New Findings in Cleavage Sites Variability across Groups, Subtypes and Recombinants of Human Immunodeficiency Virus Type 1

Esther Torrecilla,Teresa Llácer Delicado,África Holguín,Jean-Pierre Vartanian

doi:10.1371/journal.pone.0088099

Abstract

BackgroundPolymorphisms at cleavage sites (CS) can influence Gag and Pol proteins processing by the viral protease (PR), restore viral fitness and influence the virological outcome of specific antiretroviral drugs. However, data of HIV-1 variant-associated CS variability is scarce.MethodsIn this descriptive research, we examine the effect of HIV-1 variants on CS conservation using all 9,028 gag and 3,906 pol HIV-1 sequences deposited in GenBank, focusing on the 110 residues (10 per site) involved at 11 CS: P17/P24, P24/P2, P2/P7, P7/P1, P1/P6gag, NC/TFP, TFP/P6pol, P6pol/PR, PR/RTp51, RTp51/RTp66 and RTp66/IN. CS consensus amino acid sequences across HIV-1 groups (M, O, N, P), group M 9 subtypes and 51 circulating recombinant forms (CRF) were inferred from our alignments and compared to the HIV-1 consensus-of-consensuses sequence provided by GenBank.ResultsIn all HIV-1 variants, the most conserved CS were PR/RTp51, RTp51/RTp66, P24/P2 and RTp66/IN and the least P2/P7 and P6pol/PR. Conservation was significantly lower in subtypes vs. recombinants in P2/P7 and TFP/P6pol and higher in P17/P24. We found a significantly higher conservation rate among Group M vs. non-M Groups HIV-1. The late processing sites at Gag (P7/P1) and GagPol precursors (PR/RTp51) presented a significantly higher conservation vs. the first CS (P2/P7) in the 4 HIV-1 groups. Here we show 52 highly conserved residues across HIV-1 variants in 11 CS and the amino acid consensus sequence in each HIV-1 group and HIV-1 group M variant for each 11 CS.ConclusionsThis is the first study to describe the CS conservation level across all HIV-1 variants and 11 sites in one of the largest available sequence HIV-1 dataset. These results could help other researchers for the future design of both novel antiretroviral agents acting as maturation inhibitors as well as for vaccine targeting CS.

Highlights

The human immunodeficiency virus type 1 (HIV-1) Gag proteins are essential for the virus, as they have a structural and functional role in the viral cycle
As PR is only active as a dimer, it is thought that autoprocessing is initiated by dimerization of two PR domains that are embedded in the GagPol precursor [5]
Gag/Pol HIV-1 Sequences Used for the Analysis and Variants Distribution

Summary

Introduction

The human immunodeficiency virus type 1 (HIV-1) Gag proteins are essential for the virus, as they have a structural and functional role in the viral cycle. They coordinate viral trafficking, membrane binding, assembly, cofactor packaging, budding, and viral modulation. Gag proteins are generated through viral maturation, essential in the viral life cycle by enabling the generation of mature infectious viral particles through the proteolytic process in specific cleavage sites (CS) of Gag precursor (Pr55gag) and GagPol precursors (Pr160GagPol) proteins by the viral protease (PR) [1,2]. Gag precursor is cleaved within the virion in three main structural Gag proteins: matrix (P17 or MA), capsid (P24 or CA) and nucleocapsid (P7 or NC), flanked by two spacer segments (P1 and P2) with regulatory functions [3]. Data of HIV-1 variantassociated CS variability is scarce

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Results