CD4 + Memory Stem Cells Are Infected by HIV-1 in a Manner Regulated in Part by SAMHD1 Expression

Abstract

CD4 + and CD8 + memory T cells with stem cell-like properties (T SCM cells) have been identified in mice, humans, and nonhuman primates and are being investigated for antitumor and antiviral vaccines and immunotherapies. Whether CD4 + T SCM cells are infected by human immunodeficiency virus (HIV) was investigated by using a combination HIV reporter virus system in vitro and by direct staining for HIV p24 antigen ex vivo . A proportion of T SCM cells were found to express the HIV coreceptors CCR5 and CXCR4 and were infected by HIV both in vitro and in vivo . Analysis of viral outcome following fusion using the combination reporter virus system revealed that T SCM cells can become productively or latently infected, although the vast majority of T SCM cells are abortively infected. Knockdown of the HIV restriction factor SAMHD1 using Vpx-containing simian immunodeficiency virus (SIV) virion-like particles enhanced the productive infection of T SCM cells, indicating that SAMHD1 contributes to abortive infection in these cells. These results demonstrate that CD4 + T SCM cells are targets for HIV infection, that they become productively or latently infected at low levels, and that SAMHD1 expression promotes abortive infection of this important memory cell subset. IMPORTANCE Here we demonstrate the susceptibility of CD4 + memory stem cells (T SCM cells) to infection by HIV in vitro and in vivo , provide an in-depth analysis of coreceptor expression, demonstrate the infection of naïve and memory CD4 + T cell subsets with both CCR5- and CXCR4-tropic HIV, and also perform outcome analysis to calculate the percentage of cells that are productively, latently, or abortively infected. Through these outcome studies, we determined that the vast majority of T SCM cells are abortively infected by HIV, and we demonstrate that knockdown of SAMHD1 significantly increases the frequency of infection of this CD4 + T cell subset, indicating that SAMHD1 is an active restriction factor in T SCM cells.