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Differential coreceptor expression allows for independent evolution of non-syncytium-inducing and syncytium-inducing HIV-1.

ABSTRACT: We demonstrated previously that CD45RA(+) CD4(+) T cells are infected primarily by syncytium-inducing (SI) HIV-1 variants, whereas CD45RO(+) CD4(+) T cells harbor both non-SI (NSI) and SI HIV-1 variants. Here, we studied evolution of tropism for CD45RA(+) and CD45RO(+) CD4(+) cells, coreceptor usage, and molecular phylogeny of coexisting NSI and SI HIV-1 clones that were isolated from four patients in the period spanning SI conversion. NSI variants were CCR5-restricted and could be isolated throughout infection from CD45RO(+) CD4(+) cells. SI variants seemed to evolve in CD45RO(+) CD4(+) cells, but, in time, SI HIV-1 infection of CD45RA(+) CD4(+) cells equaled infection of CD45RO(+) CD4(+) cells. In parallel with this shift, SI HIV-1 variants first used both coreceptors CCR5 and CXCR4, but eventually lost the ability to use CCR5. Phylogenetically, NSI and SI HIV-1 populations diverged over time. We observed a differential expression of HIV-1 coreceptors within CD45RA(+) and CD45RO(+) cells, which allowed us to isolate virus from purified CCR5(+) CXCR4(-) and CCR5(-) CXCR4(+) CD4(+) cells. The CCR5(+) subset was exclusively infected by CCR5-dependent HIV-1 clones, whereas SI clones were preferentially isolated from the CXCR4(+) subset. The differential expression of HIV-1 coreceptors provides distinct cellular niches for NSI and SI HIV-1, contributing to their coexistence and independent evolutionary pathways.

SUBMITTER: van Rij RP

PROVIDER: S-EPMC314337 | biostudies-literature | 2000 Oct

REPOSITORIES: biostudies-literature

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Differential coreceptor expression allows for independent evolution of non-syncytium-inducing and syncytium-inducing HIV-1.

van Rij R P RP Blaak H H Visser J A JA Brouwer M M Rientsma R R Broersen S S de Roda Husman A M AM Schuitemaker H H

The Journal of clinical investigation 20001001 8

We demonstrated previously that CD45RA(+) CD4(+) T cells are infected primarily by syncytium-inducing (SI) HIV-1 variants, whereas CD45RO(+) CD4(+) T cells harbor both non-SI (NSI) and SI HIV-1 variants. Here, we studied evolution of tropism for CD45RA(+) and CD45RO(+) CD4(+) cells, coreceptor usage, and molecular phylogeny of coexisting NSI and SI HIV-1 clones that were isolated from four patients in the period spanning SI conversion. NSI variants were CCR5-restricted and could be isolated thro ...[more]

PMID: 11032864

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Project description:Two distinct biological phenotypes of human immunodeficiency virus (HIV) have been described: the non-syncytium-inducing (NSI) phenotype, best characterized by the inability to infect MT-2 cells, and the syncytium-inducing (SI) phenotype, with the ability to infect MT-2 cells. The earliest virus population observed following HIV transmission is generally of the NSI phenotype, even after exposure to inocula of mixed NSI/SI phenotype. In this study, the issue of intrapatient selection of virus phenotype following transmission was addressed by studying two cases of accidental transmission. A comparison of the sequences of the V1-V2 and the V3 coding regions of the envelope gene and the p17 region of the gag gene showed that the donor-recipient pairs were tightly clustered in all gene segments, but away from local and published transmission controls. The intrasample variation of the p17 sequence was greater in the recipients and smaller in the donors than that of the V3 region sequence, indicating selection of V3 at transmission. In these transmission cases, the effects of an intravenous inoculation of a small quantity of blood containing predominantly SI V3 sequences (6 of 8 clonal sequences) were compared with those of an intramuscular inoculation of a large quantity of blood containing predominantly NSI viruses (14 of 16 clonal sequences). Both SI and NSI V3 regions were demonstrated to be phenotypic expressions of genetically related viral strains. The inoculation of the predominantly SI virus population resulted in the persistence of an SI virus population in the recipient and a rapid CD4+ T-cell decline. The inoculation of the predominantly NSI population resulted in a selective amplification of SI viruses before seroconversion, followed by a suppression of SI viruses at seroconversion and a rapid decline of CD4+ T-cell numbers. These data suggest that the suppression of SI viruses can be accomplished following the development of HIV-specific immunity and that the ability to suppress SI viruses does not prevent the development of immunodeficiency.

