1. HIV-1 and SIV predominantly use CCR5 expressed on a precursor population to establish infection in T follicular helper cells
- Author
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Xu, Y, Phetsouphanh, C, Suzuki, K, Aggrawal, A, Graff-Dubois, S, Roche, M, Bailey, M, Alcantara, S, Cashin, K, Sivasubramaniam, R, Koelsch, KK, Autran, B, Harvey, R, Gorry, PR, Moris, A, Cooper, DA, Turville, S, Kent, SJ, Kelleher, AD, Zaunders, J, Xu, Y, Phetsouphanh, C, Suzuki, K, Aggrawal, A, Graff-Dubois, S, Roche, M, Bailey, M, Alcantara, S, Cashin, K, Sivasubramaniam, R, Koelsch, KK, Autran, B, Harvey, R, Gorry, PR, Moris, A, Cooper, DA, Turville, S, Kent, SJ, Kelleher, AD, and Zaunders, J
- Abstract
© 2017 Xu, Phetsouphanh, Suzuki, Aggrawal, Graff-Dubois, Roche, Bailey, Alcantara, Cashin, Sivasubramaniam, Koelsch, Autran, Harvey, Gorry, Moris, Cooper, Turville, Kent, Kelleher and Zaunders. Background: T follicular helper (Tfh) cells are increasingly recognized as a major reservoir of HIV infection that will likely need to be addressed in approaches to curing HIV. However, Tfh express minimal CCR5, the major coreceptor for HIV-1, and the mechanism by which they are infected is unclear. We have previously shown that macaque Tfh lack CCR5, but are infected in vivo with CCR5-using SIV at levels comparable to other memory CD4+ T cells. Similarly, human splenic Tfh cells are highly infected with HIV-1 DNA. Therefore, we set out to examine the mechanism of infection of Tfh cells. Methodology: Tfh and other CD4+ T cell subsets from macaque lymph nodes and spleens, splenic Tfh from HIV+ subjects, and tonsillar Tfh from HIV-uninfected subjects were isolated by cell sorting prior to cell surface and molecular characterization. HIV proviral gp120 sequences were submitted to genotypic and phenotypic tropism assays. Entry of CCR5- and CXCR4-using viruses into Tfh from uninfected tonsillar tissue was measured using a fusion assay. Results: Phylogenetic analysis, genotypic, and phenotypic analysis showed that splenic Tfh cells from chronic HIV+ subjects were predominantly infected with CCR5-using viruses. In macaques, purified CCR5+PD-1intermediate(int)+ memory CD4+ T cells were shown to include pre-Tfh cells capable of differentiating in vitro to Tfh by upregulation of PD-1 and Bcl6, confirmed by qRT-PCR and single-cell multiplex PCR. Infected PD-1int cells survive, carry SIV provirus, and differentiate into PD-1hi Tfh after T cell receptor stimulation, suggesting a pathway for SIV infection of Tfh. In addition, a small subset of macaque and human PD-1hi Tfh can express low levels of CCR5, which makes them susceptible to infection. Fusion assays demonstrated CCR5-using HIV-1
- Published
- 2017