CD4dim CD8bright T Cells Home to the Brain and Mediate HIV Neuroinvasion

Abstract

CD4^dim CD8^bright T cells are a mature population of CD8⁺ T cells that upon activation upregulate CD4 dimly on their surface. Expression of CD4 on these cells suggests that they can be an additional source of HIV neuroinvasion and persistence in the brain. We used HIV-infected NOD/SCID/IL-2rcγ^-/- (NSG) humanized mice to track CD4^dim CD8^bright T cell homing to the brain and define their role in HIV dissemination into the brain. We report here that CD4^dim CD8^bright T cells are found in the brain at a median frequency of 2.6% and in the spleen at median frequency of 7.6% of CD3⁺ T cells. In the brain, 10 to 20% of CD4^dim CD8^bright T cells contain integrated provirus, which is infectious as demonstrated by viral outgrowth assay. CD4^dim CD8^bright T cells in the brain exhibited significantly higher expression of the brain homing receptors CX3CR1 and CXCR3 in comparison to their single-positive CD8⁺ T cell counterpart. Blocking lymphocyte trafficking into the brain of humanized mice via anti-VLA4 and anti-LFA1 antibodies reduced CD4^dim CD8^bright T cell trafficking into the brain by 60% and diminished brain HIV proviral DNA by 72%. Collectively, our findings demonstrate that CD4^dim CD8^bright T cells can home to the brain and support productive HIV replication. These studies also reveal for the first time that CD4^dim CD8^bright T cells are capable of HIV neuroinvasion and are a reservoir for HIV. IMPORTANCE We report here a seminal finding of a novel population of T cells, termed CD4^dim CD8^bright T cells, that plays a role in HIV neuroinvasion and is a reservoir for HIV in the brain.

Keywords: AIDS; CD4dim CD8bright double-positive T cells; CD8+ T cells; HIV neuroinvasion; T cell immunity; T cells; droplet digital PCR (ddPCR); human immunodeficiency virus; immunology; lymphocyte trafficking; molecular biology; neuroimmunology; virology.