Three immunoregulatory signatures define non-productive HIV infection in stem cell memory CD4⁺ T cells

The persistent HIV reservoir constitutes the main obstacle to curing HIV/AIDS disease. Our understanding of how non-productive HIV infections are established in primary human CD4⁺ T cells during the first round of infection is still incomplete. In this study, we leverage the HIV reporter virus pMorpheus-V5 to delineate cellular expression patterns upregulated in non-productively infected stem cell memory (T_SCM) CD4⁺ T cells. We find that CD4⁺ T_SCM harboring non-productive proviruses display a distinct transcriptomic signature comprising 118 upregulated genes, distinct from that of productively infected cells as well as from negative-exposed and mock-infected cells. Among the cellular genes most upregulated in CD4⁺ T_SCM cells harboring non-productive proviruses are CCR4-binding migratory chemokines (CCL22, CCL17), tryptophan catabolic enzymes (IDO1, KYNU), and genes encoding cytoskeletal rearrangement proteins (BASP1, TNFAIP2). Flow cytometry-based analyses confirm that non-productively infected CD4⁺ T_SCM cells are enriched for CCL22 and IDO1 co-expression compared to other CD4⁺ T memory subsets, underscoring a CD4⁺ T cell subset specificity for the upregulation of these two immune gene sets associated with non-productive infections. These findings suggest that primary human CD4⁺ T_SCM harboring non-productive proviruses display a distinct immunoregulatory phenotype which may facilitate immune evasion and contribute to the persistence of the HIV reservoir.