Dendritic cells (DCs) have been (i) implicated, along with T cells, as one of the first leukocytes 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 a precious tool 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 (wrt) vs ne/-defective {Anef) 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 Anef infection of macaques affords protection against wt infection, suggesting that in the absence of /7ef stronger effector immunity is mounted. In addition, HSV-2 infection augments HIV transmission possibly through the persistence of increased numbers of HIV target cells within the tissues and down-modulation of DC immunostimulatory capacity. But the exact mechanisms of such remain unclear. Within this new 5-year proposal we are expanding our current research to delve more deeply into this biology in order to define these early events in HIV transmission. This will be achieved through two new Specific Aims. Specifically, we hypothesize that HSV-2 enhances DCdriven HIV infection by initially increasing the numbers of highly susceptible a4/J7'^'^''CD4* T cells in the earliest stages of infection, as well as dampening overall effective immunity (reduced DC function, increased Tregs). Conversely, DC activation 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 (e.g.. APOBEC) and adaptive responses that limit HIV/SIV spread. By studying wt and 4rtef infections we plan to delineate the role of iDCs and T cells (a4p7'^'^'^CD4''T cells and Tregs) in mucosal transmission. We propose that the down-modulation of DC function by HSV-2 will enhance iDC-a4/J7'""""""""^''T cell and IDC-Treg involvement even in Anef infection, while poly(lC) wilt limit HIV/SIV (and HSV-2) replication and augment anti-viral immunity (increased DC activation, fewer a4l3f'^'^CD4* T cells). 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.

Public Health Relevance

This research aims to define the earliest events that are critical to the onset and spread of HIV infection across the mucosa and how this biology is exploited by other pathogens to exacerbate HIV spread, in order to identify strategies to prevent the sexual transmission of HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI040877-18
Application #
8702072
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Sharma, Opendra K
Project Start
1997-07-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Population Council
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10017
Guerra-Pérez, Natalia; Aravantinou, Meropi; Veglia, Filippo et al. (2016) Rectal HSV-2 Infection May Increase Rectal SIV Acquisition Even in the Context of SIVΔnef Vaccination. PLoS One 11:e0149491
Guerra-Pérez, Natalia; Frank, Ines; Veglia, Filippo et al. (2015) Retinoic acid imprints a mucosal-like phenotype on dendritic cells with an increased ability to fuel HIV-1 infection. J Immunol 194:2415-23
Teleshova, Natalia; Derby, Nina; Martinelli, Elena et al. (2013) Simian immunodeficiency virus interactions with macaque dendritic cells. Adv Exp Med Biol 762:155-81
Martinelli, Elena; Veglia, Filippo; Goode, Diana et al. (2013) The frequency of α₄β₇(high) memory CD4⁺ T cells correlates with susceptibility to rectal simian immunodeficiency virus infection. J Acquir Immune Defic Syndr 64:325-31
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Luchins, Kerith R; Baker, Kate C; Gilbert, Margaret H et al. (2011) Application of the diagnostic evaluation for alopecia in traditional veterinary species to laboratory rhesus macaques (Macaca mulatta). J Am Assoc Lab Anim Sci 50:926-38
Frank, Ines; Robbiani, Melissa (2011) Attachment and fusion inhibitors potently prevent dendritic cell-driven HIV infection. J Acquir Immune Defic Syndr 56:204-12
Martinelli, Elena; Tharinger, Hugo; Frank, Ines et al. (2011) HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target. PLoS Pathog 7:e1002109
Derby, Nina; Martinelli, Elena; Robbiani, Melissa (2011) Myeloid dendritic cells in HIV-1 infection. Curr Opin HIV AIDS 6:379-84
Pugach, Pavel; Krarup, Anders; Gettie, Agegnehu et al. (2010) In vivo binding and retention of CD4-specific DARPin 57.2 in macaques. PLoS One 5:e12455

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