Department of Microbial Pathogens and Immunity, Rush University Medical Centergrid.240684.c, Chicago, Illinois, USA.
Department of Biology, College of Science, Jouf University, Sakaka, Aljouf, Saudi Arabia.
J Virol. 2022 Aug 10;96(15):e0080422. doi: 10.1128/jvi.00804-22. Epub 2022 Jul 19.
CD4 CD8 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 CD8 T cell homing to the brain and define their role in HIV dissemination into the brain. We report here that CD4 CD8 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 CD8 T cells contain integrated provirus, which is infectious as demonstrated by viral outgrowth assay. CD4 CD8 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 CD8 T cell trafficking into the brain by 60% and diminished brain HIV proviral DNA by 72%. Collectively, our findings demonstrate that CD4 CD8 T cells can home to the brain and support productive HIV replication. These studies also reveal for the first time that CD4 CD8 T cells are capable of HIV neuroinvasion and are a reservoir for HIV. We report here a seminal finding of a novel population of T cells, termed CD4 CD8 T cells, that plays a role in HIV neuroinvasion and is a reservoir for HIV in the brain.
CD4 CD8 T 细胞是成熟的 CD8 T 细胞群体，在激活后会在其表面轻度上调 CD4。这些细胞表达 CD4 表明它们可能是 HIV 神经入侵和在大脑中持续存在的另一个来源。我们使用感染 HIV 的 NOD/SCID/IL-2rcγ（NSG）人源化小鼠来追踪 CD4 CD8 T 细胞归巢到大脑，并确定它们在 HIV 传播到大脑中的作用。我们在此报告，CD4 CD8 T 细胞在大脑中的中位数频率为 2.6%，在脾脏中的中位数频率为 CD3 T 细胞的 7.6%。在大脑中，10%至 20%的 CD4 CD8 T 细胞含有整合的前病毒，如病毒生长测定所示，这些前病毒是具有感染力的。与它们的单阳性 CD8 T 细胞对应物相比，大脑中的 CD4 CD8 T 细胞表现出明显更高的脑归巢受体 CX3CR1 和 CXCR3 的表达。通过抗 VLA4 和抗 LFA1 抗体阻断淋巴细胞进入人源化小鼠的大脑，可使 CD4 CD8 T 细胞向大脑的迁移减少 60%，并使大脑 HIV 前病毒 DNA 减少 72%。总的来说，我们的研究结果表明 CD4 CD8 T 细胞可以归巢到大脑并支持 HIV 的复制。这些研究还首次揭示 CD4 CD8 T 细胞能够进行 HIV 神经入侵，并且是 HIV 的储库。我们在此报告了一个开创性的发现，即一种新型 T 细胞群体，称为 CD4 CD8 T 细胞，它在 HIV 神经入侵中发挥作用，是大脑中 HIV 的储库。
