Previously a new cellular system was identified, consisting of dendritic cells (DCs) and T cells from human skin that supports active replication of HIV in vitro. The skin is a useful model for the less accessible human mucosal tissues involved in HIV transmission. It was found that virus replication needs both DCs and T cells, which fuse to form virus-producing syncytia. DC-syncytia producing HIV proteins have now been identified in the adenoid mucosa of 13/13 HIV-infected individuals. Preliminary studies on the role of mucosal leukocytes in pathogenesis using the SIV-macaque system, has revealed similar observations to the HIV-human skin system. The DC-T cell mixtures isolated from macaque skin or oral mucosae support active replication of SIV in vitro. In a vaginally infected macaque, SIV-carrying cells were isolated from the tonsillar mucosa that formed virus-producing syncytia upon in vitro culture without added stimuli. Therefore, much like the HIV-infected individuals who have a productive infection in the tonsillar mucosa, so too does a monkey infected intravaginally with SIV. The SIV-macaque model will be used to identify cells that are critical for mucosal infection, systemic spread, and chronic replication of SIV. The hypothesis is that mucosal leukocytes will be pivotal in the replication of SIV especially DCs that contact CD4+ T cells (in vitro and in vivo). These studies cannot be performed in man and will identify cell-cell and cell-virus interactions crucial to SIV spread and replication. This proposal will address several issues: 1. Are mucosal DCs and T cells (versus blood and lymph node cells), needed for SIV replication in vitro? 2. What cells are involved in the spread of infection to blood and distal tissues following vaginal infection? 3. In what cells and tissues does SIV replication occur during the chronic phase of immunodeficiency? 4. What cell types, following infection with SIV in vitro, elicit infection in vivo upon reinfusion? 5. Are the tonsillar mucosae unusually susceptible sites for the onset of SIV infection? These studies will provide a better understanding of how infection is established in the mucosae during both sexual and perinatal transmission. Identifying the cells critical in the onset and spread of infection, as well as chronic virus replication, will direct the development of specific therapies that block infection and control virus replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040877-03
Application #
2887375
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Plaeger, Susan F
Project Start
1997-07-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Physiology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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
Aravantinou, Meropi; Frank, Ines; Arrode-Bruses, Geraldine et al. (2017) A model of genital herpes simplex virus Type 1 infection in Rhesus Macaques. J Med Primatol 46:121-128
Guerra-Pérez, Natalia; Aravantinou, Meropi; Veglia, Filippo et al. (2016) Rectal HSV-2 Infection May Increase Rectal SIV Acquisition Even in the Context of SIV?nef Vaccination. PLoS One 11:e0149491
Aravantinou, Meropi; Frank, Ines; Hallor, Magnus et al. (2016) PolyICLC Exerts Pro- and Anti-HIV Effects on the DC-T Cell Milieu In Vitro and In Vivo. PLoS One 11:e0161730
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
Derby, Nina; Zydowsky, Thomas; Robbiani, Melissa (2013) In search of the optimal delivery method for anti-HIV microbicides: are intravaginal rings the way forward? Expert Rev Anti Infect Ther 11:5-8
Maverakis, Emanual; Menezes, Juscilene S; Ametani, Akio et al. (2010) Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity. Proc Natl Acad Sci U S A 107:2550-5
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
Trapp, Susanna; Derby, Nina R; Singer, Rachel et al. (2009) Double-stranded RNA analog poly(I:C) inhibits human immunodeficiency virus amplification in dendritic cells via type I interferon-mediated activation of APOBEC3G. J Virol 83:884-95
Frank, I; Stossel, H; Gettie, A et al. (2008) A fusion inhibitor prevents spread of immunodeficiency viruses, but not activation of virus-specific T cells, by dendritic cells. J Virol 82:5329-39

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