Integrin α 4 β 7 mediates the trafficking of leukocytes, including CD4 + T cells, to lymphoid tissues in the gut. Virus mediated damage to the gut is implicated in HIV and SIV mediated chronic immune activation and leads to irreversible damage to the immune system. We employed an immuno-PET/CT imaging technique to evaluate the impact of an anti-integrin α 4 β 7 mAb alone or in combination with ART, on the distribution of both SIV infected cells and CD4 + cells in rhesus macaques infected with SIV. We determined that α 4 β 7 mAb reduced viral antigen in an array of tissues of the lung, spleen, axillary, and inguinal lymph nodes. These sites are not directly linked to α 4 β 7 mediated homing; however, the most pronounced reduction in viral load was observed in the colon. Despite this reduction, α 4 β 7 mAb treatment did not prevent an apparent depletion of CD4 + T cells in gut in the acute phase of infection that is characteristic of HIV/SIV infection. However, α 4 β 7 mAb appeared to facilitate the preservation or restoration of CD4 + T cells in gut tissues at later stages of infection. Since damage to the gut is believed to play a central role in HIV pathogenesis, these results support further evaluation of α 4 β 7 antagonists in the study and treatment of HIV disease.
Antiretroviral drug therapy (ART) effectively suppresses replication of both the immunodeficiency viruses, human (HIV) and simian (SIV); however, virus rebounds soon after ART is withdrawn. SIV-infected monkeys were treated with a 90-day course of ART initiated at 5 weeks post infection followed at 9 weeks post infection by infusions of a primatized monoclonal antibody against the α 4 β 7 integrin administered every 3 weeks until week 32. These animals subsequently maintained low to undetectable viral loads and normal CD4 + T cell counts in plasma and gastrointestinal tissues for more than 9 months, even after all treatment was withdrawn. This combination therapy allows macaques to effectively control viremia and reconstitute their immune systems without a need for further therapy.
by
Sakaorat Lertjuthaporn;
Claudia Cicala;
Donald Van Ryk;
Matthew Liu;
Jason Yolitz;
Danlan Wei;
Fatima Nawaz;
Allison Doyle;
Brooke Horowitch;
Chung Park;
Shan Lu;
Yang Lou;
Shixia Wang;
Ruimin Pan;
Xunqing Jiang;
Francois Villinger;
Siddappa Byrareddy;
Philip Santangelo;
Lynn Morris;
Constantinos Kurt Wibmer;
Kristin Biris;
Rosemarie D. Mason;
Jason Gorman;
Joseph Hiatt;
Elena Martinelli;
Mario Roederer;
Dai Fujikawa;
Giacomo Gorini;
Genoveffa Franchini;
Anush Arakelyan;
Aftab Ansari;
Kovit Pattanapanyasat;
Xiang-Peng Kong;
Anthony S. Fauci;
James Arthos
The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin α4β7, a gut-homing receptor. Using both cell-surface expressed α4β7and a soluble α4β7heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of α4β7in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to α4β7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, α4β7antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to α4β7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to α4β7. It includes the canonical LDV/I α4β7binding site, a cryptic epitope that lies 7–9 amino acids amino terminal to the LDV/I, and residues K169 and I181. These two residues were identified in a sieve analysis of the RV144 vaccine trial as sites of vaccine -mediated immune pressure. HIV and SIV V2 mAbs elicited by both vaccination and infection that recognize this peptide block V2-α4β7interactions. These mAbs recognize conformations absent from the β- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-α4β7interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.