The use of drug combinations has revolutionized the treatment of HIV but there is no equivalent combination product that exists for prevention, particularly for topical HIV prevention. Strategies to combine chemically incompatible agents may facilitate the discovery of unique drug-drug activities, particularly unexplored combination drug synergy. We fabricated two types of nanoparticles, each loaded with a single antiretroviral (ARV) that acts on a specific step of the viral replication cycle. Here we show unique combination drug activities mediated by our polymeric delivery systems when combined with free tenofovir (TFV).
Abstract We previously observed limited cross-reactive T cell responses in two HIV-1-superinfected injection drug users (IDUs) before superinfection [Ramos A, et al.: J Virol 2002;76(15):7444-7452]. To elucidate the role of such responses in superinfection we examined cross-reactive T cell responses in IDUs infected with a single HIV-1 subtype. In this study, IFN-gamma ELISPOT assays were performed using recombinant vaccinia constructs and peripheral blood mononuclear cells (PBMCs) from 43 IDUs singly infected with CRF01_AE or B from the same cohort as the superinfected IDUs. PBMCs were from time points corresponding to pre- (early) or post- (late) superinfection in the superinfected IDUs. We observed that most singly infected IDUs had cross-reactivity in samples from early (84% of CRF01_AE and 78% of B-infected IDUs) and late (96% of CRF_01AE and 77% of B-infected IDUs) time points. Frequent homologous reactivity at early (67% of CRF-01AE and 100% of B) and late (84% of CRF01_AE-infected and 100% of B-infected IDUs) time points was also observed. Cross-reactive responses were predominantly to Pol and were broader and higher in CRF01_AE than in B-infected IDUs (medians of 825 vs. 90 and 585 vs. 60 spot-forming units/10(6) PBMCs at early and late time points, respectively). Our results show that cross-reactive responses were more prevalent with greater height and breadth in singly infected IDUs than previously observed in corresponding collection time points of superinfected IDU. Thus, low or absent cross-reactivity may have contributed to the previously observed superinfections. These data are relevant for understanding superinfection and improving vaccine design.
Multipurpose prevention technologies (MPTs) that simultaneously prevent sexually transmitted infections (STIs) and unintended pregnancy are a global health priority. Combining chemical and physical barriers offers the greatest potential to design effective MPTs, but integrating both functional modalities into a single device has been challenging. Here we show that drug-eluting fiber meshes designed for topical drug delivery can function as a combination chemical and physical barrier MPT. Using FDA-approved polymers, we fabricated nanofiber meshes with tunable fiber size and controlled degradation kinetics that facilitate simultaneous release of multiple agents against HIV-1, HSV-2, and sperm. We observed that drug-loaded meshes inhibited HIV-1 infection in vitro and physically obstructed sperm penetration. Furthermore, we report on a previously unknown activity of glycerol monolaurate (GML) to potently inhibit sperm motility and viability. The application of drug-eluting nanofibers for HIV-1 prevention and sperm inhibition may serve as an innovative platform technology for drug delivery to the lower female reproductive tract.
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