HIV 1 fusion/entry inhibitors in tissue models

Shattock, Robin

Abstract

The potential role of microbicides in preventing the mucosal transmission of HIV-l has been clearly identified. However, rigorous pre-clinical evaluation of candidate microbicides is essential to the selection of the best compounds for clinical trials. While mononuclear cell cultures and animal models may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately model events that occur in human mucosal tissue. A comprehensive program for preclinical development of microbicide candidates, therefore, requires that information be accrued from several different model systems. Dr Shattock's group has established human mucosal explant cultures as a model system for the evaluation of potential microbicides and has already used them to assess the properties of microbicide that are currently entering Phase II and III clinical trials. Such explants are highly susceptible to HIV-1 infection in vitro. Cells present within the explants represent the immune population first exposed to HIV-l during sexual transmission in terms of their phenotype (e.g., co-receptor expression), state of activation an anatomical location. Thus, as a model, it directly reflects what happens during mucosal challenge of human with HIV-1. The goal of this Research Project is the evaluation of specific inhibitors of HIV-1 attachment, fusion and entry (AFE inhibitors) for their potential as mucosal microbicides to prevent sexual transmission of HIV-1 infection.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Research Program Projects (P01)
• Project #: 1P01AI052048-01
• Application #: 6548521
• Study Section: Special Emphasis Panel (ZHD1)
• Project Start: 2001-09-30
• Project End: 2005-09-29
• Support Year: 1
• Fiscal Year: 2001

Institution

• Name: Weill Medical College of Cornell University
• DUNS #: 201373169
• City: New York
• State: NY
• Country: United States
• Zip Code: 10065

Publications

Frank, Ines; Robbiani, Melissa (2011) Attachment and fusion inhibitors potently prevent dendritic cell-driven HIV infection. J Acquir Immune Defic Syndr 56:204-12

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

Veazey, Ronald S (2008) Microbicide safety/efficacy studies in animals: macaques and small animal models. Curr Opin HIV AIDS 3:567-73

Turville, Stuart G; Aravantinou, Meropi; Stossel, Hella et al. (2008) Resolution of de novo HIV production and trafficking in immature dendritic cells. Nat Methods 5:75-85

Hu, Qinxue; Younson, Justine; Griffin, George E et al. (2006) Pertussis toxin and its binding unit inhibit HIV-1 infection of human cervical tissue and macrophages involving a CD14 pathway. J Infect Dis 194:1547-56

Teleshova, N; Kenney, J; Robbiani, M (2006) Dendritic cells and HIV infection: activating dendritic cells to boost immunity. Adv Dent Res 19:36-41

Morcock, David R; Thomas, James A; Gagliardi, Tracy D et al. (2005) Elimination of retroviral infectivity by N-ethylmaleimide with preservation of functional envelope glycoproteins. J Virol 79:1533-42

Cilliers, Tonie; Willey, Samantha; Sullivan, W Mathew et al. (2005) Use of alternate coreceptors on primary cells by two HIV-1 isolates. Virology 339:136-44

Hu, Qinxue; Napier, Kelby B; Trent, John O et al. (2005) Restricted variable residues in the C-terminal segment of HIV-1 V3 loop regulate the molecular anatomy of CCR5 utilization. J Mol Biol 350:699-712

Turville, Stuart G; Santos, John J; Frank, Ines et al. (2004) Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells. Blood 103:2170-9