Fitness-Balanced Escape Determines Resolution of Dynamic Founder Virus Escape Processes in HIV-1 Infection

• DOI: 10.1128/jvi.01876-15
• Publication Date: 2015-07-30T02:55:30Z
• Authors: Justine E. Sunshine; Brendan B. Larsen; Brandon Maust; Ellie Casey; Wenje Deng; Lennie Chen; Dylan H. Westfall; Moon Kim; Hong Zhao; Suvankar Ghorai; Erinn Lanxon-Cookson; Morgane Rolland; Ann C. Collier; Janine Maenza; James I. Mullins; Nicole Frahm
• Keywords: CTL*; Reversion; Genetic Fitness

To understand the interplay between host cytotoxic T-lymphocyte (CTL) responses and mechanisms by which HIV-1 evades them, we studied viral evolutionary patterns associated with CTL in six linked transmission pairs. sequences corresponding to full-length p17 p24 gag were generated 454 pyrosequencing for all pairs near time of transmission, seroconverting partners followed a median 847 days postinfection. T-cell screened gamma interferon/interleukin-2 (IFN-γ/IL-2) FluoroSpot using autologous peptide sets reflecting any Gag variant present at least 5% sequence reads individual's population. While found little evidence occurrence reversions, escape processes be highly dynamic, multiple epitope variants emerging simultaneously. We correlation entropy number per response (r = 0.43; P 0.05). In cases mutations developed within targeted epitope, no fitness cost became fixed When an achieved fitness-balanced escape, these mutants each maintained Additional confer but undetected populations incurred high costs, suggesting that functional constraints limit available sites tolerable mutations. These results further our understanding impact reversion from founder virus HIV infection contribute identification immunogenic regions most vulnerable attack.Rapid diversification population is hallmark infection, selective forces driving emergence can provide critical insight into immune evolution. used deep sequencing comprehensively follow evolution over then mapped explore if arose due adaption often arising epitopes. explored on replicative capacity, dynamic only resolve selection conferred virus. complicated viral-host interactions occur during early may help inform design future vaccine immunogens.