Incomplete APOBEC3G/F neutralization by HIV-1 Vif mutants facilitates the genetic evolution from CCR5 to CXCR4 usage

Claudia Alteri, Matteo Surdo, Maria Concetta Bellocchi, Patrizia Saccomandi, Fabio Continenza, Daniele Armenia, Lucia Parrotta, Luca Carioti, Giosuè Costa, Slim Fourati, Fabiola Di Santo, Rossana Scutari, Silvia Barbaliscia, Valentina Fedele, Stefania Carta, Emanuela Balestra, Stefano Alcaro, Anne Genevieve Marcelin, Vincent Calvez, Francesca Ceccherini-SilbersteinAnna Artese, Carlo Federico Perno, Valentina Svicher

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)4870-4881
Number of pages12
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

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ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Alteri, C., Surdo, M., Bellocchi, M. C., 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. G., Calvez, V., ... Svicher, V. (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. https://doi.org/10.1128/AAC.00137-15