Navegando por Palavras-chave "Quasispecies"

Agora exibindo 1 - 4 de 4
  • Imagem de Miniatura
    Item
    Acesso aberto (Open Access)
    A evolução genética do HIV-1 entre indivíduos em tratamento antirretroviral
    (Universidade Federal de São Paulo (UNIFESP), 2017-02-09) Giron, Leila Bertoni [UNIFESP]; Diaz, Ricardo Sobhie [UNIFESP]; http://lattes.cnpq.br/0846508761438062; http://lattes.cnpq.br/3122722993515096; Universidade Federal de São Paulo (UNIFESP)
    Abstract Background: Although antiretroviral therapy (ART) suppresses HIV to undetectable levels in plasma, it is unclear if treatment fully suppresses HIV replication. We aimed to determine if current ART is fully suppressive by investigating HIV genetic diversity and divergence during ART as a proxy for ongoing viral residual replication. Methods: Peripheral blood from 34 HIV-infected individuals were evaluated immediately before ART onset and after four years of continuous ART treatment with undetectable viral loads. Ultradeep sequencing (UDS) of the gp41 and C2V3 regions of HIV gp160 was performed. Lowfrequency viral variants were filtered based on an error rate of 0.5% derived from misincorporations in the HIV BAL plasmid, which was amplified and sequenced with the samples. HIV divergence and diversity at each time point were calculated using average pairwise distance. Genetic compartmentalization analyses between time points based on tree topologies and pairwise distance were also performed. Correlations between genetic divergence and elapsed time between sampling points were evaluated using linear regression, implemented using TempEst software (root-to-tip analysis). Results: There was no correlation between read depth and the number of viral variants recorded in UDS. gp41 and C2V3 sequences strains after four years of ART demonstrated significant increases in viral genetic divergence from the most recent common ancestor sequence as compared to baseline variants from the same individual (p=0.0003 and p<0.0001 respectively). Viral divergence values exhibited trend to negative correlations with the CD4/CD8 ratio (p=0.07 and 0.09). No difference was observed in viral diversity between time points. Compartmentalization analyses indicated the presence of distinct virus populations emerging at each time point in 54% individuals based on both tree topologies and pairwise distance analysis tests to gp41 and in 50% of individual in C2V3. Root-to-tip analyses yielded R2 values ranging from 0.01 to 0.96 in both regions, indicating high correlation between genetic divergence and time and therefore viral evolution. Conclusion: Ongoing viral genetic evolution was detected in the majority of individuals on continuous ART. These results suggest that current ART regimens do not completely suppress viral replication. Residual replicating virus may replenish the proviral reservoir and sustain inflammatory responses, perhaps especially in sanctuaries.
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    Modelo Matemático E Computacional Para O Estudo De Evolução E Adaptação Viral Com Presença De Reservatório
    (Universidade Federal de São Paulo (UNIFESP), 2017-05-25) Gorzoni, Bruno Zanardo [UNIFESP]; Janini, Luiz Mario Ramos [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Abstract The theory of lethal mutagenesis predicts that RNA virus populations could become extinct by reduction of their mean replication capacity (mean number of progeny per infected cell), triggered by the elevation of detrimental mutation rates. However, there are RNA viruses, such as HIV-1, capable of escaping extinction, even after long ART (Antiretroviral Therapy) periods due to the presence of an integrated latent viral reservoir. We believe that the reservoir can play an important role in the evolution of viral populations, acting as an evolutionary strategy to delay its own extinction. We developed a mathematical model to emulate the reservoir by applying the concept of aging to particles integrated in cells with latent infection. By adding ages to particles, we sought to represent the latent reservoir containing resting cells harboring the integrated viral genome. We implemented the model as a user-friendly program, which is an upgrade from a previous published model by our group, which is capable of performing simulations and displaying the results in real time. In our results, we show that the emulated reservoir delays viral extinction in comparison to simulations performed without reservoir. We believe that there is a strong indication that the reservoir could even avoid complete extinction in certain adaptive scenarios helping the virus population to escape from the lethal mutagenesis. According to our simulations, the reservoir can act as a viral population memory retaining particles with greater replication capacity that have been lost from the replicating viral population. The reintroduction of highly replicative particles allows the population to survive for longer periods even in the presence of elevated mutation rates.
  • Imagem de Miniatura
    Item
    Acesso aberto (Open Access)
    Simulação computacional e análise de um modelo de recombinação retroviral
    (Universidade Federal de São Paulo (UNIFESP), 2017-04-28) Santos, Diogo Castro dos [UNIFESP]; Janini, Luiz Mario Ramos [UNIFESP]; Antoneli Junior, Fernando Martins; http://lattes.cnpq.br/4503426222486154; http://lattes.cnpq.br/5713863164263481; http://lattes.cnpq.br/7298729170514521; Universidade Federal de São Paulo (UNIFESP)
    Retroviruses cause major diseases in humans, such as Acquired Human Immunodeficiency Syndrome (AIDS), caused by HIV-1, which accounts for 2.1 million new cases in 2015 alone, and T-cell lymphoma, caused by HTLV-1. One of the hallmarks of retroviruses is the high frequency of genetic recombination during replication, associated with a high mutational rate, considered one of the highest in nature. These characteristics contribute to the generation of expressive genetic diversity in the viral population, strongly impacting its virulence, facilitating evasion from detection by the immune system, increasing resistance to antiviral treatment, hindering diagnosis, and the development of effective vaccines. With the purpose of guiding experimental studies and investigating scenarios that cannot yet be approached experimentally, in addition to providing support to elaborate new scientific predictions, we propose, in this work, a model to study mutational rates and genetic recombination in retroviruses. Custom software for the model was also developed. It performs computational simulations and analysis to understand how mutational rates and genetic recombination affect the evolution of the retrovirus population, in the host organism, during four stages of infection: recovery time, mutation-selection equilibrium, extinction threshold, and lethal mutagenesis.
  • Imagem de Miniatura
    Item
    Acesso aberto (Open Access)
    Simulação computacional e análise de um modelo fenotípico de evolução viral
    (Universidade Federal de São Paulo (UNIFESP), 2011-01-26) Castro, Diogo [UNIFESP]; Janini, Luiz Mário Ramos [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    A large amount of viruses of medical importance such as HIV, respiratory syncytial virus, the hepatitis C virus, influenza A (H1N1) and polio virus, has RNA genome. These viruses exhibit extremely high mutational rate, fast replicative kinetics, large population of particles and high genetic diversity. Manifested during the infectious process, these features allow the virus population to adapt quickly to dynamic environments, escape from the immune system, develop resistance to vaccines and antiviral drugs, and display complex evolutionary dynamics whose understanding represents a challenge to the traditional population genetics and for effective therapeutic intervention strategies. To describe mathematically and biological evolution of RNA viruses, theoretical models of virus evolution have been proposed, and many of their predictions were experimentally confirmed. This study aimed to simulate and analyze computationally a model of viral evolution that represents evolutionary relationships between the population of viral RNA genome and the different selective pressures on it in its interaction with the host organism. It also aimed to develop computational simulation software for the viral evolution model, and demonstrate the possibility of describing the model as a Galton-Watson branching process. Among the results and discussions outlined, there are an analytical criterion to study the recovery time and the critical regime of a Galton-Watson branching process applied to viral evolution; predictions about the correlation between factors of the host organism and the evolutionary dynamics of viral population; predictions about the contribution of mutational rate, the size and maximum replicative capacity of viral population for the prognosis and four stages of infection: recovery time, mutation-selection equilibrium, extinction threshold, and lethal mutagenesis.