Endogenous IFN-α Production by Plasmacytoid Dendritic Cells Exerts an Antiviral Effect on Thymic HIV-1 Infection

Abstract

Plasmacytoid dendritic cells (pDC) are the principal producers of IFN-α in response to viral infection. Because pDC are present in the thymus, we investigated the consequences of HIV-1-induced IFN-α production by thymic pDC. We observed that thymic pDC as well as thymocytes express intracellular IFN-α upon infection with HIV-1. However, only the pDC could suppress HIV-1 replication, because depletion of pDC resulted in enhancement of HIV-1 replication in thymocytes. Thymic pDC could also produce IFN-α in response to CpG oligonucleotides, consistent with the observations of others that peripheral pDC produce IFN-α upon engagement of TLR-9. Importantly, CpG considerably increased IFN-α production induced by HIV-1, and addition of CpG during HIV-1 infection enhanced expression of the IFN response protein MxA in thymocytes and strongly reduced HIV-replication. Our data indicate that thymic pDC modulate HIV-1 replication through secretion of IFN-α. The degree of inhibition depends on the level of IFN-α produced by the thymic pDC.

TLR7/8 Triggering Exerts Opposing Effects in Acute versus Latent HIV Infection

“…PDC are the most potent IFN-␣-producing cells (31), and IFN-␣ has strong antiviral activity (32). However, depleting PDC from lymphoid tissue did not reverse the anti-HIV effects observed.…”

Factors Contributing to HIV-1 Induced Pathogenesis in the Human Thymus

“…Thymic pDC consistently express CD2, CD5 and CD7, while peripheral pDC do not express CD7 and are heterogeneous with respect to the expression of CD2 and CD5 (Bendriss-Vermare et al, 2001;Schmitt et al, 2006). Interestingly, thymic pDC constitutively express low levels of IFN-, which is upregulated by HIV-1 infection in vivo (Gurney et al, 2004). Moreover, thymic pDC produce less IFN-upon infection with virus (Schmitt et al, 2006).…”

“…Recent reports suggest that in HIV-1 infection IFN-production by pDC is stimulated through interaction of HIV-1 RNA with Toll like receptor (TLR)7 (Beignon et al, 2005;Hardy et al, 2007;O'Brien et al, 2011). Although it has been shown that pDC can be productively infected by R5-tropic and X4-tropic HIV-1 (Gurney et al, 2004;Keir et al, 2002), IFN-production by pDC does not depend on productive HIV-1 infection (Beignon et al, 2005;Hardy et al, 2007). Furthermore, pDC express TLR9, which after engagement by oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs mimicking bacterial DNA, activate the cells to secrete high levels of type I IFNs (Kadowaki et al, 2001b).…”

“…One explanation can be that in addition to TCR + T cells, other CCR5 + cells are found in the thymus, including conventional DC (cDC), plasmacytoid DC (pDC), macrophages, CD161 + T cells and T cells (Gurney et al, 2002;Gurney et al, 2004;Keir et al, 2002;Rozmyslowicz et al, 2010;Schmitt et al, 2006). Another explanation can be that pDC (see paragraph below) in response to the virus produce large amounts of type I IFNs (Gurney et al, 2004), which contributes to immune activation followed by cell death and T cell depletion. The pDC are likely more susceptible to R5-tropic HIV infection as they express CCR5 at higher levels compared to single positive thymocytes (Gurney et al, 2004).…”

“…Another explanation can be that pDC (see paragraph below) in response to the virus produce large amounts of type I IFNs (Gurney et al, 2004), which contributes to immune activation followed by cell death and T cell depletion. The pDC are likely more susceptible to R5-tropic HIV infection as they express CCR5 at higher levels compared to single positive thymocytes (Gurney et al, 2004). It was recently reported that IFN- induced expression of CCR5 on CD4 ISP thymocytes, which consequently expands the tropism for R5-tropic viruses (Stoddart et al, 2010).…”