Project description:Studies of feline leukemia virus (FeLV) have illustrated the importance of the genotype of the infecting virus in determining disease outcome. In FeLV infections, as in other retroviral infections, it is less clear how virus variants that evolve from the transmitted virus affect pathogenesis. We previously reported an analysis of the genotypic changes that occur in the viral envelope gene (env) in cats infected with a prototype transmissible FeLV clone, 61E (J. Rohn, M. Linenberger, E. Hoover, and J. Overbaugh, J. Virol. 68:2458-2467, 1994). In one cat, each variant (81T) had evolved, in addition to scattered amino acid changes, a four-amino-acid insertion with respect to 61E. This insertion was located at the same site in the extracellular envelope glycoprotein where the immunodeficiency-inducing molecular clone 61C possesses a six-amino-acid insertion critical for its pathogenic phenotype, although the sequences of the insertions were distinct. To determine whether acquisition of the four-amino-acid insertion was associated with a change in the replication or cytopathic properties of the virus, we constructed chimeras encoding 81T env genes in a 61E background. One representative chimeric virus, EET(TE)-109, was highly cytopathic despite the fact that it replicated with delayed kinetics in the feline T-cell line 3201 compared to the parental 61E virus. The phenotype of this virus was also novel compared to other FeLVs, including both the parental virus 61E and the immunodeficiency-inducing variant 61C, because infection of T cells was associated with syncytium formation. Moreover, in single-cycle infection assays, the 81T-109 envelope demonstrated receptor usage properties distinct from those of both 61E and 61C envelope. Thus, these studies demonstrate the evolution of a novel T-cell cytopathic and syncytium-inducing FeLV in the host. The 81T virus will be valuable for dissecting the mechanism of T-cell killing by cytopathic variants in the FeLV model.

Project description:BACKGROUND: This paper lies in the context of modeling the evolution of gene expression away from stationary states, for example in systems subject to external perturbations or during the development of an organism. We base our analysis on experimental data and proceed in a top-down approach, where we start from data on a system's transcriptome, and deduce rules and models from it without a priori knowledge. We focus here on a publicly available DNA microarray time series, representing the transcriptome of Drosophila across evolution from the embryonic to the adult stage. RESULTS: In the first step, genes were clustered on the basis of similarity of their expression profiles, measured by a translation-invariant and scale-invariant distance that proved appropriate for detecting transitions between development stages. Average profiles representing each cluster were computed and their time evolution was analyzed using coupled differential equations. A linear and several non-linear model structures involving a transcription and a degradation term were tested. The parameters were identified in three steps: determination of the strongest connections between genes, optimization of the parameters defining these connections, and elimination of the unnecessary parameters using various reduction schemes. Different solutions were compared on the basis of their abilities to reproduce the data, to keep realistic gene expression levels when extrapolated in time, to show the biologically expected robustness with respect to parameter variations, and to contain as few parameters as possible. CONCLUSIONS: We showed that the linear model did very well in reproducing the data with few parameters, but was not sufficiently robust and yielded unrealistic values upon extrapolation in time. In contrast, the non-linear models all reached the latter two objectives, but some were unable to reproduce the data. A family of non-linear models, constructed from the exponential of linear combinations of expression levels, reached all the objectives. It defined networks with a mean number of connections equal to two, when restricted to the embryonic time series, and equal to five for the full time series. These networks were compared with experimental data about gene-transcription factor and protein-protein interactions. The non-uniqueness of the solutions was discussed in the context of plasticity and cluster versus single-gene networks.

Dataset Information

Differential coreceptor expression allows for independent evolution of non-syncytium-inducing and syncytium-inducing HIV-1.

Publications

Differential coreceptor expression allows for independent evolution of non-syncytium-inducing and syncytium-inducing HIV-1.

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