Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection

Abstract

Human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/ SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4 ؉ T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV in vivo identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor. IMPORTANCEThe ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing. C hronic inflammation and immune activation in human immunodeficiency virus (HIV)-infected humans and in simian immunodeficiency virus (SIV)-infected macaques (MAC) lead to depletion of CD4ϩ T cells and progression to AIDS. Natural hosts of SIV, such as African green monkeys (AGM) and sooty mangabeys (SM), do not display chronic inflammation or AIDS (1). This is due to resolution of inflammation before the end of acute infection rather than to a lack of SIV recognition by the innate immune system (2). Natural hosts further differ from pathogenic HIV/SIV infections by exhibiting reduced infection rates in certain cell subsets, such as central memory CD4ϩ T cells (Tcm) (...

CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections

“…This exceedingly low CCR5 expression level has represented a paradox given the sustained high-level viremia seen in natural hosts. Similarly, cell-associated infection in natural hosts exceeds the proportion of cells expressing CCR5 (53). The observation that alternative corecep-tors, particularly CXCR6, are used for SIV entry in infections of multiple natural hosts provides an explanation for the robust replication in the face of limited CCR5 expression and suggests that CCR5 Ϫ CD4 ϩ cells expressing CXCR6 (or other alternative coreceptors) are a major site of virus replication in these species.…”

Immune activation in HIV infection

“…It has been suggested that this is due to a combination of entry and post-entry restriction mechanisms. In contrast to macrophages, pDC seem to be highly infected in natural hosts, as much as in macaques [26]. Further studies in the non-human primates are needed to better understand the contribution of antigenpresenting cells as viral reservoirs.…”

“…during the acute phase of infection [20,21]. Natural hosts' pDC have a normal capacity to produce IFN-a upon exposure to SIV [21-23, 25, 26].There even seems to be a selective pressure in natural hosts to maintain capacity by PDC to sense species-specific SIV [26]. NK cells are highly activated during primary infection in natural hosts [24].…”

Non-human primates in HIV research: Achievements, limits and alternatives

“…Ancient infection that ledto an adaptation of thehost"s immune response responsible fordifferences inthe intensityornatureofSIV sensing. The capacityto produceIFN-Iis normalin natural hosts, but othersensingpathways haveonly poorlybeen explored innatural hosts so far 101,102 . The abilityof the Nef protein toblock the activation ofinfected Tcells by downregulation of CD3 103 .…”