RESUMO
The goal of this work was to compare the differences between human immunodeficiency virus type 1 (HIV-1) of B and F1 subtypes in the acquisition of major and minor protease inhibitor (PI)-associated resistance mutations and of other polymorphisms at the protease (PR) gene, through a cross sectional study. PR sequences from subtypes B and F1 isolates matched according to PI exposure time from Brazilian patients were included in this study. Sequences were separated in four groups: 24 and 90 from children and 141 and 99 from adults infected with isolates of subtypes F1 and B, respectively. For comparison, 211 subtype B and 79 subtype F1 PR sequences from drug-naïve individuals were included. Demographic and clinical data were similar among B- and F1-infected patients. In untreated patients, mutations L10V, K20R, and M36I were more frequent in subtype F1, while L63P, A71T, and V77I were more prevalent in subtype B. In treated patients, K20M, D30N, G73S, I84V, and L90M, were more prevalent in subtype B, and K20T and N88S were more prevalent in subtype F1. A higher proportion of subtype F1 than of subtype B strains containing other polymorphisms was observed. V82L mutation was present with increased frequency in isolates from children compared to isolates from adults infected with both subtypes. We could observe a faster resistance emergence in children than in adults, during treatment with protease inhibitors. This data provided evidence that, although rates of overall drug resistance do not differ between subtypes B and F1, the former accumulates resistance at higher proportion in specific amino acid positions of protease when compared to the latter.
Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/virologia , Protease de HIV/genética , HIV-1/genética , Mutação , Polimorfismo Genético , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Brasil , Criança , Pré-Escolar , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estatísticas não Paramétricas , Carga ViralRESUMO
HIV, the cause of AIDS in humans, is characterized by great genetic heterogeneity. In particular, HIV-1 group M subtypes are responsible for most of the infections worldwide. We investigate the demographic history of HIV-1B and HIV-1C subtypes in South Africa and Brazil using both a parametric and a nonparametric approach based on coalescent theory. Our results show that although both subtypes are spreading exponentially in Brazil, the HIV-1C growth rate is about twice that of Brazilian HIV-1B or South African HIV-1C, providing evidence, for the first time, of a different epidemic potential between two HIV-1 subtypes. The present study not only may have important consequences for devising future vaccination and therapeutic strategies, but also offers additional evidence that skyline plots are indeed a simple and powerful tool for monitoring and predicting the behavior of viral epidemics.
Assuntos
Síndrome da Imunodeficiência Adquirida/epidemiologia , Demografia , Evolução Molecular , Variação Genética , HIV-1/genética , Modelos Biológicos , Filogenia , Síndrome da Imunodeficiência Adquirida/genética , Humanos , Funções Verossimilhança , Modelos Genéticos , Dinâmica Populacional , África do Sul/epidemiologia , América do Sul/epidemiologia , Especificidade da EspécieRESUMO
BACKGROUND: Most published data on antiretroviral-drug resistance is generated from in vitro or in vivo studies of subtype B virus. However, this subtype is associated with <10% of HIV infections worldwide, and it is essential to explore subtype-specific determinants of drug resistance. One potential cause of the differences between subtypes is the synonymous codon usage at key resistance positions. METHODS: We investigated the nucleotide sequences at drug resistance-related sites, for all major Brazilian subtypes (B, C, and F1) of human immunodeficiency virus type 1 (HIV-1) group M. RESULTS: We identified a change at positions 151 and 210 of the reverse-transcriptase region in subtype F1, such that the emergence of these key nucleoside/nucleotide analogue resistance mutations required an extra nucleotide change in subtype F1, compared with subtypes B and C. The clinical significance of position 210 was confirmed within a large Brazilian database, in which we identified a lower prevalence of the L210W mutation in subtype F1 virus, compared with subtype B virus, in patients matched for thymidine-analogue experience. An inverse relationship between the L210W and K70R mutations was also observed. CONCLUSIONS: The findings of the present study illustrate an important mechanism by which a subtype may determine genetic routes to resistance, with implications for treatment strategies for populations infected with HIV-1 subtype F.
Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Sequência de Bases , Brasil , Códon/genética , DNA Viral/química , DNA Viral/genética , Protease de HIV/genética , HIV-1/metabolismo , Humanos , Dados de Sequência Molecular , Mutação Puntual/genética , Polimorfismo Genético , DNA Polimerase Dirigida por RNA/genética , Alinhamento de SequênciaRESUMO
The prevalence of mutations that confer resistance to protease inhibitors and to nucleoside and nonnucleoside reverse transcriptase inhibitors in 49 blood samples from drug-naïve human immunodeficiency virus type 1-infected blood donors living in Rio de Janeiro state, Brazil, in 1998 was evaluated genotypically and phenotypically.