A Novel DARPins Strategy for Combating HIV
Council researchers are exploring the use of DARPins to limit HIV replication in vitro and provide the first tests of this novel antiviral strategy in vivo.
A particular type of white blood cell, the dendritic cell (DC), is critical for the activation of immune responses against infectious agents. However, HIV exploits DCs to promote virus growth, while also subverting the DC-induced immunity needed to control infection. Therefore, in order to curb HIV spread, it is critical to identify strategies that impede DC-driven virus growth, while not interfering with or perhaps boosting DC-mediated immune responses.
Our collaborators recently identified a novel approach to inhibiting HIV infection using the Designed Ankyrin Repeat Protein (DARPin) technology. CD4-specific DARPins that they generated are highly specific and efficiently prevent in vitro infection with a wide range of HIV isolates without interfering with basic cellular functions. DARPins possess unique characteristics exhibiting exceptional stability and specificity, and cost little to produce. We recently demonstrated that CD4-specific DARPins efficiently bind CD4+ T cells, DCs, and monocytes in vivo after intravenous injection into monkeys (Pugach et al., PLoS ONE 5(8):e12455). This provides direct evidence that DARPins can bind their intended targets in vivo.
DARPins represent a novel strategy to limit HIV spread. Combining their stability, specificity, and low cost with their ability to prevent HIV infection represents a promising strategy to explore for the prevention of HIV spread. Future strategies will be aimed at developing new DARPins to more broadly target HIV–host interactions. With our collaborators we are working on identifying HIV envelope-specific DARPins that will be tested for their ability to prevent mucosal transmission of HIV. In parallel, we can utilize these DARPins to dissect the biology of DC-driven infection in order to better understand early events in HIV infection.
See also: Robbiani laboratory
Conformation-dependent recognition of HIV gp120 by designed ankyrin repeat proteins provides access to novel HIV entry inhibitors (abstract) (HTML)
Mann,Axel; Friedrich,Nikolas; Krarup,Anders; Weber,Jacqueline; Stiegeler,Emanuel; Dreier,Birgit; Pugach,Pavel; Robbiani,Melissa; Riedel,Tina; Moehle,Kerstin; Robinson,John A.; Rusert,Peter; Pluckthun,Andreas; Trkola,Alexandra
Journal of Virology 87(10): 5868-5881
Publication date: 2013
In vivo binding and retention of CD4-Specific DARPin 57.2 in macaques (abstract) (PDF)
Pugach,Pavel; Krarup,Anders; Gettie,Agegnehu; Kuroda,Marcelo; Blanchard,James; Piatak Jr.,Michael; Lifson,Jeffrey D.; Trkola,Alexandra; Robbiani,Melissa
PLoS ONE 5(8): e12455 (1)-e12455 (9)
Publication date: 2010
CD4-specific Designed Ankyrin Repeat Proteins are novel potent HIV entry inhibitors with unique characteristics (abstract) (PDF)
Schweizer,Andreas; Rusert,Peter; Berlinger,Livia; Ruprecht,Claudia R.; Mann,Axel; Corthesy,Stephanie; Turville,Stuart G.; Aravantinou,Meropi; Fischer,Marek; Robbiani,Melissa; Amstutz,Patrick; Trkola,Alexandra
PLoS Pathogens 4(7): e1000109-
Publication date: 2008
Location: Switzerland, United States
HIV and AIDS
HIV biomedical research
Duration: 7/2008 - 6/2014
Agegnehu Gettie (Aaron Diamond AIDS Research Center)
Alexandra Trkola (University of Zurich)
James Blanchard (Tulane National Primate Research Center)
Jeffrey Lifson (National Cancer Institute)
Julian Bess (National Cancer Institute)
Michael Piatak (National Cancer Institute)
National Institutes of Health
The Campbell Foundation