Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation

Hashim Ali, Miguel Mano, Luca Braga, Asma Naseem, Bruna Marini, Diem My Vu, Chiara Collesi, Germana Meroni, Marina Lusic and Mauro Giacca ()
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Hashim Ali: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Miguel Mano: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Luca Braga: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Asma Naseem: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Bruna Marini: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Diem My Vu: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Chiara Collesi: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Germana Meroni: University of Trieste
Marina Lusic: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Mauro Giacca: International Centre for Genetic Engineering and Biotechnology (ICGEB)

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Productive HIV-1 replication requires viral integrase (IN), which catalyzes integration of the viral genome into the host cell DNA. IN, however, is short lived and is rapidly degraded by the host ubiquitin-proteasome system. To identify the cellular factors responsible for HIV-1 IN degradation, we performed a targeted RNAi screen using a library of siRNAs against all components of the ubiquitin-conjugation machinery using high-content microscopy. Here we report that the E3 RING ligase TRIM33 is a major determinant of HIV-1 IN stability. CD4-positive cells with TRIM33 knock down show increased HIV-1 replication and proviral DNA formation, while those overexpressing the factor display opposite effects. Knock down of TRIM33 reverts the phenotype of an HIV-1 molecular clone carrying substitution of IN serine 57 to alanine, a mutation known to impair viral DNA integration. Thus, TRIM33 acts as a cellular factor restricting HIV-1 infection by preventing provirus formation.

Date: 2019
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DOI: 10.1038/s41467-019-08810-0

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