Productive infection of double-negative T cells with HIV in vivo

HIV induces CD4 down-regulation from the surface of infected cells by sever al independent mechanisms, suggesting an important biological role for this phenomenon. In vitro CD4 down-regulation generates T cells with a double-n egative (DN) CD4(-)CD8(-) T cell receptor-alpha beta(+) phenotype, However, evidence that this down-regulation occurs in vivo in HIV-infected subjects is lacking, and viral load or viral production assays invariably focus on CD4(+) T cells. We show here that HIV infection can often be detected in so rted DN cells from peripheral blood and lymph nodes, even when plasma viral load is undetectable. DN T cells infected with HIV represented up to 20% o f the cellular viral load in T cells, as determined by DNA PCR. In patients on successful highly active antiretroviral therapy, the viral load decreas ed in the plasma in CD4(+) and in DN T cells, suggesting that infected DN c ells, like CD4(+) cells, contribute to viral production and are sensitive t o highly active antiretroviral therapy, Indeed, HIV unspliced and multispli ced RNAs were often detectable in DN T cells in spite of the small size of this subset. Infectious virus from DN T cells was transmitted efficiently i n coculture experiments with uninfected T cell lymphoblasts, even when vira l DNA in the DN cells was barely detectable. We conclude that a discrete po pulation of infected DN T cells exists in HIV-positive subjects, even when the plasma viral load is undetectable, These cells may represent an importa nt source of infectious virus.