Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques

Kwa, Suefen; Kannanganat, Sunil; Nigam, Pragati; Siddiqui, Mariam; Shetty, Ravi Dyavar; Armstrong, Wendy S.; Ansari, Aftab A.; Bosinger, Steven E.; Silvestri, Guido; Amara, Rama Rao

doi:10.1182/blood-2011-02-339515

Cited by 91 publications

(107 citation statements)

References 49 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…Similar to what has been observed in HIV, pDC depletion has been demonstrated during acute and chronic SIV infection of RMs, pig-tailed, and cynomolgus macaques [56,120,121], but not nonpathogenic host species of SIV such as SMs and AGMs [122][123][124]. Interestingly, studies of acute pathogenic SIV infection in macaques have demonstrated a transient increase of pDCs in peripheral blood after rapid egress from the bone marrow, followed by depletion of circulating pDCs and accumulation of apoptotic pDCs in lymph nodes [57,120].…”

Section: Plasmacytoid Dcssupporting

confidence: 73%

“…Interestingly, studies of acute pathogenic SIV infection in macaques have demonstrated a transient increase of pDCs in peripheral blood after rapid egress from the bone marrow, followed by depletion of circulating pDCs and accumulation of apoptotic pDCs in lymph nodes [57,120]. Furthermore, recent evidence from multiple laboratories has shown that pDCs are not necessarily depleted during pathogenic SIV infection, but rather, accumulate in large numbers in the GI tract [124][125][126]. Of note, this phenomenon appears to be absent in nonpathogenic SIV infections.…”

Section: Plasmacytoid Dcsmentioning

confidence: 99%

See 1 more Smart Citation

Innate Immunity in Simian Immunodeficiency Virus Infection

Reeves

Bosinger²

2014

Natural Hosts of SIV

Self Cite

View full text Add to dashboard Cite

Section: Plasmacytoid Dcssupporting

confidence: 73%

Section: Plasmacytoid Dcsmentioning

confidence: 99%

Innate Immunity in Simian Immunodeficiency Virus Infection

Reeves

Bosinger²

2014

Natural Hosts of SIV

Self Cite

View full text Add to dashboard Cite

“…Indeed, while CCR5 is not a specific gut-homing receptor, it can induce migration to inflamed tissues (14). Such extremely low levels of CCR5 ϩ pDC in natural hosts could therefore be related to the lack of pDC accumulation in the gut after infection (32). Our results therefore suggest that evaluation of the function of CCR5 in the seeding of viral reservoirs outside its role as an HIV coreceptor is warranted.…”

Section: Discussionmentioning

confidence: 88%

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

Jochems

Jacquelin

Chauveau

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

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) (...

show abstract

“…Env is critical for this synapse to function (70,71), and it is possible that the ⌬GY mutation disrupts Env delivery to and/or formation of this structure. Dendritic cells have also been proposed to play a key role in targeting virions to mucosal sites (72,73) and alterations in the incorporation or expression of Env trimers on virions could impact interactions with dendritic cells and impair this process. In addition, HIV-1 Env has been shown to bind to the ␣4␤7 integrin on CD4 ϩ /CCR5 ϩ effector memory cells in lamina propria, possibly directing virions and/or virally infected cells to this site (72,74,75), and quantitative or qualitative alterations in Env on particles or infected cells caused by the ⌬GY mutation could impede this interaction as well.…”

Section: Discussionmentioning

confidence: 99%

Loss of a Tyrosine-Dependent Trafficking Motif in the Simian Immunodeficiency Virus Envelope Cytoplasmic Tail Spares Mucosal CD4 Cells but Does Not Prevent Disease Progression

Breed

Jordan

Aye

et al. 2013

J Virol

View full text Add to dashboard Cite

A hallmark of pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections is the rapid and near-complete depletion of mucosal CD4؉ T lymphocytes from the gastrointestinal tract. Loss of these cells and disruption of epithelial barrier function are associated with microbial translocation, which has been proposed to drive chronic systemic immune activation and disease progression. Here, we evaluate in rhesus macaques a novel attenuated variant of pathogenic SIVmac239, termed ⌬GY, which contains a deletion of a Tyr and a proximal Gly from a highly conserved YxxØ trafficking motif in the envelope cytoplasmic tail. Compared to SIVmac239, ⌬GY established a comparable acute peak of viremia but only transiently infected lamina propria and caused little or no acute depletion of mucosal CD4؉ T cells and no detectable microbial translocation. Nonetheless, these animals developed T-cell activation and declining peripheral blood CD4؉ T cells and ultimately progressed with clinical or pathological features of AIDS. ⌬GY-infected animals also showed no infection of macrophages or central nervous system tissues even in late-stage disease. Although the ⌬GY mutation persisted, novel mutations evolved, including the formation of new YxxØ motifs in two of four animals. These findings indicate that disruption of this trafficking motif by the ⌬GY mutation leads to a striking alteration in anatomic distribution of virus with sparing of lamina propria and a lack of microbial translocation. Because these animals exhibited wild-type levels of acute viremia and immune activation, our findings indicate that these pathological events are dissociable and that immune activation unrelated to gut damage can be sufficient for the development of AIDS.

show abstract

Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques

Cited by 91 publications

References 49 publications

Innate Immunity in Simian Immunodeficiency Virus Infection

Innate Immunity in Simian Immunodeficiency Virus Infection

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

Loss of a Tyrosine-Dependent Trafficking Motif in the Simian Immunodeficiency Virus Envelope Cytoplasmic Tail Spares Mucosal CD4 Cells but Does Not Prevent Disease Progression

Contact Info

Product

Resources

About