Differential coreceptor expression allows for independent evolution of non–syncytium-inducing and syncytium-inducing HIV-1
Ronald P. van Rij, Hetty Blaak, Janny A. Visser, Margreet Brouwer, Ronald Rientsma, Silvia Broersen, Ana-Maria de Roda Husman, Hanneke Schuitemaker
Ronald P. van Rij, Hetty Blaak, Janny A. Visser, Margreet Brouwer, Ronald Rientsma, Silvia Broersen, Ana-Maria de Roda Husman, Hanneke Schuitemaker
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Article

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.

Authors

Ronald P. van Rij, Hetty Blaak, Janny A. Visser, Margreet Brouwer, Ronald Rientsma, Silvia Broersen, Ana-Maria de Roda Husman, Hanneke Schuitemaker

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Tropism for CD45RA+ and CD45RO+ CD4+ T cells during NSI to SI HIV-1 conv...
Tropism for CD45RA+ and CD45RO+ CD4+ T cells during NSI to SI HIV-1 conversion. Patient PBMCs were FACS sorted in CD45RA+ CD45RO– CD4+ and CD45RA– CD45RO+ CD4+ T cells, and clonal virus isolation was performed on these T-cell subsets. (a) The frequency of infected cells with either NSI or SI HIV-1 variants (NSI or SI load) in total (top), CD45RO+ (middle), and CD45RA+ (bottom) CD4+ T cells relative to SI conversion in patient ACH171 (left panels) and 490 (right panels). Filled symbols indicate SI clones, and open symbols indicate NSI clones. In the top panel, serum RNA load is indicated by triangles. (b) Ratio of NSI load in CD45RO+ to NSI load in CD45RA+ CD4+ T cells (left) and ratio of SI load in CD45RA+ to SI load in CD45RO+ CD4+ T cells (right) of patient ACH171 (filled circles) and ACH490 (open circles). (c) Prevalence of SI phenotype among HIV-1 clones isolated from CD45RA+ (circles) or CD45RO+ (squares) CD4+ T-cell subset in ACH171 and ACH490.