Improved HIV-1 replication capacity mediated by late domain duplications in isolates carrying drug resistance mutations to protease inhibitors

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NCI	VIROL/MICRO-16

* FARE Award Winner

Authors

• AN Martins
• SD Ablan
• RM Brindeiro
• EO Freed

Abstract

HIV-1 subverts cellular machinery to allow viral egress from the host cell. The major viral determinant that recruits host cell factors to promote efficient budding from the infected cell is the Pro-Thr-Ala-Pro (PTAP) late domain, located in the p6 region of Gag. Duplications within the PTAP domain occur more frequently in isolates from patients failing antiretroviral (ARV) therapy, than isolates from drug-naïve patients. Duplications within PTAP were selected during ARV therapy in HIV-1 subtypes B, F1 and C. All subtypes accumulated 2 to 2.5 times more duplications in isolates failing ARV. This is the first work describing significant accumulation of PTAP duplications (PTAPdup) in clinical isolates failing therapy, and we suggest a potential role of the duplications in ARV drug resistance developed by these patients. To address the role of PTAPdup in vitro, we built viruses carrying the duplications with and without drug resistance mutations (DRM) in the protease (PR) gene, and also carrying only the DRM in PR (PRmut). Our results demonstrate that advantages in viral replication capacity are conferred by PTAP duplications in viruses carrying PR DRM, highlighting the interconnected role of PTAP duplications and PR DRMs in patients’ clinical evolution.

back to top