title: 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.
abstract: 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 3rd codon mutation rate was equal or even lower than that observed at the 1st and 2nd 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.
authors.affiliation: Laboratorio di Microbiologia e Virologa, Università Vita-Salute San Raffaele, Milan, Italy. canducci.filippo@hsr.it
authors.forename: Filippo
authors.initials: F
authors.lastname: Canducci
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Marinozzi
authors.forename: Michela
authors.initials: M
authors.lastname: Sampaolo
authors.forename: Stefano
authors.initials: S
authors.lastname: Berrè
authors.forename: Patrizia
authors.initials: P
authors.lastname: Bagnarelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Degano
authors.forename: Giulia
authors.initials: G
authors.lastname: Gallotta
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzi
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemey
authors.forename: Roberto
authors.initials: R
authors.lastname: Burioni
authors.forename: Massimo
authors.initials: M
authors.lastname: Clementi
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology*; D003062:Codon; D018450:Disease Progression; D019143:Evolution, Molecular; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D012641:Selection, Genetic
chemical_list: D015704:CD4 Antigens; D003062:Codon; D015699:HIV Envelope Protein gp120; D015235:HLA-B Antigens