Abstract
Background:
CNS infection by HIV-1 contributes to neuroinflammation, cognitive impairments, and the establishment of viral reservoirs. Although HIV-1 is known to enter the brain early in infection via “Trojan horse” leukocytes, including infected monocytes and CD4⁺ T cells, the specific cellular phenotypes facilitating this process during acute infection remain incompletely characterized.
Objective:
This study aims to characterize the roles of brain lymphocytes during acute infection and primary CD4 + T cell phenotypes seeding the SIV to the CNS.
Methods:
scRNA-seq was performed on brain and blood cells of three acutely SIV-infected rhesus macaques. The transcriptomic data were analyzed using bioinformatics approaches and validated through in vitro co-culture assays and re-analysis of a publicly available scRNA-seq dataset.
Results:
scRNA-seq of brain and blood immune cells from acutely SIV-infected rhesus macaques revealed an expansion of proliferating CD4⁺ cytotoxic T lymphocytes (CTLs) in the blood, characterized by high CD4, CCR5, and adhesion molecule expression, indicating strong potential for CNS infiltration. In the brain, CD4⁺ CTLs, tissue-resident memory cells, and a unique Myeloid–T cell cluster were enriched for SIV⁺ cells. Integration of brain and blood data revealed transcriptomic maturation of CD4⁺ CTLs upon brain entry. To validate the biological relevance of the Myeloid–T cluster, we used a macrophage–T cell co-culture system, which reproduced similar dual-marker expression and identified chemokines (e.g., CCL3, CCL4) as potential markers of T cell–myeloid cell interaction.
Conclusion:
Our findings suggest that CD4⁺ cytotoxic-like T cells represent a key lymphocyte subset responsible for initiating SIV entry into the brain and triggering neuroinflammatory processes. Furthermore, interactions between infiltrating lymphocytes and brain-resident myeloid cells, potentially through chemokine signaling, may facilitate viral propagation within the CNS.
Supplementary Information:
The online version contains supplementary material available at 10.1186/s12974-025-03543-y.
Keywords:
Acute SIV infection; CD4 + T cells; ScRNA-seq; Viral entry.