Lieven Gentaur
News
HIV-1 entry into a target cell requires two things: CD4 and a coreceptor, most commonly CCR5 or CXCR4. Viruses that preferentially use CCR5 are termed R5-tropic; those that use CXCR4 are X4-tropic (or dual-tropic if they can use both). Hematopoietic stem and multipotent progenitor cells (HSCs/HPCs; often identified by CD34+ and other markers) express CXCR4 at higher levels than CCR5, especially the more primitive long-term repopulating HSCs. That cell-surface pattern partly explains why CXCR4-using viruses not CCR5-using ones are capable of infecting multipotent HSPCs.
The landmark experimental demonstration came from Carter et al. (Cell Host & Microbe, 2011): the group infected human HSPC populations in vitro and in xenograft models and showed that CXCR4-tropic HIV-1 (but not CCR5-tropic strains) can enter multipotent HSC/HPCs and produce multilineage, long-term engraftment of infected cells in mice i.e., infected HSCs could generate diverse progeny that carry viral DNA, demonstrating a potential long-lived cellular reservoir. Their assays included receptor-usage mapping, colony-forming assays and xenotransplantation to demonstrate functional HSC infection. This work established the mechanistic link between CXCR4 usage and infection of primitive hematopoietic compartments.
What infection of HSPCs means for the reservoir
Because HSCs are long-lived and self-renewing, infection of bona fide HSCs could, in principle, produce a durable, possibly lifelong reservoir of HIV-1 that is independent of the short-lived CD4+ T cell pool. However, whether infected HSCs meaningfully contribute to rebound after therapy interruption in people remains under active study some human and animal data support the possibility, but quantifying the contribution is technically challenging owing to rarity of infected HSCs and assay sensitivity limits. Recent work continues to emphasize heterogeneity and plasticity of reservoirs across tissues and cell types.
CXCR4 expression dynamics and susceptibility
Multiple groups have characterized CXCR4 expression across hematopoietic compartments. Primitive, long-term repopulating HSCs express CXCR4 at levels that facilitate homing and niche interactions; that expression also renders them susceptible to CXCR4-tropic HIV entry. Conversely, more differentiated progenitors may have a different pattern of CXCR4 and other co-receptors, affecting permissiveness. Functional assays (colony-forming unit assays, engraftment in immunodeficient mice, flow cytometry for receptor density, single-cell RNA profiling) are commonly used to map susceptibility.
Therapeutic and cure implications
Allogeneic HSCT cures (Berlin/London and more recent cases) taught that replacing the hematopoietic system with resistant donor cells can produce durable remission, but most cures exploited CCR5Δ32/Δ32 donors (which protect against R5 viruses). CXCR4-tropic strains—and infection of HSCs—indicate that CCR5-targeted strategies alone may be insufficient in some patients. Recent reports of durable remission after allo-HSCT using different donor genotypes continue to inform the landscape.
Gene editing approaches therefore increasingly aim to protect HSPCs from both CCR5- and CXCR4-mediated entry (dual targeting). A 2024 Cell Stem Cell study described strategies to simultaneously disrupt CCR5 and CXCR4 in autologous HSPCs to render them resistant to both R5 and X4 viruses — an approach that directly responds to the Carter et al. observation.
Small-molecule or biologic CXCR4 targeting: CXCR4 antagonists (e.g., plerixafor) have been explored historically; clinical success for HIV treatment has been limited. Still, CXCR4 remains an attractive target both for direct antiviral strategies and for modulating trafficking/homing of infected HSPCs. Newer structural and computational studies are helping identify residues and interaction pockets on CXCR4 that could be leveraged for safer, more selective inhibitors.