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Enhanced anti-HIV efficacy of indinavir after inclusion in CD4-targeted lipid nanoparticles.

ABSTRACT: BACKGROUND:Combination drug therapy has reduced plasma HIV to undetectable levels; however, drug-sensitive virus persists in patients' lymphoid tissue. We have reported significant lymphoid tissue drug localization with indinavir-associated lipid nanoparticles (LNPs). Our current objective is to evaluate whether additional enhancement is achievable by targeting these particles to CD4-HIV host cells. METHODS:We characterized 2 peptide-coated (CD4-BP2 and CD4-BP4) drug-associated LNPs and demonstrated CD4-cell specificity. Drug-associated LNPs expressing polyethyleneglycol were exposed on HIV-2-infected cells under dynamic conditions that emulated lymph node physiology for 15, 30, and 60 minutes at concentrations from 0 to 25 ?M and evaluated for antiviral activity and cell-associated drug concentrations. The specificity of CD4-mediated enhancement of indinavir LNPs antiviral activity was evaluated by blocking with anti-CD4 antibody. RESULTS:Inclusion of CD4-binding peptides on LNPs enhanced antiviral activity for all incubation conditions, compared with control particles or soluble drug (eg, 60 minutes exposure, EC50 = 0.12-0.13 vs. 0.46 ?M for targeted nanoparticles vs. soluble drug). The CD4-BP4 peptide exhibited higher efficiency in eliciting antiviral activity than CD4-BP2-coated particles (EC50 = 7.5 ?M vs. >25 ?M at 15 minutes drug exposure). This enhancement seems to be driven by CD4 availability and cell-associated indinavir concentrations, as blocking of CD4 significantly ablated indinavir efficacy in targeted particles and indinavir concentrations reflected the observed anti-HIV activity. CONCLUSIONS:We constructed CD4-targeted LNPs that provide selective binding and efficient delivery of indinavir to CD4-HIV host cells. Inclusion of polyethyleneglycol in LNPs would minimize immune recognition of peptides. The enhancement of anti-HIV effects is effective even under limited time exposure.

SUBMITTER: Endsley AN

PROVIDER: S-EPMC3551348 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Enhanced anti-HIV efficacy of indinavir after inclusion in CD4-targeted lipid nanoparticles.

Endsley Aaron N AN Ho Rodney J Y RJ

Journal of acquired immune deficiency syndromes (1999) 20121201 4

<h4>Background</h4>Combination drug therapy has reduced plasma HIV to undetectable levels; however, drug-sensitive virus persists in patients' lymphoid tissue. We have reported significant lymphoid tissue drug localization with indinavir-associated lipid nanoparticles (LNPs). Our current objective is to evaluate whether additional enhancement is achievable by targeting these particles to CD4-HIV host cells.<h4>Methods</h4>We characterized 2 peptide-coated (CD4-BP2 and CD4-BP4) drug-associated LN ...[more]

PMID: 22743598

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Project description:UnlabelledAdoptive transfer of CD8 T cells genetically engineered to express "chimeric antigen receptors" (CARs) represents a potential approach toward an HIV infection "functional cure" whereby durable virologic suppression is sustained after discontinuation of antiretroviral therapy. We describe a novel bispecific CAR in which a CD4 segment is linked to a single-chain variable fragment of the 17b human monoclonal antibody recognizing a highly conserved CD4-induced epitope on gp120 involved in coreceptor binding. We compared a standard CD4 CAR with CD4-17b CARs where the polypeptide linker between the CD4 and 17b moieties is sufficiently long (CD4-35-17b CAR) versus too short (CD4-10-17b) to permit simultaneous binding of the two moieties to a single gp120 subunit. When transduced into a peripheral blood mononuclear cell (PBMC) or T cells thereof, all three CD4-based CARs displayed specific functional activities against HIV-1 Env-expressing target cells, including stimulation of gamma interferon (IFN-γ) release, specific target cell killing, and suppression of HIV-1 pseudovirus production. In assays of spreading infection of PBMCs with genetically diverse HIV-1 primary isolates, the CD4-10-17b CAR displayed enhanced potency compared to the CD4 CAR whereas the CD4-35-17b CAR displayed diminished potency. Importantly, both CD4-17b CARs were devoid of a major undesired activity observed with the CD4 CAR, namely, rendering the transduced CD8(+) T cells susceptible to HIV-1 infection. Likely mechanisms for the superior potency of the CD4-10-17b CAR over the CD4-35-17b CAR include the greater potential of the former to engage in the serial antigen binding required for efficient T cell activation and the ability of two CD4-10-17b molecules to simultaneously bind a single gp120 subunit.ImportanceHIV research has been energized by prospects for a cure for HIV infection or, at least, for a "functional cure" whereby antiretroviral therapy can be discontinued without virus rebound. This report describes a novel CD4-based "chimeric antigen receptor" (CAR) which, when genetically engineered into T cells, gives them the capability to selectively respond to and kill HIV-infected cells. This CAR displays enhanced features compared to previously described CD4-based CARs, namely, increased potency and avoidance of the undesired rendering of the genetically modified CD8 T cells susceptible to HIV infection. When adoptively transferred back to the individual, the genetically modified T cells will hopefully provide durable killing of infected cells and sustained virus suppression without continued antiretroviral therapy, i.e., a functional cure.

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Enhanced anti-HIV efficacy of indinavir after inclusion in CD4-targeted lipid nanoparticles.

Publications

Enhanced anti-HIV efficacy of indinavir after inclusion in CD4-targeted lipid nanoparticles.

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