CD34-positive monocytes are highly susceptible to HIV-1

HIV-1 persists in cellular reservoirs despite effective combined antiretroviral therapy (cART). CD4 ⁺ T cells are a well-known reservoir, but there is evidence suggesting that myeloid cells, including circulating monocytes, are also a clinically relevant reservoir. However, it is not fully understood which subsets of monocytes are preferentially infected in vivo. Here, we show that a monocyte fraction expressing a stem cell marker CD34 is more susceptible to HIV-1 infection than the CD34-negative major subset. In cART-untreated viremic individuals, the CD34 ⁺ fraction increased in the percentage in total monocytes, and harbored higher copies of proviral DNA than the major subset. Consistent with this, the CD34 ⁺ fraction expressed HIV-1 receptors CD4 and CCR5 at higher levels and HIV-1 restriction factors MX2 and SAMHD1 at lower levels. Interestingly, proviral DNA was still detectable in the CD34 ⁺ fraction of cART-treated virologically suppressed individuals. CD34 ⁺ monocytes were also present in lymph nodes, and expressed CD4 and CCR5 at higher levels than the major subset, as observed in peripheral blood. Moreover, CD34 ⁺ monocytes present in peripheral blood and lymph nodes highly expressed CCR7 and sphingosine-1-phosphate receptor 1 (S1PR1), critical regulators of in vivo cellular trafficking. Collectively, our findings raise the new possibility that lymph node CD34 ⁺ monocytes, which originate from the circulation, are infected with HIV-1 owing to their high susceptibility to HIV-1, and return to circulation, which explains the detection of proviral DNA in peripheral CD34 ⁺ monocytes even after long-term cART.