HIV-1 and SIV Predominantly Use CCR5 Expressed on a Precursor Population to Establish Infection in T Follicular Helper Cells
AuthorXu, Y; Phetsouphanh, C; Suzuki, K; Aggrawal, A; Graff-Dubois, S; Roche, M; Bailey, M; Alcantara, S; Cashin, K; Sivasubramaniam, R; ...
Source TitleFrontiers in Immunology
PublisherFRONTIERS MEDIA SA
AffiliationMicrobiology and Immunology
Document TypeJournal Article
CitationsXu, Y., Phetsouphanh, C., Suzuki, K., Aggrawal, A., Graff-Dubois, S., Roche, M., Bailey, M., Alcantara, S., Cashin, K., Sivasubramaniam, R., Koelsch, K. K., Autran, B., Harvey, R., Gorry, P. R., Moris, A., Cooper, D. A., Turville, S., Kent, S. J., Kelleher, A. D. & Zaunders, J. (2017). HIV-1 and SIV Predominantly Use CCR5 Expressed on a Precursor Population to Establish Infection in T Follicular Helper Cells. FRONTIERS IN IMMUNOLOGY, 8 (APR), https://doi.org/10.3389/fimmu.2017.00376.
Access StatusOpen Access
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 entry into CCR5+ Tfh and pre-Tfh cells from human tonsils. CONCLUSION: The major route of infection of Tfh in macaques and humans appears to be via a CCR5-expressing pre-Tfh population. As the generation of Tfh are important for establishing effective immune responses during primary infections, Tfh are likely to be an early target of HIV-1 following transmission, creating an important component of the reservoir that has the potential to expand over time.
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