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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CD4+ T-cell subsets with distinct HIV-1–coreceptor expression provide di...
CD4+ T-cell subsets with distinct HIV-1–coreceptor expression provide distinct niches for NSI and SI HIV-1. Cryopreserved PBMCs were sorted based on expression of CD45RO and HIV-1 coreceptors CCR5 and CXCR4, and virus was isolated by cocultivation with PHA-PBMCs under limiting dilution conditions. In addition to SI-infected patients ACH039, ACH171, ACH208, and ACH490, one patient (ACH001) who was infected solely with NSI HIV-1 variants, was studied. (a) Frequency of CD45RO– CXCR4+ CCR5–; CD45RO+ CXCR4+ CCR5–; and CD45RO+ CXCR4– CCR5+ CD4+ T cells productively infected with HIV-1. NT, not tested. (b and c) Phenotype of virus clones from CD45RO– CXCR4+ (left panel), CD45RO+ CXCR4+ (middle), and CD45RO+ CCR5+ (right) cells as defined by the ability to infect MT2 cells (b) or CCR5Δ32/Δ32 PBMCs (c). Filled bars reflect the percentage of clones able to infect the indicator cells, whereas gray bars reflect clones unable to infect these cells. (d) The difference in the proportion of clones with SI phenotype (left panel) and clones able to infect CCR5 Δ32/Δ32 PBMCs (right panel) isolated from CD45RO+ CXCR4+ and CD45RO+ CCR5+ cells were compared pairwise by Wilcoxon signed rank test (P = 0.07, in both panels).