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Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4⁺ T cell activation and HIV-1 latency reversal.

ABSTRACT: A proposed strategy to cure HIV uses latency-reversing agents (LRAs) to reactivate latent proviruses for purging HIV reservoirs. A variety of LRAs have been identified, but none has yet proven effective in reducing the reservoir size in vivo. Nanocarriers could address some major challenges by improving drug solubility and safety, providing sustained drug release, and simultaneously delivering multiple drugs to target tissues and cells. Here, we formulated hybrid nanocarriers that incorporate physicochemically diverse LRAs and target lymphatic CD4⁺ T cells. We identified one LRA combination that displayed synergistic latency reversal and low cytotoxicity in a cell model of HIV and in CD4⁺ T cells from virologically suppressed patients. Furthermore, our targeted nanocarriers selectively activated CD4⁺ T cells in nonhuman primate peripheral blood mononuclear cells as well as in murine lymph nodes, and substantially reduced local toxicity. This nanocarrier platform may enable new solutions for delivering anti-HIV agents for an HIV cure.

SUBMITTER: Cao S

PROVIDER: S-EPMC6436934 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4<sup>+</sup> T cell activation and HIV-1 latency reversal.

Cao Shijie S Slack Sarah D SD Levy Claire N CN Hughes Sean M SM Jiang Yonghou Y Yogodzinski Christopher C Roychoudhury Pavitra P Jerome Keith R KR Schiffer Joshua T JT Hladik Florian F Woodrow Kim A KA

Science advances 20190327 3

A proposed strategy to cure HIV uses latency-reversing agents (LRAs) to reactivate latent proviruses for purging HIV reservoirs. A variety of LRAs have been identified, but none has yet proven effective in reducing the reservoir size in vivo. Nanocarriers could address some major challenges by improving drug solubility and safety, providing sustained drug release, and simultaneously delivering multiple drugs to target tissues and cells. Here, we formulated hybrid nanocarriers that incorporate ph ...[more]

PMID: 30944862

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Project description:During antiretroviral therapy (ART), human immunodeficiency virus type 1 (HIV-1) persists as a latent reservoir in CD4+ T cell subsets in central memory (TCM), transitional memory (TTM), and effector memory (TEM) CD4+ T cells. We have identified differences in mechanisms underlying latency and responses to latency-reversing agents (LRAs) in ex vivo CD4+ memory T cells from virally suppressed HIV-infected individuals and in an in vitro primary cell model of HIV-1 latency. Our ex vivo and in vitro results demonstrate the association of transcriptional pathways of T cell differentiation, acquisition of effector function, and cell cycle entry in response to LRAs. Analyses of memory cell subsets showed that effector memory pathways and cell surface markers of activation and proliferation in the TEM subset are predictive of higher frequencies of cells carrying an inducible reservoir. Transcriptional profiling also demonstrated that the epigenetic machinery (known to control latency and reactivation) in the TEM subset is associated with frequencies of cells with HIV-integrated DNA and inducible HIV multispliced RNA. TCM cells were triggered to differentiate into TEM cells when they were exposed to LRAs, and this increase of TEM subset frequencies upon LRA stimulation was positively associated with higher numbers of p24+ cells. Together, these data highlight differences in underlying biological latency control in different memory CD4+ T cell subsets which harbor latent HIV in vivo and support a role for differentiation into a TEM phenotype in facilitating latency reversal.IMPORTANCE By performing phenotypic analysis of latency reversal in CD4+ T cells from virally suppressed individuals, we identify the TEM subset as the largest contributor to the inducible HIV reservoir. Differential responses of memory CD4+ T cell subsets to latency-reversing agents (LRAs) demonstrate that HIV gene expression is associated with heightened expression of transcriptional pathways associated with differentiation, acquisition of effector function, and cell cycle entry. In vitro modeling of the latent HIV reservoir in memory CD4+ T cell subsets identify LRAs that reverse latency with ranges of efficiency and specificity. We found that therapeutic induction of latency reversal is associated with upregulation of identical sets of TEM-associated genes and cell surface markers shown to be associated with latency reversal in our ex vivo and in vitro models. Together, these data support the idea that the effector memory phenotype supports HIV latency reversal in CD4+ T cells.

Dataset Information

Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4⁺ T cell activation and HIV-1 latency reversal.

Publications

Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4<sup>+</sup> T cell activation and HIV-1 latency reversal.

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Dataset Information

Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4+ T cell activation and HIV-1 latency reversal.

Publications

Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4<sup>+</sup> T cell activation and HIV-1 latency reversal.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4⁺ T cell activation and HIV-1 latency reversal.