JCI Insight. 2024 Jan 9;9(1):e173738. doi: 10.1172/jci.insight.173738.
Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection to adult T cell leukemia and HTLV-1-associated myelopathy (HAM), an inflammatory disease of the CNS. The mechanisms by which HTLV-1 induces HAM are poorly understood. By directly examining the ex vivo phenotype and function of T cells from asymptomatic carriers and patients with HAM, we show that patients with HAM have a higher frequency of CD4+CD8+ double-positive (DP) T cells, which are infected with HTLV-1 at higher rates than CD4+ T cells. Displaying both helper and cytotoxic phenotypes, these DP T cells are highly proinflammatory and contain high frequencies of HTLV-1-specific cells. Mechanistically, we demonstrate that DP T cells arise by direct HTLV-1 infection of CD4+ and CD8+ T cells. High levels of CD49d and CXCR3 expression suggest that DP T cells possess the ability to migrate to the CNS, and when cocultured with astrocytes, DP T cells induce proinflammatory astrocytes that express high levels of CXCL10, IFN-γ, and IL-6. These results demonstrate the potential of DP T cells to directly contribute to CNS pathology.