIV-1, the main risk factor being transmission from the child's father who was seroconverting at the time of the child's birth. In the context of a forensic investigation, we aimed to identify the source of infection of the child and date of the transmission event. Samples were collected from the father and child at two time points about 4 years after the child's birth. Partial segments of three HIV-1 genes (gag, pol, and env) were sequenced and maximum likelihood (ML) and Bayesian methods were used to determine direction and estimate date of transmission. Neutralizing antibodies were determined using a single cycle assay. Bayesian trees displayed a paraphyletic–monophyletic topology in all three genomic regions, with the father's host label at the root, which is consistent with father-to-son transmission. ML trees found similar topologies in gag and pol and a monophyletic–monophyletic topology in env. Analysis of the time of the most recent common ancestor of each HIV-1 gene population indicated that the child was infected shortly after the father. Consistent with the infection history, both father and son developed broad and potent HIV-specific neutralizing antibody responses. In conclusion, the direction of transmission implicated the father as the source of transmission. Transmission occurred during the seroconversion period when the father was unaware of the infection and was likely accidental. This case shows how genetic, phylogenetic, and serological data can contribute for the forensic investigation of HIV transmission.
- Donor-Recipient identification in para- and poly-phyletic trees under alternative HIV-1 transmission hypotheses using approximate Bayesian computationPublication . Romero-Severson, Ethan O.; Bulla, Ingo; Hengartner, Nick; Bártolo, Inês; Abecasis, Ana; Azevedo-Pereira, José M.; Taveira, Nuno; Leitner, ThomasDiversity 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.
- Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody responsePublication . Rocha, Cheila; Calado, Rita; Borrego, Pedro; Marcelino, José Maria; Bártolo, Inês; Rosado, Lino; Cavaco-Silva, Patrícia; Perpétua, Gomes; Família, Carlos; Quintas, Alexandre; Skar, Helena; Leitner, Thomas; Barroso, Helena; Taveira, Nuno"Background: Differently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4+ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth. Results: CD4+ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5-to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a β-hairpin structure were related with rate of escape from the neutralizing antibodies. Conclusion: Our data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis."
- Long-term and low-level envelope C2V3 stimulation by highly diverse virus isolates leads to frequent development of broad and elite antibody neutralization in HIV-1-infected individualsPublication . Martin, Francisco; Marcelino, José Maria; Palladino, Claudia; Bártolo, Inês; Tracana, Susana; Moranguinho, Inês; Gonçalves, Paloma; Mateus, Rita; Calado, Rita; Borrego, Pedro; Leitner, Thomas; Clemente, Sofia; Taveira, NunoA minority of HIV-1-infected patients produce broadly neutralizing antibodies (bNAbs). Identification of viral and host correlates of bNAb production may help develop vaccines. We aimed to characterize the neutralizing response and viral and host-associated factors in Angola, which has one of the oldest, most dynamic, and most diverse HIV-1 epidemics in the world. Three hundred twenty-two HIV-1-infected adults from Angola were included in this retrospective study. Phylogenetic analysis of C2V3C3 env gene sequences was used for virus subtyping. Env-binding antibody reactivity was tested against polypeptides comprising the C2, V3, and C3 regions. Neutralizing-antibody responses were determined against a reference panel of tier 2 Env pseudoviruses in TZM-bl cells; neutralizing epitope specificities were predicted using ClustVis. All subtypes were found, along with untypeable strains and recombinant forms. Notably, 56% of the patients developed cross neutralizing, broadly neutralizing, or elite neutralizing responses. Broad and elite neutralization was associated with longer infection time, subtype C, lower CD4+ T cell counts, higher age, and higher titer of C2V3C3-specific antibodies relative to failure to develop bNAbs. Neutralizing antibodies targeted the V3-glycan supersite in most patients. V3 and C3 regions were significantly less variable in elite neutralizers than in weak neutralizers and nonneutralizers, suggesting an active role of V3C3-directed bNAbs in controlling HIV-1 replication and diversification. In conclusion, prolonged and low-level envelope V3C3 stimulation by highly diverse and ancestral HIV-1 isolates promotes the frequent elicitation of bNAbs. These results provide important clues for the development of an effective HIV-1 vaccine.
- On the contribution of Angola to the initial spread of HIV-1Publication . Pineda-Peña, Andrea-Clemencia; Varanda, Jorge; Sousa, João Dinis; Theys, Kristof; Bártolo, Inês; Leitner, Thomas; Taveira, Nuno; Vandamme, Anne-Mieke; Abecasis, Ana B.Angola borders and has long-term links with Democratic Republic of Congo (DRC) as well as high levels of Human Immunodeficiency Virus (HIV) genetic diversity, indicating a potential role in the initial spread of the HIV-1 pandemic. Herein, we analyze 564 C2V3 and 354 pol publicly available sequences from DRC, Republic of Congo (RC) and Angola to better understand the initial spread of the virus in this region. Phylogeographic analyses were performed with the BEAST software. While our results pinpoint the origin of the pandemic to Kinshasa (DRC) around 1906, the introduction of HIV-1 to Angola could have occurred early between the 1910s and 1940s. Furthermore, most of the HIV-1 migrations out of Kinshasa were directed not only to Lubumbashi and Mbuji-Mayi (DRC), but also to Luanda and Brazzaville. Kinshasa census records corroborate these findings, indicating that the early exportation of the virus to Angola might be related to the high number of Angolans in Kinshasa at that time, originated mostly from the North of Angola. In summary, our results place Angola at the epicenter of the early HIV dissemination, together with DRC and RC.
- The contribution of Angola to the early spread of the HIV-1 epidemicPublication . 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."