Dendritic cells (DCs) have been (i) implicated, along with T cells, as one of the first cells targeted by HIV after mucosal exposure and (ii) shown to transmit virus efficiently to CD4+ T cells: direct transfer of captured/internalized virus (immature and mature DCs) and transfer of newly synthesized virus (immature DCs {iDCs}). The SIV-macaque model is being used to study the role of DCs in HIV transmission and disease progression. The DC-T cell milieu provides a distinctive niche in which SIV/HIV can propagate in vitro and in vivo, with different subsets of DCs and T cells influencing the level of virus growth. Wild type (wt) vs nef-defective (?nef) virus replication is dependent on the state of activation of the DC: wt overcomes the limitations of iDCs to foster infection in the DC-T cell milieu. In vivo ?nef infection of macaques affords a certain level of protection against wt infection, suggesting that in the absence of nef stronger effector immunity is mounted. Yet how this is mediated is still not understood. Thus, we need to identify ways to harness the potent immunostimulatory activity of DCs to boost effector responses, while preventing DC-driven infection. We hypothesize that pathogenic HIV/SIV exploits iDC biology by augmenting their ability to activate regulatory T cells (Tregs) and that this is exacerbated in the presence of pathogens like HSV-2. This would favor increased wt virus spread and replication in the face of poor effector immunity. Evidence suggests that TLR3 ligation (via poly(IC), a synthetic analog of dsRNA) shuts down HIV/SIV replication. We believe that this might be due (at least in part) to the """"""""proper"""""""" activation of DCs resulting in the triggering of important innate and adaptive responses that limit HIV/SIV spread. By studying wt and ?nef infections we plan to determine the role of iDCs and Tregs in mucosal transmission and how pathogenic virus manipulates this biology. We propose that the down-modulation of DC function by HSV-2 will enhance iDC-Treg involvement even in ?nef infection, while poly(IC) will limit HIV/SIV (and HSV-2) replication and augment anti-viral immunity (increased DC activation, fewer Tregs). Identifying the molecular requirements for virus transmission and the innate and adaptive responses that coincide with virus control, will provide new targets for novel blocking strategies, as well as dictate how we can redirect DCs to induce strong anti-viral immunity rather than virus dissemination.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-AARR-C (03))
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Sharma, Opendra K
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Population Council
New York
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Aravantinou, Meropi; Mizenina, Olga; Calenda, Giulia et al. (2017) Experimental Oral Herpes Simplex Virus-1 (HSV-1) Co-infection in Simian Immunodeficiency Virus (SIV)-Infected Rhesus Macaques. Front Microbiol 8:2342
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