HIV Impacts CD34+ Progenitors Involved in T-Cell Differentiation During Coculture With Mouse Stromal OP9-DL1 Cells

Abstract

HIV-1 causes the loss of CD4+ T cells via depletion or impairment of their production. The latter involves infection of thymocytes, but the involvement of hematopoietic CD34+ cells remains unclear even though HIV-positive patients frequently manifest myelosuppression. In order to have a closer look at the impact of HIV-1 on T-lineage differentiation, this study utilized the OP9-DL1 coculture system, which supports in vitro T-lineage differentiation of human hematopoietic stem/progenitor cells. In the newly developed in vitro OP9-DL1/HIV-1 model, cord-derived CD34+ cells were infected with CXCR4-tropic HIV-1NL4−3 and cocultured. The HIV-infected cocultures exhibited reduced CD4+ T-cell growth at weeks 3–5 post infection compared to autologous uninfected cocultures. Further assays and analyses revealed that CD34+CD7+CXCR4+ cells can be quickly depleted as early as 1 week after infection of the subset, and this was accompanied by the emergence of rare CD34+CD7+CD4+ cells. A subsequent theoretical model analysis suggested potential influence of HIV-1 on the differentiation rate or death rate of lymphoid progenitor cells. These results indicate that CXCR4-tropic HIV-1 strains may impact the dynamics of CD34+CD7+ lymphoid progenitor cell pools, presumably leading to impaired T-cell production potential.

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

“…These results suggest that the CXCR4-tropic HIV-1 strain may affect the differentiation rate or death rate of CD34 + CD7 + lymphoid progenitor cells, resulting in impaired T-cell production capacity. 33 and HSCs from INRs is much lower than that the colony-forming ability of those from IRs. 39 These studies suggest that incomplete immune reconstitution in HIV-1-infected individuals may be associated with impaired bone marrow hematopoietic function and decreased proliferative capacity.…”

“…utilized the in vitro OP9‐DL1/HIV‐1 model, cocultured cord‐derived CD34 + HPCs and CXCR4‐tropic HIV‐1 NL4‐3, and showed that CD34 + CD7 + CXCR4 + cells were rapidly depleted 1 week after HIV‐1 infection, accompanied by dramatically diminished numbers of CD34 + CD7 + CD4 + cells. These results suggest that the CXCR4‐tropic HIV‐1 strain may affect the differentiation rate or death rate of CD34 + CD7 + lymphoid progenitor cells, resulting in impaired T‐cell production capacity . Li et al.…”

Hematopoietic Stem/Progenitor Cells and the Pathogenesis of HIV/AIDS

“…Also, in a macaque model, following challenge with simian immunodeficiency virus, BMderived CD34 + cells exhibited reduced T-lineage differentiation potential in vitro without significant changes in phenotypic analysis of CD34 + subsets (Thiebot et al, 2005). Another recent study suggested that CD34 + CD7 + CXCR4 + cells may be depleted in response to CXCR4-tropic HIV-1 infection in a coculture of HIV-infected umbilical cord-derived CD34 + and OP9-DL1 cells (Tsukamoto, 2019b ; Figure 1). Despite the evidence of LPs during HIV-1 infection, our understanding of the impact of HIV-1 on LPs remains limited.…”

HIV and haematopoiesis

“…[5,40] The majority of studies that have investigated the ability of HIV to infect HSPCs are laboratory-based. [40][41][42]47,48] Due to ethical and logistical challenges related to obtaining sufficient volumes of bone marrow aspirate from HIV-infected individuals, patient (ex vivo)-based studies are scarce. In an isolated study, Redd et al [40] reported that HIV-1 subtype C (HIV-1C), but not HIV-1 subtype B (HIV-1B), has the potential to infect HSCs.…”