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Perfil filogenético estrutural e imunológico do VIH-1 em crianças de Moçambique
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A diversidade genética e a rápida evolução do VIH-1 influenciam diretamente a disseminação do vírus e a sua capacidade de adaptação à pressão exercida pelo sistema imunitário e pela terapêutica antirretroviral (TARV). Em Moçambique, um dos países com maior prevalência e incidência de VIH no mundo, a transmissão vertical permanece um desafio significativo, apesar da expansão da TARV na gravidez e dos avanços nos programas de prevenção. O diagnóstico tardio, a baixa retenção em cuidados e a adesão insuficiente à TARV por mães e crianças continuam a contribuir para taxas elevadas de transmissão mãe-filho. Neste contexto, terapias de longa duração, incluindo anticorpos neutralizantes de largo espectro (bNAbs), surgem como alternativas promissoras para reforçar estratégias de controlo e prevenção.
O presente estudo teve como objetivo avaliar a suscetibilidade de vírus VIH-1 provenientes de 38 crianças moçambicanas infetadas por via vertical a um painel de bNAbs atualmente em uso clínico. Para tal, foram geradas sequências do gene env dos vírus destas crianças, seguidas de análises filogenéticas, predição de tropismo, identificação de locais potenciais de N-glicosilação e avaliação da sensibilidade aos anticorpos.
Todas as sequências analisadas pertenciam ao subtipo C, em concordância com a epidemiologia nacional. A análise filogenética revelou elevada heterogeneidade genética entre os vírus do subtipo C em circulação no país, refletindo uma epidemia antiga, diversa e em contínua evolução. As regiões V1/V2 e V3 apresentaram características típicas deste subtipo, incluindo variação substancial no tamanho e padrão de glicosilação de V1/V2, bem como relativa conservação de V3 e do local de ligação ao recetor CD4. A maioria dos vírus mostrou tropismo para CCR5, embora tenha sido observada uma frequência de utilização de CXCR4 superior ao habitual.
Na avaliação da suscetibilidade aos bNAbs, apenas seis anticorpos neutralizaram mais de 50% dos isolados analisados, destacando-se o N6, capaz de neutralizar todos os invólucros testados. Combinações envolvendo bNAbs dirigidos ao CD4bs e ao apex da V2 revelaram potencial atividade sinérgica.
Os resultados obtidos contribuem para uma compreensão mais aprofundada das características estruturais e funcionais dos vírus transmitidos verticalmente em Moçambique e oferecem informação útil para o desenvolvimento de estratégias baseadas em bNAbs destinadas a reforçar a prevenção e o controlo da transmissão vertical no país.
The genetic diversity and rapid evolution of HIV-1 are central to the dissemination of the virus and its ability to adapt to the pressures exerted by the immune system and antiretroviral drugs. Mozambique is one of the countries with the highest rates of HIV prevalence and incidence worldwide. Despite the expansion of antiretroviral therapy (ART) during pregnancy and significant progress in prevention programmes, vertical transmission remains a major public health challenge. Late diagnosis, low retention of mothers in HIV care and poor ART adherence by mothers and infants contribute to persistently high mother-to-child transmission rates. In this context, long-acting therapeutics, including broadly neutralising antibodies (bNAbs), have emerged as a promising area of research for improving HIV control and prevention. This study aimed to assess the susceptibility of HIV-1 viruses from 38 Mozambican children infected via vertical transmission to a panel of clinically relevant bNAbs. To this end, envelope (env) gene sequences were generated from the children’s viruses and analysed using phylogenetics, tropism prediction, identification of potential N-glycosylation sites and sensitivity testing against the bNAb panel. All sequences belonged to subtype C, consistent with national epidemiological data. Phylogenetic analysis revealed substantial genetic heterogeneity among circulating subtype C viruses in Mozambique, reflecting an old and continually evolving epidemic. The V1/V2 and V3 regions exhibited characteristic subtype-specific features, including variation in V1/V2 length and glycosylation patterns, as well as relative conservation of V3 and the CD4 binding site. While most viruses showed CCR5 tropism, the frequency of CXCR4 usage was higher than is usually observed. In the bNAb susceptibility analysis, only six antibodies were found to neutralise more than 50% of the isolates, with N6 demonstrating exceptional neutralising activity against all envelopes tested. Several combinations of bNAbs directed at the CD4bs and V2 apex showed potentially synergistic activity. These findings deepen our understanding of the structural and functional properties of vertically transmitted HIV-1 in Mozambique, supporting the design and implementation of bNAb-based strategies for national prevention and mother-to-child transmission control programmes.
The genetic diversity and rapid evolution of HIV-1 are central to the dissemination of the virus and its ability to adapt to the pressures exerted by the immune system and antiretroviral drugs. Mozambique is one of the countries with the highest rates of HIV prevalence and incidence worldwide. Despite the expansion of antiretroviral therapy (ART) during pregnancy and significant progress in prevention programmes, vertical transmission remains a major public health challenge. Late diagnosis, low retention of mothers in HIV care and poor ART adherence by mothers and infants contribute to persistently high mother-to-child transmission rates. In this context, long-acting therapeutics, including broadly neutralising antibodies (bNAbs), have emerged as a promising area of research for improving HIV control and prevention. This study aimed to assess the susceptibility of HIV-1 viruses from 38 Mozambican children infected via vertical transmission to a panel of clinically relevant bNAbs. To this end, envelope (env) gene sequences were generated from the children’s viruses and analysed using phylogenetics, tropism prediction, identification of potential N-glycosylation sites and sensitivity testing against the bNAb panel. All sequences belonged to subtype C, consistent with national epidemiological data. Phylogenetic analysis revealed substantial genetic heterogeneity among circulating subtype C viruses in Mozambique, reflecting an old and continually evolving epidemic. The V1/V2 and V3 regions exhibited characteristic subtype-specific features, including variation in V1/V2 length and glycosylation patterns, as well as relative conservation of V3 and the CD4 binding site. While most viruses showed CCR5 tropism, the frequency of CXCR4 usage was higher than is usually observed. In the bNAb susceptibility analysis, only six antibodies were found to neutralise more than 50% of the isolates, with N6 demonstrating exceptional neutralising activity against all envelopes tested. Several combinations of bNAbs directed at the CD4bs and V2 apex showed potentially synergistic activity. These findings deepen our understanding of the structural and functional properties of vertically transmitted HIV-1 in Mozambique, supporting the design and implementation of bNAb-based strategies for national prevention and mother-to-child transmission control programmes.
Descrição
Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas Moniz
Palavras-chave
VIH-1 subtipo C Transmissão vertical Anticorpos neutralizantes de largo espectro (bNAbs) Diversidade genética viral Moçambique