Human Immunodeficiency Virus CCR5 Research Articles

Population-specific profiling of CCL3L1 copy number of the three major ethnic groups in Malaysia and the implication on HIV susceptibility.

CC chemokine ligand 3 like-1 (CCL3L1) encodes for CCL3L1 protein, which is a human immunodeficiency virus (HIV) suppressive chemokine and a potent ligand of HIV CCR5 co-receptor. CCL3L1 exhibits variation in the gene copy number (CN) and could influence HIV susceptibility through gene dosage effect. The study aims to determine the distribution of CCL3L1 CN among HIV subjects of Malay, Chinese, and Indian ethnics in Malaysia and to evaluate the impact of CCL3L1 CN on susceptibility to HIV. This study involved 182 HIV patients who attended outpatient clinics of three hospitals in Malaysia and 150 non-HIV (control) subjects. Typing of CCL3L1 CN was conducted via multiplex paralogue ratio tests (PRTs), followed by validation of the CCL3L1 CN by microsatellite analyses. Both Malay and Indian HIV subjects had the CN mode of two, while the CN mode for the Chinese was four. The CCL3L1 gene CN was found to be strongly associated with ethnicity (p<0.001) with the diverse distribution of CCL3L1 CN between the Malay (range=0-6), Chinese (range=0-9), and Indian (range=1-4) ethnic groups. CCL3L1 CN higher than and equal to the average was associated with reduced HIV susceptibility among the Malays (p<0.05). However, the negative results found for the Indian and Chinese need to be further analysed in a larger sample size.

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginally-administered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women. Currently, the lead candidate microbicide is a 28-day silicone elastomer vaginal ring releasing dapivirine (Ring-004), an experimental non-nucleoside reverse transcriptase inhibitor. The ring was tested in two pivotal Phase III clinical studies in 2016 and is currently undergoing review by the European Medicines Agency. Recently, we described a new type of silicone elastomer vaginal ring offering sustained release of the protein molecule 5P12-RANTES, a potent experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. Building on our previous work, here we report the preclinical development of a new combination vaginal ring that offers sustained release of both 5P12-RANTES and dapivirine, in which the 5P12-RANTES is incorporated into an exposed core within the ring body and the dapivirine in the sheath. In this way, in vitro release of dapivirine matches closely that for Ring-004. Also, we report the pharmacokinetic testing of this combination ring formulation in sheep, where vaginal concentrations of both drugs are maintained over 28 days at levels potentially useful for preventing HIV infection in women.

Vaginal rings with exposed cores for sustained delivery of the HIV CCR5 inhibitor 5P12-RANTES

Antiretroviral-releasing vaginal rings are at the forefront of ongoing efforts to develop microbicide-based strategies for prevention of heterosexual transmission of the human immunodeficiency virus (HIV). However, traditional ring designs are generally only useful for vaginal administration of relatively potent, lipophilic, and small molecular weight drug molecules that have sufficient permeability in the non-biodegradable silicone elastomer or thermoplastic polymers. Here, we report a novel, easy-to-manufacture ‘exposed-core’ vaginal ring that provides sustained release of the protein microbicide candidate 5P12-RANTES, an experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. In vitro release, mechanical, and stability testing demonstrated the utility and practicality of this novel ring design. In a sheep pharmacokinetic model, a ring containing two ¼-length excipient-modified silicone elastomer cores – each containing lyophilised 5P12-RANTES and exposed to the external environment by two large windows – provided sustained concentrations of 5P12-RANTES in vaginal fluid and vaginal tissue between 10 and 10,000 ng/g over 28days, at least 50 and up to 50,000 times the reported in vitro IC50 value.