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.
Highlights
Chronic immune activation induced by human immunodeficiency virus type 1 (HIV-1) infection is highly correlated with CD4 T cell depletion and immunodeficiency [1,2,3]
We discover that plasmacytoid dendritic cells (pDC) are the critical IFN-I producer cells in response to acute HIV-1 infection, because depletion of pDC completely abolished induction of IFN-I or interferon-stimulated genes (ISGs) by HIV-1 infection, correlated with elevated level of HIV-1 replication
When pDC were depleted during chronic HIV-1 infection in humanized mice, pDC were still the major IFN-I producing cells in vivo, which contributed to HIV-1 suppression
Summary
Chronic immune activation induced by HIV-1 infection is highly correlated with CD4 T cell depletion and immunodeficiency [1,2,3]. The level of T cell activation (HLADR+CD38+CD8+ T cells) is correlated with disease progression independent of HIV-1 viral load and CD4+ T cell count [4]. It is proposed that immune activation drives AIDS development in simian immunodeficiency virus (SIV) infected monkeys. SIV infection of African monkeys (African Green monkeys and sooty mangabeys, e.g.) leads to no AIDS progression, correlated with only a transient and selflimiting immune activation despite similar levels of viral replication as pathogenic SIV infections [2,5,6]. Anti-inflammatory treatment with chloroquine [10] or hydroxychloroquine in combination with antivirals [11] inhibits immune activation in HIV-1 infected patients, correlated with elevated CD4+ T cells [11]
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