Work

Assessing antiretroviral drug (ARV) bioavailability in HIV tissue reservoirs using in vitro and in vivo pharmacokinetic (PK) studies with human primary lymphoid endothelial cells and mice

Year: 2017

Type: article

Abstract: Background: Persistent latent HIV-infected cells capable of producing infectious virus are the primary obstacle to curing HIV-1 infection.They are rare and difficult to target, making their elimination challenging.The development of treatments to cure HIV is hampered by the lack of latency models which recapitulate the in vivo activation and elimination of latent infected cells from patients.Methods: We developed a novel pre-clinical model to evaluate in vivo strategies to eliminate reactivated primary latent infected cells (huPAT-LAT mice).Immunodeficient NSG mice were intrasplenically injected with PBMCs (30 x 10 6 cells) from a leukapheresed HIVinfected donor containing latent HIV-infected CD4+ T cells (~10 IUPM by QVOA), virally suppressed by cART (<50 copies/ml) for 8 years.To maximize latent cell-activation, we co-injected irradiated allogeneic cells.We investigated whether broadly neutralizing antibodies (bNAbs) could reduce the latent reservoir by mobilizing antibody dependent cellular cytotoxicity (ADCC).huPAT-LAT mice were treated with one dose of bNAb 10-1074 or 10-1074 whose Fc domain contains a GRLR mutation (10-1074-GRLR) to reduce FcgR binding and ADCC activity.We bled the huPAT-LAT mice weekly and measured plasma viremia by qPCR and 10-1074 levels by ELISA.After 5 weeks, spleens were harvested and viral DNA and RNA were quantified by qPCR.Results: Viremia (average >10 5 copies/ml) was detected in all huPAT-LAT mice 1 week after PBMC injection, which persisted until sacrifice 4 weeks later.Viremia was completely suppressed in all of the 10-1074-treated hu-PAT-LAT mice for at least two weeks.Three weeks after 10-1074 injection, viremia was detected in some 10-1074-treated mice while other 10-1074-treated mice displayed further delay in the onset of the viremia and/or reduction in the amplitude of the viremia.huPat-Lat Mice treated with 10-1074-GRLR displayed more rapid onset of viremia than 10-1074-treated mice, supporting the role of Fc-mediated ADCC in reducing the viral reservoir, which was further bolstered by sequence analysis of plasma virus.Conclusions: We developed a new pre-clinical humanized mouse model that enabled us to demonstrate that bNAb-mediated in vivo elimination of reactivated latent HIV-infected cells from an HIVinfected patient and can be used to evaluate the efficacy of other HIV cure treatments.PP 3.

Source: Journal of Virus Eradication

DOI: 10.1016/s2055-6640(20)30598-7