HIV disrupts CD34⁺progenitors involved in T-cell differentiation

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 other cells including haematopoietic CD34+ cells remains unclear even though HIV-positive patients frequently manifest myelosuppression. This study utilised the OP9-DL1 coculture system, which supports in vitro T-lineage differentiation of human haematopoietic stem/progenitor cells. Cord-derived CD34+ cells were infected with CXCR4-tropic HIV-1NL4-3 and cocultured. HIV-infected cocultures exhibited sustained viral replication for 5 weeks, as well as reduced CD4+ T-cell growth at weeks 3–5. It was further revealed that CD34+CD7+CXCR4+ cells can be quickly depleted as early as in 1 week after infection of the subset, and this was accompanied by the emergence of CD34+CD7+CD4+ cells. These results indicate that CXCR4-tropic HIV-1 strains may disrupt CD34+CD7+ lymphoid progenitor cell pools, presumably leading to impaired T-cell production potential.

CXCR4-associated depletion of bone marrow CD34+cells following CCR5-tropic HIV-1 infection of humanized NOD/SCID/JAK3nullmice and partial protection of those cells by a promotor-targeting shRNA

“…implicates the advantages of an anti-HIV gene therapy of CD34 + HSPCs over the equivalent gene therapy of PBMC, because in the former shPromA may confer protection of HSPCs and their derivatives from HIV-1 replication20,28 . As multiple types of hematopoietic progenitor cells may harbor CCR5-or CXCR4-tropic virus for a long time29 , the expression of an anti-HIV modality in all of those cell types may be highly effective on protection of the hematopoietic system in HIV-infected patients.The limited duration of the collaboration, the limited number of mice available, the limited technical expertise in the field of humanized mouse models, and the lack of an empty lentivirus vector for the patented shPromA lentivirus vector, prevented the inclusion of most appropriate control animals transduced with a control lentivirus vector.…”