Incomplete APOBEC3G/F neutralization by a defective HIV-1Vif protein can promote genetic diversification by inducing G-to-A mutations in the HIV-1 genome. The HIV-1 Env V3 loop, critical for coreceptor usage, contains several putative APOBEC3G/F target sites. Here, we determined if APOBEC3G/F, in the presence of Vif-defective HIV-1 virus, can induce G-to-A mutations at V3 positions critical to modulation of CXCR4 usage. Peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) from 2 HIV-1-negative donors were infected with CCR5-using 81.A-VifWT virus (i.e., with wild-type [WT] Vif protein), 81.A-VifE45G, or 81.A-VifK22E (known to incompletely/partially neutralize APOBEC3G/F). The rate of G-toA mutations was zero or extremely low in 81.A-VifWT- and 81.A-VifE45G-infected PBMC from both donors. Conversely, G-to-A enrichment was detected in 81.A-VifK22E-infected PBMC (prevalence ranging from 2.18% at 7 days postinfection [dpi] to 3.07% at 21 dpi in donor 1 and from 10.49% at 7 dpi to 8.69% at 21 dpi in donor 2). A similar scenario was found in MDM. G-to-A mutations occurred at 8 V3 positions, resulting in nonsynonymous amino acid substitutions. Of them, G24E and E25K strongly correlated with phenotypically/genotypically defined CXCR4-using viruses (P = 0.04 and 5.5e-7, respectively) and increased the CXCR4 N-terminal binding affinity for V3 (WT, -40.1 kcal/mol; G24E, -510 kcal/mol; E25K, -522 kcal/mol). The analysis of paired V3 and Vif DNA sequences from 84 HIV-1-infected patients showed that the presence of a Vif-defective virus correlated with CXCR4 usage in proviral DNA (P = 0.04). In conclusion, incomplete APOBEC3G/F neutralization by a single Vif amino acid substitution seeds a CXCR4-using proviral reservoir. This can have implications for the success of CCR5 antagonist-based therapy, as well as for the risk of disease progression.
Alteri, C., Surdo, M., Bellocchi, M.C., Saccomandi, P., Continenza, F., Armenia, D., et al. (2015). Incomplete APOBEC3G/F neutralization by HIV-1 Vif mutants facilitates the genetic evolution from CCR5 to CXCR4 usage. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 59(8), 4870-4881.
|Tipologia:||Articolo su rivista|
|Citazione:||Alteri, C., Surdo, M., Bellocchi, M.C., Saccomandi, P., Continenza, F., Armenia, D., et al. (2015). Incomplete APOBEC3G/F neutralization by HIV-1 Vif mutants facilitates the genetic evolution from CCR5 to CXCR4 usage. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 59(8), 4870-4881.|
|Settore Scientifico Disciplinare:||Settore MED/07 - Microbiologia e Microbiologia Clinica|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1128/AAC.00137-15|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||giu-2015|
|Titolo:||Incomplete APOBEC3G/F neutralization by HIV-1 Vif mutants facilitates the genetic evolution from CCR5 to CXCR4 usage|
|Autori:||Alteri, C; Surdo, M; Bellocchi, MC; Saccomandi, P; Continenza, F; Armenia, D; Parrotta, L; Carioti, L; Costa, G; Fourati, S; Di Santo, F; Scutari, R; Barbaliscia, S; Fedele, V; Carta, S; Balestra, E; Alcaro, S; Marcelin, A; Calvez, V; Ceccherini Silberstein, F; Artese, A; Perno, CF; Svicher, V|
|Appare nelle tipologie:||01 - Articolo su rivista|
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