Human immunodeficiency virus type 1 capsid mutation N74D alters cyclophilin A dependence and impairs macrophage infection.
The antiviral factor CPSF6-358 interferes with the nuclear entry of human immunodeficiency virus type 1 (HIV-1). HIV-1 acquires resistance to CPSF6-358 through the N74D mutation of the capsid (CA), which alters its nuclear entry pathway. Here we show that compared to wild-type (WT) HIV-1, N74D HIV-1 is more sensitive to cyclosporine, has increased sensitivity to nevirapine, and is impaired in macrophage infection prior to reverse transcription. These phenotypes suggest a difference in the N74D reverse transcription complex that manifests early after infection and prior to interaction with the nuclear pore. Overall, our data indicate that N74D HIV-1 replication in transformed cells requires cyclophilin A but is dependent on other interactions in macrophages.
Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. zaa4@pitt.edu
Zandrea
Z
Ambrose
KyeongEun
K
Lee
Jean
J
Ndjomou
Hongzhan
H
Xu
Ilker
I
Oztop
James
J
Matous
Taichiro
T
Takemura
Derya
D
Unutmaz
Alan
A
Engelman
Stephen H
SH
Hughes
Vineet N
VN
KewalRamani
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000090103:Antiviral Restriction Factors; D016645:Aotidae; D036022:Capsid Proteins / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D021984:Cyclophilin A / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000821:virology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
D000090103:Antiviral Restriction Factors; D036022:Capsid Proteins; D002352:Carrier Proteins; D018894:Reverse Transcriptase Inhibitors; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases; D012194:RNA-Directed DNA Polymerase; D021984:Cyclophilin A