Genetic evolution of human immunodeficiency virus type 1 in two spouses responding successfully to highly active antiretroviral therapy.
ABSTRACT The current case study provided an unusual setting to track the evolution of HIV-1 envelope gene over a maximum period of 6 years in two asymptomatic spouses undergoing suppressive highly active antiretroviral therapy. For this purpose, proviral DNA samples taken from uncultured peripheral blood mononuclear cells and spanning the C2-V5 regions of env were analyzed at three sampling points per subject. Two distinct topological patterns were observed in the phylogenetic reconstructions of the genetically linked sequences of the couple: an intermingled pattern and a sequentially shifting pattern in the virus populations of the male index case and his spouse, respectively. Application of three evolutionary models for the amino acid-encoded sites, using the maximum likelihood approach, indicated the operation of positive selection in the region only at the second time point in the woman, before receiving therapy. These findings reinforce the evidence of a crucial role for host-selective constraints on HIV-1 env evolution in vivo.
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ABSTRACT: The third variable domain (V3) of the human immunodeficiency virus type 1 external envelope contains determinants of cell tropism, cytopathicity, and infectivity and elicits antibodies able to block infectivity in vitro and in vivo. Our study encompassed point-mutational analysis of HXB-2 viruses containing patient-derived V3 regions and expressing a non-syncytium-inducing, low-replicating phenotype in T-cell line SupT1. The mutation within V3 of a serine at position 306 into an also naturally occurring arginine (S to R) required an additional, naturally occurring mutation at position 320 (aspartate to glutamine, D to Q) or 324 (aspartate to asparagine, D to N) for full expression of the syncytium-inducing, high-replicating (SI) phenotype. The naturally occurring mutation of an aspartate into an arginine at position 320 (D to R) was sufficient for production of the SI phenotype. This study proves that introduction of a positively charged amino acid at position 306 or 320, previously shown to be strongly associated with the SI phenotype in field isolates (R.A.M. Fouchier, M. Groenink, N.A. Kootstra, M. Tersmette, H.G. Huisman, F. Miedema, and H. Schuitemaker, J. Virol. 66:3183-3187, 1992), is minimally required for production of SI viruses. In addition, naturally occurring mutations at residue 324 also modulate the virus phenotype.Journal of Virology 12/1992; 66(11):6777-80. · 5.08 Impact Factor
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ABSTRACT: Several codon-based models for the evolution of protein-coding DNA sequences are developed that account for varying selection intensity among amino acid sites. The "neutral model" assumes two categories of sites at which amino acid replacements are either neutral or deleterious. The "positive-selection model" assumes an additional category of positively selected sites at which nonsynonymous substitutions occur at a higher rate than synonymous ones. This model is also used to identify target sites for positive selection. The models are applied to a data set of the V3 region of the HIV-1 envelope gene, sequenced at different years after the infection of one patient. The results provide strong support for variable selection intensity among amino acid sites The neutral model is rejected in favor of the positive-selection model, indicating the operation of positive selection in the region. Positively selected sites are found in both the V3 region and the flanking regions.Genetics 03/1998; 148(3):929-36. · 4.39 Impact Factor
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ABSTRACT: DNA sequences encoding the C2 to V3 region of envelope glycoprotein gp120 of human immunodeficiency virus type 1 (HIV-1) were amplified by PCR from uncultured peripheral blood mononuclear cells obtained from 24 of 25 HIV-1-seropositive patients from Cyprus. By using a heteroduplex mobility assay (HMA), all amplified products were studied genetically and compared with 16 previously characterized HIV-1 strains belonging to subtypes A through F. HMA results revealed that HIV-1 gp120 sequences from 15 of our patients were of subtype B of HIV-1, whereas one isolate was of subtype C. However, gp120 sequences from eight patients had no obvious similarities to the known subtypes as defined by HMA. DNA sequencing and phylogenetic analyses of molecular clones confirmed the HMA results and placed the eight undefined HIV-1 isolates into three distinct genetic clusters. On the basis of branch topology and lengths of the phylogenetic tree, we conclude that one group consisting of three clones from two patients represents a new HIV-1 env subtype, which we have termed subtype I. The remaining two sequence clusters, consisting of five sequences from four patients and two sequences from two other patients, are distally related to subtypes A and F. These data demonstrate the extensive heterogeneity of HIV-1 in Cyprus, including the presence of new subtype.Journal of Virology 11/1995; 69(10):6122-30. · 5.08 Impact Factor