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Differential impact of APOBEC3-driven mutagenesis on HIV evolution in diverse anatomical compartments

Fourati, Slima,b; Lambert-Niclot, Sidoniea,b; Soulie, Cathiaa,b; Wirden, Marca,b; Malet, Isabellea,b; Valantin, Marc A.a,c; Tubiana, Rolanda,c; Simon, Annea,d; Katlama, Christinea,c,e; Carcelain, Guislainee,f,g,h; Calvez, Vincenta,b,e; Marcelin, Anne-Genevievea,b,e

doi: 10.1097/QAD.0000000000000182
Basic Science: Concise Communication

Objective: Previous studies on HIV quasispecies have revealed HIV compartmentalization in various tissues within an infected individual. Such HIV variation is a result of a combination of factors including high replication and mutation rates, recombination, and APOBEC3-host selective pressure.

Methods: To evaluate the differential impact of APOBEC3 editing in HIV-1 compartments, we analyzed the level of G-to-A hypermutation in HIV-1 protease and reverse transcriptase sequences among 30 HAART-treated patients for whom peripheral blood mononuclear cells and body tissues or fluids [cerebral spinal fluid (CSF), rectal tissue, or renal tissue] were collected on the same day.

Results: APOBEC3-mediated hypermutation was identified in 36% (11/30) of participants in at least one viral reservoir. HIV hypermutated sequences were often observed in viral sanctuaries (total n = 10; CSF, n = 6; renal tissue, n = 1; rectal tissue n = 3) compared with peripheral blood (total n = 4). Accordingly, APOBEC3 editing generated more G-to-A drug resistance mutations in sanctuaries: three patients’ CSF (i.e. G73S in protease; M184I, M230I in reverse transcriptase) and two other patients’ rectal tissues (M184I, M230I in reverse transcriptase) while such mutations were absent from paired peripheral blood mononuclear cells.

Conclusion: APOBEC3-induced mutations observed in peripheral blood underestimate the overall proportion of hypermutated viruses in anatomical compartments. The resulting mutations may favor escape to antiretrovirals in these compartments in conjunction with a lower penetration of drugs in some sanctuaries. On the other side, because hypermutated sequences often harbor inactivating mutations, our results suggest that accumulation of defective viruses may be more dominant in sanctuaries than in peripheral blood of patients on effective HAART.

aInserm UMR S-943

bVirology Department

cInfectious Disease Department

dInternal Medicine Department, Pitie-Salpetriere Hospital

eUniversité Pierre and Marie Curie

fInserm UMR S945

gAP-HP

hImmunology Department, Pitie-Salpetriere Hospital, Paris, France.

Correspondence to Slim Fourati, Department of Virology, CERVI Pitie-Salpetriere Hospital, 83 boulevard de l’Hopital, 75013 Paris, France. Tel: +33 142175843; fax: +33 142177411; e-mail: slim.fourati@psl.aphp.fr

Received 29 August, 2013

Revised 10 December, 2013

Accepted 10 December, 2013

This work has been presented at the International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies; 4–8 June 2013.

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