Implant delivering hydroxychloroquine attenuates vaginal T lymphocyte activation and inflammation

Abstract

Evidence suggests that women who are naturally resistant to HIV infection exhibit low baseline immune activation at the female genital tract (FGT). This "immune quiescent" state is associated with lower expression of T-cell activation markers, reduced levels of gene transcription and pro-inflammatory cytokine or chemokine production involved in HIV infection while maintaining an intact immune response against pathogens. Therefore, if this unique immune quiescent state can be pharmacologically induced locally, it will provide an excellent women-oriented strategy against HIV infection To our knowledge, this is the first research article evaluating in vivo, an innovative trackable implant that can provide controlled delivery of hydroxychloroquine (HCQ) to successfully attenuate vaginal T lymphocyte activation and inflammation in a rabbit model as a potential strategy to induce an "immune quiescent" state within the FGT for the prevention of HIV infection. This biocompatible implant can deliver HCQ above therapeutic concentrations in a controlled manner, reduce submucosal immune cell recruitment, improve mucosal epithelium integrity, decrease protein and gene expression of T-cell activation markers, and attenuate the induction of key pro-inflammatory mediators. Our results suggest that microbicides designed to maintain a low level of immune activation at the FGT may offer a promising new strategy for reducing HIV infection.

Current State of Microbicide Development

“…Our group recently developed a polyurethane vaginal implant delivering the immunomodulatory drug hydroxychloroquine (HCQ) within the vaginal tract of rabbits. Our results showed that the implant was capable of attenuating pro‐inflammatory mediator production and decrease gene expression of CCR5 and CD69 in isolated vaginal mucosal T cells even after challenge with the surfactant nonoxynol‐9 . A recently published study by Lajoie et al ., presents a clinical trial on low‐risk HIV seronegative women from Nairobi (Kenya) taking either HCQ or acetylsalicylic acid orally for 6 weeks.…”

“…Our results showed that the implant was capable of attenuating pro-inflammatory mediator production and decrease gene expression of CCR5 and CD69 in isolated vaginal mucosal T cells even after challenge with the surfactant nonoxynol-9. 19 A recently published study by Lajoie et al, 13 presents a clinical trial on low-risk HIV seronegative women from Nairobi (Kenya) taking either HCQ or acetylsalicylic acid orally for 6 weeks. This study showed that low-dose oral HCQ reduced systemic immune activation and oral acetylsalicylic acid is capable of reducing systemic and mucosal activated immune cells.…”

Novos sistemas de delivery, uso tecnológico e reposicionamento da cloroquina e hidroxicloroquina: Uma revisão integrativa

“…Com isso foram desenvolvidos diferentes dispositivos de liberação controlada de HCQ intravaginal, de maneira a reduzir o recrutamento de células imunes submucosas, melhorar a integridade do epitélio da mucosa, diminuir a expressão de proteínas e genes de marcadores de ativação de células T e atenuar a indução de mediadores pró-inflamatórios chaves. Ambos os sistemas podem ser adequados para a prevenção da transmissão do HIV e outras infecções sexualmente transmissíveis (Chen et al, 2014(Chen et al, , 2018.…”

Repurposing of well-known medications as antivirals: hydroxychloroquine and chloroquine – from HIV-1 infection to COVID-19

“…A biocompatible vaginal implant system of HCQ capable of prolonged medication release also tried in rabbits. It attenuated the protein expression of the T-cell activation marker RLA-DR (rabbit equivalent of human HLA-DR) and mRNA expression of CCR5 and CD69 on vaginal mucosal T lymphocytes [15]. HCQ-Loaded Polyurethane Intravaginal Rings also used for the prevention of HIV transmission without significant negative effect on vaginal microflora specially Lactobacilli in an in vitro study [16].…”