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Interaction of Vpx and apolipoprotein B mRNA-editing catalytic polypeptide 3 family member A (APOBEC3A) correlates with efficient lentivirus infection of monocytes.

ABSTRACT: The accessory protein Vpx is encoded by lentiviruses of the human immunodeficiency virus type 2 (HIV-2) and the simian immunodeficiency SIVsm/SIVmac lineage. It is packaged into virions and is indispensable in early steps of monocyte infection. HIV-1, which does not encode Vpx, is not able to infect human monocytes, but Vpx enables infection with HIV-1. The underlying mechanism is not completely understood. In this work, we focus on Vpx-mediated intracellular postentry events as counteraction of host cell proteins. We found that Vpx binds to apolipoprotein B mRNA-editing catalytic polypeptide 3 family member A (APOBEC3A; A3A), a member of the family of cytidine deaminases, present in monocytes. This interaction led to a reduction of the steady-state protein level of A3A. A single-point mutation in Vpx (H82A) abrogated binding to A3A and single-round infection of monocytes by HIV-1. Taken together, our data indicate that lentiviral Vpx counteracts A3A in human monocytes.

SUBMITTER: Berger A

PROVIDER: S-EPMC2852964 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeApolipoprotein B mRNA-Editing Catalytic Polypeptide-like (APOBEC) enzymes are mutagenic factors contributing to tumor progression and therapy resistance. However, the effects of APOBEC-induced protein changes have not been systematically assessed. Here, we describe the effects of APOBEC on the coding sequence in primary and metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC).MethodsWe determined the enrichment of amino acid (AA) changes resulting from APOBEC mutagenesis in 323 primary BC tumors and 424 metastatic breast cancer (mBC) lesions via comparison with a simulated mutational genomic landscape not under selection pressure. We subsequently explored genes with recurrent APOBEC-associated AA changes and investigated the clonality of individual APOBEC-associated mutations. Using public sequencing data from an independent primary BC and mBC cohort, we further confirm our findings by reporting genes having these enriched AA changes in an APOBEC context.ResultsOur analysis demonstrated that several APOBEC-derived AA changes are significantly enriched compared with a simulated AA change distribution drawn at random. Among the enriched AA changes, Glutamate(E)>Lysine(K) and Glutamate(E)>Glutamine(Q) were mostly found at hotspots in oncogenes, whereas termination codons (Glutamine[Q]>STOP[X] and Serine[S]>STOP[X]) occurred in tumor suppressor genes and, mostly, not at hotspot locations. These mutations are found in genes contributing to BC initiation, eg, introduction of termination codons in TP53, MAP3K1, and CDH1 (in lobular BC) and two oncogenic hotspots in PIK3CA (p.E542K and p.E545K). In endocrine-resistant BC, we observed APOBEC-induced termination codons at ER-modulating genes, KMT2C, ARID1A, NF1, and ZFHX3. Finally, in mBC, compared with single PIK3CA mutations, dual PIK3CA mutations occurred more frequently in an APOBEC context (Fisher's exact P < .001).ConclusionOur results show that APOBEC mutagenesis recurrently targets various known drivers of BC initiation, progression, and endocrine resistance.

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Interaction of Vpx and apolipoprotein B mRNA-editing catalytic polypeptide 3 family member A (APOBEC3A) correlates with efficient lentivirus infection of monocytes.

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