Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice

Abstract

The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5-tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDC-depleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDC-depleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment.

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

“…We have recently reported that pDCs play a pathogenic role in HIV-1 infection and pathogenesis (28). We also demonstrated the role of human pDCs in HIV-1-induced depletion of ILC3s.…”

“…We recently reported that depletion of pDCs using the anti-blood dendritic cell antigen-2 (anti-BDCA2) Ab (15B) in NRG-hu mice led to elevated HIV-1 replication, but with reduced immunopathogenesis (28). In humanized mice with persistent HIV-1 infection, we detected high levels of plasma IFN-α, although pDC levels were reduced in the spleen ( Figure 5A).…”

“…We thus tested the role of pDCs in the loss of ILC3 cells through depleting pDCs using the anti-BDCA2 Ab (15B) in NRG-hu mice with persistent HIV-1 infection as reported (28). We observed that pDC depletion with the 15B mAb significantly rescued splenic ILC3s ( Figure 6, A and B) and restored their IL-17a and IL-22 production capacity in NRG-hu mice with persistent HIV-1 infection ( Figure 6, C and D).…”

“…We thus took advantage of the well-developed humanized mouse model to investigate the function and role of ILC3 in HIV-1 pathogenesis (28)(29)(30)(31) Figure 2). We found that ILC3s were efficiently developed in all lymphoid organs of humanized mice including spleen, mesenteric lymph node (mLN), peripheral lymph node (pLN), BM, and peripheral blood lymphocytes (PBL) ( Figure 2A).…”

HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells

“…In HIV and SIV infection, persistent high-level IFN production is associated with chronic immune activation, including higher levels of activation molecule expression, increased immune activation gene expression, and/or more rapid CD4 depletion (4,5). Increased circulating IFN during the chronic stage of HIV infection has been associated with rapid progression to AIDS (6,7).…”