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Dynamic features of the selective pressure on the human immunodeficiency virus type 1 (HIV-1) gp120 CD4-binding site in a group of long term non progressor (LTNP) subjects

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The characteristics of intra-host human immunodeficiency virus type 1 (HIV-1) env evolution were evaluated in untreated HIV-1-infected subjects with different patterns of disease progression, including 2 normal progressor [NP], and 5 Long term non-progressor [LTNP] patients. High-resolution phylogenetic analysis of the C2-C5 env gene sequences of the replicating HIV-1 was performed in sequential samples collected over a 3–5 year period; overall, 301 HIV-1 genomic RNA sequences were amplified from plasma samples, cloned, sequenced and analyzed. Firstly, the evolutionary rate was calculated separately in the 3 codon positions. In all LTNPs, the 3 rd codon mutation rate was equal or even lower than that observed at the 1 st and 2 nd positions (p = 0.016), thus suggesting strong ongoing positive selection. A Bayesian approach and a maximum-likelihood (ML) method were used to estimate the rate of virus evolution within each subject and to detect positively selected sites respectively. A great number of N-linked glycosylation sites under positive selection were identified in both NP and LTNP subjects. Viral sequences from 4 of the 5 LTNPs showed extensive positive selective pressure on the CD4-binding site (CD4bs). In addition, localized pressure in the area of the IgG-b12 epitope, a broad neutralizing human monoclonal antibody targeting the CD4bs, was documented in one LTNP subject, using a graphic colour grade 3-dimensional visualization. Overall, the data shown here documenting high selective pressure on the HIV-1 CD4bs of a group of LTNP subjects offers important insights for planning novel strategies for the immune control of HIV-1 infection.

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Published 01 January 2009
Reads 17
Language English
Retrovirology
BioMedCentral
Open Access Research Dynamic features of the selective pressure on the human immunodeficiency virus type 1 (HIV1) gp120 CD4binding site in a group of long term non progressor (LTNP) subjects 1 11 Filippo Canducci*, Maria Chiara Marinozzi, Michela Sampaolo, 1 23 4 Stefano Berrè, Patrizia Bagnarelli, Massimo Degano, Giulia Gallotta, 5 61 Benedetta Mazzi, Philippe Lemey, Roberto Burioniand 1 Massimo Clementi
1 2 Address: Laboratoriodi Microbiologia e Virologa, Università VitaSalute San Raffaele, Milan, Italy,Istituto di Microbiologia, Università 3 4 Politecnica delle Marche, Ancona, Italy,Unità di Biocristallografia, Istituto Scientifico San Raffaele, Milan, Italy,Dipartimento di Malattie 5 Infettive, Università VitaSalute San Raffaele, Milan, Italy,Laboratorio di Ematologia Molecolare, Istituto Scientifico San Raffaele, Milan, Italy and 6 Rega Institute, Katholieke Universiteit Leuven, Leuven, Belgium
Email: Filippo Canducci*  canducci.filippo@hsr.it; Maria Chiara Marinozzi  marinozzi.mariachiara@hsr.it; Michela Sampaolo  sampaolo.michela@hsr.it; Stefano Berrè  stefanoberre@yahoo.it; Patrizia Bagnarelli  bagnarelli@univpm.it; Massimo Degano  degano.massimo@hsr.it; Giulia Gallotta  gallotta.giulia@hsr.it; Benedetta Mazzi  mazzi.benedetta@hsr.it; Philippe Lemey  philippe.lemey@gmail.com; Roberto Burioni  burioni.roberto@hsr.it; Massimo Clementi  clementi.massimo@hsr.it * Corresponding author
Published: 15 January 2009Received: 6 October 2008 Accepted: 15 January 2009 Retrovirology2009,6:4 doi:10.1186/1742469064 This article is available from: http://www.retrovirology.com/content/6/1/4 © 2009 Canducci et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract The characteristics of intrahost human immunodeficiency virus type 1 (HIV1)envevolution were evaluated in untreated HIV1infected subjects with different patterns of disease progression, including 2 normal progressor [NP], and 5 Long term nonprogressor [LTNP] patients. High resolution phylogenetic analysis of the C2C5envgene sequences of the replicating HIV1 was performed in sequential samples collected over a 3–5 year period; overall, 301 HIV1 genomic RNA sequences were amplified from plasma samples, cloned, sequenced and analyzed. Firstly, the rd evolutionary rate was calculated separately in the 3 codon positions. In all LTNPs, the 3codon st nd mutation rate was equal or even lower than that observed at the 1and 2positions (p = 0.016), thus suggesting strong ongoing positive selection. A Bayesian approach and a maximumlikelihood (ML) method were used to estimate the rate of virus evolution within each subject and to detect positively selected sites respectively. A great number of Nlinked glycosylation sites under positive selection were identified in both NP and LTNP subjects. Viral sequences from 4 of the 5 LTNPs showed extensive positive selective pressure on the CD4binding site (CD4bs). In addition, localized pressure in the area of the IgGb12 epitope, a broad neutralizing human monoclonal antibody targeting the CD4bs, was documented in one LTNP subject, using a graphic colour grade 3dimensional visualization. Overall, the data shown here documenting high selective pressure on the HIV1 CD4bs of a group of LTNP subjects offers important insights for planning novel strategies for the immune control of HIV1 infection.
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