Determinants of cyclophilin A-dependent TRIM5 alpha restriction against HIV-1.
TRIM5 alpha is a host protein that can bind to incoming retroviral capsid (CA) and inhibit retroviruses in a species-specific manner. The CA protein of HIV-1 also interacts with high affinity to the host protein cyclophilin A (CypA). This binding has been shown to positively affect some early stage of the viral life cycle in human cells. However, the CypA/CA interaction also renders HIV-1 more susceptible to rhesus TRIM5 alpha (rhTRIM5 alpha) restriction. We find that the ability of old world monkey TRIM5 alpha genes to restrict HIV-1 in a CypA-dependent manner is widespread. On the other hand, we find that simian immunodeficiency viruses from tantalus monkeys (SIVagmTAN), is unlike HIV-1 in that CypA does not enhance the rhTRIM5 alpha restriction against the virus even though the CA of this virus, like HIV-1, does bind CypA. Mapping of the determinants for this phenotype by swapping regions on CA between SIVagmTAN and HIV-1 showed that when SIVagmTAN contains loops between helices 4/5 (4-5 loop) and 6/7 (6-7 loop) from HIV-1 CA, it becomes susceptible to the CypA-enhanced rhTRIM5 alpha restriction. Surprisingly, when SIVagmTAN contains either loop from HIV-1 CA, it gains sensitivity to TRIM5 alpha from species which originally have no effect on the wild-type virus. Moreover, we find that CypA/CA interaction occurs early after viral entry but the CypA-enhanced restriction mostly acts on the stage after reverse transcription.
Lin
Tsai-Yu
TY
Pathobiology Graduate Program, Department of Global Health, University of Washington, Seattle, WA 98195, USA.
Emerman
Michael
M
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D036022:Capsid Proteins / Q000737:chemistry / Q000502:physiology; D002460:Cell Line; D002522:Chlorocebus aethiops; D021984:Cyclophilin A / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008253:Macaca mulatta; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000502:physiology*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity / Q000502:physiology; D013045:Species Specificity; D044767:Ubiquitin-Protein Ligases; D053586:Virus Internalization
D036022:Capsid Proteins; D017931:DNA Primers; D004279:DNA, Viral; D011506:Proteins; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases; D021984:Cyclophilin A