The massive depletion of CD4+ T cells within the gut associated lymphoid tissues (GALT) during acute HIV/SIV followed by sustained CD4+ T cell loss during chronic infection leads to progressive damage to the GALT and the overlying mucosal epithelium. These events contribute to immune dysfunction, viral loads and the rate of disease progression over time. The CD4+ T cells traffic to the GALT by signals generated within the GALT which include the release of retinoic acid which in turn leads to upregulation of the ?47 integrin and CCR9 on the cell surface. Cells expressing ?47 and CCR9 selectively home to the GALT by interacting with their cognate receptors MAdCAM and CCL25 expressed by epithelial cells lining the intestinal wall. Recent data show that ?47, besides serving as the homing receptor, also serves as an alternate receptor for many strains of HIV and SIV whose V1/V2 env segments have recognition 'motifs' for ?47 similar to MAdCAM its natural ligand. In addition, sequences localized to the V1/V2 and V3/C4 env region contain residues which, if deglycosylated, markedly enhance the affinity of the virus to bind ?47. Such ?47 high affinity binding HIV-1 is thought to be preferentially transmitted via the mucosal route. Our lab has recently shown that the administration of a primatized anti-?47 mAb, just prior to and during acute IV and intra-rectal SIV infection, leads to markedly reduced viral loads in the GALT and provides, for the first time, tools to examine in detail the events that occur during acute infection. The studies proposed herein are aimed at: 1) determining the clinical utility of these previous findings by determining if ?47 administration is effective in lowering GALT viral loads in animals a) infected intravaginally, b) post SIV infection, c) infected with low repeated doses intravaginally to mimic natural transmission, and d) if a small molecule inhibitor of CCR9 alone or with ?47 mAb administration leads to more effective and prolonged control of GALT viremia; 2) defining the histopathological analysis of the gut tissues with a focus on delineating the role of proteins involved in maintaining gut tissue integrity, defining the kinetics of bacteril translocation and the physiologic measurement of gut tissue permeability; and 3) determining the mechanisms involved by which ?47 induces its effect a) by determining whether ?47 mAb mediates its effect via blocking the receptor function of the ?47 or by blocking the trafficking of ?47 expressing cells by using recombinant replication competent SIV env constructs that do or do not bind ?47, b) by determining whether the in vivo effect of anti-?47 treatment is influenced by the level of env glycosylation using W.T. & recombinant env deglycosylated SHIV's that bind ?47 with low v/s high affinity, c) determine the tissue/organ localization of virus and CD4+ cells in the control and ?47 administered animals using a newly optimized real time LIVE PET-CT scanning technique developed by our lab. The realization that effective HIV vaccines require to elicit not only broad neutralizing Abs and effective virus specific CTL's but also means to prevent GALT injury which is intimately associated with disease progression, highlight the importance of these studies.

Public Health Relevance

Both the HIV/SIV appear to use ?47, a molecule expressed by CD4+ T cells as an alternate co- receptor. Our lab has used a monoclonal antibody against the ?47 molecule and shown that treatment of monkeys prior to and during the acute intravenous infection period with the monoclonal antibody leads to a marked reduction in viral loads in the gastrointestinal tract. We propose to carry out more detailed studies aimed at defining the clinical use of these initial findings to determine if we can 'blunt' the initial gastrointestinal tract pathology which will greatly enhance our understanding of the pathogenic mechanisms involved during acute infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI098628-05
Application #
9052112
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Church, Elizabeth S
Project Start
2012-05-17
Project End
2017-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Santangelo, P J; Cicala, C; Byrareddy, S N et al. (2018) Early treatment of SIV+ macaques with an ?4?7 mAb alters virus distribution and preserves CD4+ T cells in later stages of infection. Mucosal Immunol 11:932-946
Calenda, Giulia; Keawvichit, Rassamon; Arrode-Brusés, Géraldine et al. (2018) Integrin ?4?7 Blockade Preferentially Impacts CCR6+ Lymphocyte Subsets in Blood and Mucosal Tissues of Naive Rhesus Macaques. J Immunol 200:810-820
Nawaz, Fatima; Goes, Livia R; Ray, Jocelyn C et al. (2018) MAdCAM costimulation through Integrin-?4?7 promotes HIV replication. Mucosal Immunol 11:1342-1351
Lertjuthaporn, Sakaorat; Cicala, Claudia; Van Ryk, Donald et al. (2018) Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to ?4?7. PLoS Pathog 14:e1007278
Arthos, James; Cicala, Claudia; Nawaz, Fatima et al. (2018) The Role of Integrin ?4?7 in HIV Pathogenesis and Treatment. Curr HIV/AIDS Rep 15:127-135
Sivro, Aida; Schuetz, Alexandra; Sheward, Daniel et al. (2018) Integrin ?4?7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes. Sci Transl Med 10:
Ortiz, Kristina; Sampathkumar, Rebecca S; Ansari, Aftab A et al. (2017) Preliminary studies on the use of pertussis toxin for the modulation of intravaginal SIV transmission in rhesus macaques. J Med Primatol 46:327-331
Hong, Jung J; Silveira, Eduardo L di Volpe; Amancha, Praveen K et al. (2017) Early initiation of antiretroviral treatment postSIV infection does not resolve lymphoid tissue activation. AIDS 31:1819-1824
Ansari, Aftab A; Byrareddy, Siddappa N (2016) The Role of Integrin Expressing Cells in Modulating Disease Susceptibility and Progression (January 2016). Int Trends Immun 4:11-27
Byrareddy, Siddappa N; Arthos, James; Cicala, Claudia et al. (2016) Sustained virologic control in SIV+ macaques after antiretroviral and ?4?7 antibody therapy. Science 354:197-202

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