Introduction:Durable control of HIV after cessation of antiretroviral therapy is a much sought-after goal toward a “functional cure” of infection. We are developing a strategy based on targeted killing of HIV-infected cells by genetically modified T cells; when adoptively transferred back to the infected person, these cells will potentially provide the long-term control of infection needed for a functional cure.
Experimental Approach:We designed chimeric antigen receptors (CARs) with extremely high potency and breadth, and devoid of potential undesired activities. The CARs contain novel bi-specific extracellular targeting domains composed of sequences from invariant human proteins, and directed against distinct highly conserved determinants on the HIV Env glycoprotein. The targeting domains consist of human CD4 (extracellular domains 1 and 2) linked to the carbohydrate recognition domain (CRD) of a human C-type lectin, which specifically recognizes the high-mannose glycans on gp120. To test activity, T cells expressing experimental and control CARs were mixed with HIV-infected autologous PMBC; HIV suppression was assessed by measuring p24. Compared to a monospecific CD4 CAR, the bi-specific CD4-CRD CARs exhibited extraordinary potency; very similar patterns were observed with genetically diverse HIV-1 isolates. Importantly, the CRD moiety prevented the CD4 component from acting as an entry receptor and rendering transduced CD8+ T cells susceptible to HIV-1 infection.
Conclusions:The minimal immunogenicity predicted for invariant all-human sequences, coupled with likely limits on virus escape imposed by targeting 2 highly conserved Env determinants, highlight the potential of these CARs toward an HIV functional cure.
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