Nuclear architecture dictates HIV-1 integration site selection.
Long-standing evidence indicates that human immunodeficiency virus type 1 (HIV-1) preferentially integrates into a subset of transcriptionally active genes of the host cell genome. However, the reason why the virus selects only certain genes among all transcriptionally active regions in a target cell remains largely unknown. Here we show that HIV-1 integration occurs in the outer shell of the nucleus in close correspondence with the nuclear pore. This region contains a series of cellular genes, which are preferentially targeted by the virus, and characterized by the presence of active transcription chromatin marks before viral infection. In contrast, the virus strongly disfavours the heterochromatic regions in the nuclear lamin-associated domains and other transcriptionally active regions located centrally in the nucleus. Functional viral integrase and the presence of the cellular Nup153 and LEDGF/p75 integration cofactors are indispensable for the peripheral integration of the virus. Once integrated at the nuclear pore, the HIV-1 DNA makes contact with various nucleoporins; this association takes part in the transcriptional regulation of the viral genome. These results indicate that nuclear topography is an essential determinant of the HIV-1 life cycle.
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
Bruna
B
Marini
Protein Structure and Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
Attila
A
Kertesz-Farkas
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
Hashim
H
Ali
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
Bojana
B
Lucic
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
Kamil
K
Lisek
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
Lara
L
Manganaro
Protein Structure and Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
Sandor
S
Pongor
1] Struttura Complessa Malattie Infettive, Azienda Ospedaliero-Universitaria, 34134 Trieste, Italy [2] Department of Medical, Surgical and Health Sciences, University of Trieste, 34129 Trieste, Italy.
Roberto
R
Luzzati
Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy.
Alessandra
A
Recchia
1] Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy [2] Genethon, 91002 Evry, France.
Fulvio
F
Mavilio
1] Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy [2] Department of Medical, Surgical and Health Sciences, University of Trieste, 34129 Trieste, Italy.
Mauro
M
Giacca
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
Marina
M
Lusic
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D045584:Chromosome Positioning / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D019427:HIV Integrase / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology*; D006207:Half-Life; D006801:Humans; D022022:Nuclear Pore / Q000235:genetics / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D016662:Virus Integration / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; C079377:NUP153 protein, human; D028861:Nuclear Pore Complex Proteins; C504649:PSIP1 protein, human; D014157:Transcription Factors; D019427:HIV Integrase