title: Genotypic and phenotypic correlates of the HIV Type 1 env gene evolution in infected children with discordant response to antiretroviral therapy.
abstract: The genotypic-phenotypic correlates of human immunodeficiency virus type 1 (HIV-1) env gene evolution were investigated in samples from eight infected children under antiretroviral therapy (ART) and virological failure. Evolution of the gp120 C2-V5 env sequence was demonstrated in all subjects but one by sequence analysis of the replicating plasma virus collected at baseline and 12-15 months after ART initiation. The analysis of the host's selective pressure showed that in four subjects, the ratio of nonsynonymous to synonymous amino acid substitutions was higher in the V3 sequences than in the C2-V5 region ([K (a)/K (s)](V3)/[K (a)/K (s)](C2V5) >1.0). Interestingly, this feature was observed only in subjects (four of five) showing an increase in T cell receptor rearrangement excision circle (TREC)-bearing cells and in CD4(+) T-lymphocytes despite persistent viremia (discordant therapeutic response) (p = 0.02), thus suggesting that the V3 loop is a target of the immune reconstitution under ART. Using phenotypic analysis of recombinant viruses expressing exogenous V3 sequences, a reverse shift from CXCR4-tropic to CCR5-tropic variants was demonstrated in two of the four subjects, further indicating that the host's selective pressure sharply forces the V3 evolution of replicating variants. The data indicate that a complex HIV-1-host interplay occurs in children receiving antiretroviral treatments and suggest that the recovery of thymic function places a selective constraint on the viral V3 loop.
authors.affiliation: Istituto di Microbiologia e Scienze Biomediche, Università Politecnica delle Marche, Ancona, Italy. bagnarelli@univpm.it
authors.forename: Patrizia
authors.initials: P
authors.lastname: Bagnarelli
authors.forename: Manuela
authors.initials: M
authors.lastname: Vecchi
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Burighel
authors.forename: Domenico
authors.initials: D
authors.lastname: Bellanova
authors.forename: Stefano
authors.initials: S
authors.lastname: Menzo
authors.forename: Massimo
authors.initials: M
authors.lastname: Clementi
authors.forename: Anita
authors.initials: A
authors.lastname: De Rossi
mesh_terms: D044966:Anti-Retroviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral; D019143:Evolution, Molecular; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000635:transmission / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D010641:Phenotype
chemical_list: D044966:Anti-Retroviral Agents; D004279:DNA, Viral; D015699:HIV Envelope Protein gp120