AbstractsBiology & Animal Science

Human immunodeficiency virus type 1 (HIV-1) is subject to interferon-mediated antiviral defense. Among the interferon-stimulated genes, a small protein family called IFITM (interferon-induced transmembrane) proteins have been reported to inhibit a wide range of viruses including HIV-1. Yet, little is known about how IFITM proteins inhibit the infection of HIV-1 and how HIV-1 may overcome this inhibition. My thesis project is to understand the anti-HIV activity of IFITM1 and the strategy that HIV-1 adopts to overcome this restriction. Three major findings were made and are summarized as following.First, we have performed virus evolution assay in tissue culture and successfully selected IFITM1-resistance HIV-1 using a virus strain called HIV-1BH10. Sequencing the escape viruses revealed two mutations, Vpu34 in viral Vpu protein and EnvG367E in viral envelope protein, which together enabled efficient HIV-1 replication in IFITM1-expressing SupT1 cells. These two mutations did not overcome the defects in the viral p24 expression that was caused by IFITM1, rather they enhanced HIV-1 cell-to-cell transmission. For the first time, our study demonstrates that HIV-1 is able to mutate to evade IFITM1 restriction by increasing cell-to-cell transmission.Second, we observed that the HIV-1BH10 strain, but not HIV-1NL4-3, was dramatically inhibited by IFITM1 in SupT1 cells. Mutagenesis analysis of the viral genome revealed that HIV-1NL4-3 envelope protein determines the resistance to IFITM1 at least partially resulting from its greater ability to mediate HIV-1 cell-to-cell transmission. This finding further highlights the important role of HIV-1 envelope in countering IFITM1 inhibition.Third, we discovered that the C-terminal sequence of IFITM1 prevented IFITM1 from inhibiting HIV-1 entry. Removing the C-terminal sequence enabled IFITM1 to inhibit3HIV-1NL4-3 partially by diminishing virus entry. Further mutagenesis studies mapped the key amino acid residues to 117-QII-119. Importantly, HIV-1NL4-3 was able to escape from the inhibition by C-terminus truncated IFITM1 through mutating the Vpu and envelope proteins.In conclusion, we have discovered a vital role of HIV-1 envelope in determining the susceptibility of HIV-1 to IFITM1 inhibition. We also, for the first time, report a role of the C-terminal sequence of IFITM1 in regulating its anti-HIV-1 function. Le virus de l'immunodéficience humaine de type 1 (VIH-1) doit faire face à la défense antivirale médiée par l'interféron. Parmi les gènes stimulés par l'interféron, une petite famille de protéines transmembranaires induite par l'interféron (IFITM) inhibe la réplication de plusieurs virus, y compris le VIH-1. On sait peu sur la façon dont les protéines IFITM inhibent la réplication du VIH-1 et comment le VIH-1 peut surmonter cette inhibition. Mon projet de thèse est de comprendre l'activité anti-VIH de IFITM1 et la stratégie que le VIH-1 adopte pour surmonter cette restriction. Nous avons atteint trois principales conclusions qui sont résumées ci-dessous.Tout d'abord, nous avons…