Mechanisms underlying exosomal trafficking of the antiretroviral factor apobec3g: implications for the containment and eradication of HIV-1 infection

• Main Author: Mendes, Afonso Machado
• Publication Date: 2019
• Format: Master thesis
• Language: eng
• Source: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Download full: http://hdl.handle.net/10362/93640
• topic: Antiretroviral factor APOBEC3G; HIV-1 infection; Ciências Médicas

ABSTRACT: The first reports of patients with acquired immunodeficiency syndrome (AIDS) and the discovery of the Human Immunodeficiency Virus type 1 (HIV-1) as the causative agent of AIDS occurred around three decades ago. Africa is, by far, the most affected region in the world, registering over 1 million new infections in 2017. Despite the enormous progress made with the introduction of relatively effective preventive and therapeutic interventions, 37 million people are still infected and without a cure. The natural antiretroviral protein APOBEC3G catalyzes C-to-U deamination in the viral DNA and is capable of restricting HIV-1 replication in the absence of Vif, a viral protein that interacts with APOBEC3G and promotes its ubiquitylation and subsequent degradation the 26S proteasome, rendering the natural antiviral response incapable of restricting the replication of wild-type HIV-1. The presence of APOBEC3G in the exosomes (small nano-sized extracellular vesicles originated in multivesicular bodies (MVBs) and secreted by fusion of the MVBs with the cell membrane) of several cell lines has been shown. Furthermore, A3G-containing exosomes were shown to effectively restrict HIV-1 replication in cell models. However, the mechanisms underlying the import of A3G into exosomes remain unclear. In this study, the exosomes of the HEK293T cell line were found to be enriched in a EGFP-tagged version of A3G when compared to EGFP, higher than those of EGFP, a protein that is not selectively incorporated in exosomes. Furthermore, we show for the first that this enrichment depends on the presence of a specific amino acid sequence in the primary structure of A3G called the KFERQ-like motif. In the future, these mechanisms may be used to design new strategies in preventing, treating and even curing HIV-1 infection.