TY  - JOUR
A1  - Bulli, Lorenzo
A1  - Apolonia, Luis
A1  - Kutzner, Juliane
A1  - Pollpeter, Darja
A1  - Goujon, Caroline
A1  - Herold, Nikolas
A1  - Schwarz, Sarah-Marie
A1  - Giernat, Yannick
A1  - Keppler, Oliver Till
A1  - Malim, Michael H.
A1  - Schaller, Torsten
T1  - Complex interplay between HIV-1 capsid and MX2-independent alpha interferon-induced antiviral factors
T2  - Journal of virology
N2  - Type I interferons (IFNs), including IFN-α, upregulate an array of IFN-stimulated genes (ISGs) and potently suppress Human immunodeficiency virus type 1 (HIV-1) infectivity in CD4(+) T cells, monocyte-derived macrophages, and dendritic cells. Recently, we and others identified ISG myxovirus resistance 2 (MX2) as an inhibitor of HIV-1 nuclear entry. However, additional antiviral blocks exist upstream of nuclear import, but the ISGs that suppress infection, e.g., prior to (or during) reverse transcription, remain to be defined. We show here that the HIV-1 CA mutations N74D and A105T, both of which allow escape from inhibition by MX2 and the truncated version of cleavage and polyadenylation specific factor 6 (CPSF6), as well as the cyclophilin A (CypA)-binding loop mutation P90A, all increase sensitivity to IFN-α-mediated inhibition. Using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology, we demonstrate that the IFN-α hypersensitivity of these mutants in THP-1 cells is independent of MX2 or CPSF6. As expected, CypA depletion had no additional effect on the behavior of the P90A mutant but modestly increased the IFN-α sensitivity of wild-type virus. Interestingly, the infectivity of wild-type or P90A virus could be rescued from the MX2-independent IFN-α-induced blocks in THP-1 cells by treatment with cyclosporine (Cs) or its nonimmunosuppressive analogue SDZ-NIM811, indicating that Cs-sensitive host cell cyclophilins other than CypA contribute to the activity of IFN-α-induced blocks. We propose that cellular interactions with incoming HIV-1 capsids help shield the virus from recognition by antiviral effector mechanisms. Thus, the CA protein is a fulcrum for the dynamic interplay between cell-encoded functions that inhibit or promote HIV-1 infection.
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/42601
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-426016
SN  - 1098-5514
SN  - 0022-538X
N1  - Copyright © 2016 Bulli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
VL  - 90
IS  - 16
SP  - 7469
EP  - 7480
PB  - American Society for Microbiology
CY  - Baltimore, Md.
ER  -