Poster Presentation Lorne Infection and Immunity 2023

HIV-1 infected macrophages can be made susceptible to Antibody Dependent Cellular Cytotoxicity by small molecule CD4 mimetics (#153)

Annemarie Laumaea 1 2 3 , Lorie Marchitto 1 2 , Shilei Ding 1 , Guillaume Beaudoin-Bussières 1 2 , Jérémie Prévost 1 2 , Romain Gasser 1 2 , Debashree Chatterjee 1 , Gabrielle Gendron-Lepage 1 , Halima Medjahed 1 , Hung-Ching Chen 4 , Haitao Ding 5 , John Kappes 5 , Beatrice Hahn 4 , Frank Kirchhoff 6 , Jonathan Richard 1 2 , Ralf Duerr 7 , Andrés Finzi 1 2
  1. Centre de Recherche du CHUM, Montréal, Québec, Canada
  2. Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada
  3. Global Health and Diagnostics Development Laboratory, Burnet Insitute, Melbourne, VIC, Australia
  4. University of Pennsylvania, Philadelphia, PA, USA
  5. University of Alabama, Birmingham, Alabama, USA
  6. Ulm University, Ulm, Germany
  7. New York University, New York, USA

HIV evolved mechanisms to evade host immune responses allowing the persistence of the latent reservoir. Effective targeting of the HIV reservoir is the focus of intense cure research. HIV-1 envelope (Env) conformation determines the susceptibility of infected CD4+ T cells to antibody-dependent cellular cytotoxicity (ADCC). Upon interaction with CD4, Env adopts more “open” conformations, exposing ADCC epitopes. HIV-1 limits Env-CD4 interaction and protects infected cells against ADCC by downregulating CD4 via Nef, Vpu, and Env. Limited data exist, however, of the role of these proteins in downmodulating CD4 on infected macrophages and how this impacts Env conformation. Furthermore, while small molecule CD4mimetic (CD4mc) have been shown to be effective at exposing ADCC epitopes on the surface of infected CD4+T cells, limited data exists as to the effectiveness of CD4mc for exposing vulnerable Env epitopes on HIV infected macrophages and its potential for targeting the myeloid reservoir. While Nef, Vpu, and Env are all required to efficiently downregulate CD4 on infected CD4+ T cells, we show here that any one of these proteins is sufficient to downmodulate most CD4 from the surface of infected macrophages. Consistent with this finding, Nef and Vpu have a lesser impact on Env conformation and ADCC sensitivity in infected macrophages compared with CD4+ T cells. However, treatment of infected macrophages with small CD4 mimetics exposes vulnerable CD4-induced Env epitopes and sensitizes them to ADCC.

  1. https://www.sciencedirect.com/science/article/pii/S2211124722018873?via%3Dihub
  2. Laumaea A, Marchitto L, Beaudoin Bussieres G, Ding S, Gasser R, Chatterjee D, Gendron-Lepage G, Medjahed H, Chen H, Smith III AB, Ding H, Kappes JC, Hahn BH, Kirchoff F, Richard J, Duerr R, Finzi A. 2023 Small CD4 mimetics sensitize HIV-1-infected macrophages to antibody-dependent cellular cytotoxicity. Cell Reports. 42(1):111983 https://doi.org/10.1016/j.celrep.2022.111983