CD71+ erythroid cells exacerbate HIV-1 infection by reactive oxygen species and trans-infect HIV to CD4+ T cells

CD71+ erythroid cells (CECs) have a wide range of immunomodulatory properties but their potential role in HIV has never been investigated before. Here, we demonstrate that CECs are abundant in the human cord blood, placental tissue and peripheral blood of pregnant mothers. We found that CECs exacerbate HIV-1 infection/replication when co-cultured with CD4+ T cells; and that pre-exposure of CD4+ T cells to CECs make them more permissible to HIV-infection. Our observations indicate how interactions of CECs with CD4+ T cells via reactive oxygen species (ROS)-dependent mechanism results in the upregulation of NF-kB, which affects the cell cycle machinery to facilitate HIV-1 replication. We found the complement receptor-1 (CD35) and the Duffy antigen receptor for chemokines (DARC) as potential HIV-target molecules are expressed significantly higher on CECs compared to mature red blood cells. However, blocking CD35 or DARC did not inhibit HIV-1 trans-infection to uninfected CD4+ T cells. We demonstrate that CECs bind to HIV-1 via CD235a and subsequently trans-infect the virus to uninfected CD4+ T cells. In addition, we found significant abundance of CECs in the blood of HIV-1 infected and anemic subjects, which enhanced HIV infection/replication in autologous CD4+ T cells similar to what we observed for the cord blood and placenta-derived CECs. In agreement, a positive correlation between the frequency of CECs with the plasma viral load in HIV-1 infected antiretroviral therapy naive individuals was observed. In addition, we found that CECs even in the presence of Tenofovir, can trans-infect HIV-1 to CD4+ T cells. Our studies provide a novel insight into the role of CECs in HIV pathogenesis as potential contributing cells for viral persistence in the presence of antiretroviral therapy.