TY  - JOUR
A1  - Libre, Camille
A1  - Seissler, Tanja
A1  - Guerrero, Santiago
A1  - Batisse, Julien
A1  - Verriez, Cédric
A1  - Stupfler, Benjamin
A1  - Gilmer, Orian
A1  - Cabrera-Rodriguez, Romina
A1  - Weber, Melanie M.
A1  - Valenzuela-Fernandez, Agustin
A1  - Cimarelli, Andrea
A1  - Etienne, Lucie
A1  - Marquet, Roland
A1  - Paillart, Jean-Christophe
T1  - A conserved uORF regulates APOBEC3G translation and is targeted by HIV-1 Vif protein to repress the antiviral factor
JF  - Biomedicines
N2  - The HIV-1 Vif protein is essential for viral fitness and pathogenicity. Vif decreases expression of cellular restriction factors APOBEC3G (A3G), A3F, A3D and A3H, which inhibit HIV-1 replication by inducing hypermutation during reverse transcription. Vif counteracts A3G at several levels (transcription, translation, and protein degradation) that altogether reduce the levels of A3G in cells and prevent its incorporation into viral particles. How Vif affects A3G translation remains unclear. Here, we uncovered the importance of a short conserved uORF (upstream ORF) located within two critical stem-loop structures of the 5′ untranslated region (5′-UTR) of A3G mRNA for this process. A3G translation occurs through a combination of leaky scanning and translation re-initiation and the presence of an intact uORF decreases the extent of global A3G translation under normal conditions. Interestingly, the uORF is also absolutely required for Vif-mediated translation inhibition and redirection of A3G mRNA into stress granules. Overall, we discovered that A3G translation is regulated by a small uORF conserved in the human population and that Vif uses this specific feature to repress its translation.
KW  - HIV-1
KW  - APOBEC3G
KW  - Vif
KW  - mRNA
KW  - translation
KW  - uORF
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252147
SN  - 2227-9059
VL  - 10
IS  - 1
ER  - 
TY  - JOUR
A1  - Isaacs, Darren
A1  - Mikasi, Sello Given
A1  - Obasa, Adetayo Emmanuel
A1  - Ikomey, George Mondinde
A1  - Shityakov, Sergey
A1  - Cloete, Ruben
A1  - Jacobs, Graeme Brendon
T1  - Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors
JF  - Viruses
N2  - The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.
KW  - integrase
KW  - naturally occurring polymorphisms
KW  - HIV-1
KW  - molecular modelling
KW  - molecular docking
KW  - diversity
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211170
SN  - 1999-4915
VL  - 12
IS  - 9
ER  -