Oral pre-exposure prophylaxis for HIV prevention.
ABSTRACT In the absence of an effective vaccine, HIV continues to spread worldwide, emphasizing the need for new biomedical interventions to limit its transmission. Appreciation of the challenges that HIV has to face to initiate an infection mucosally has spurred interest in evaluating the use of antiretroviral drugs to prevent infection. Recent animal studies using macaques or humanized mice models of mucosal transmission of SIV or HIV have shown that daily or intermittent pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) can exploit early virus vulnerabilities and effectively prevent establishment of infection. These preclinical findings have fueled interest in evaluating the safety and efficacy of PrEP in humans. We provide an overview of the rationale behind PrEP and discuss the next steps in PrEP research, including the need to better define the ability of current drugs to reach and accumulate in mucosal tissues and protect cells that are primary targets during early HIV infection.
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ABSTRACT: The objective of this investigation was to develop a thermosensitive vaginal gel containing raltegravir+efavirenz loaded PLGA nanoparticles (RAL-EFV-NPs) for pre-exposure prophylaxis of HIV. RAL-EFV-NPs were fabricated using a modified emulsion-solvent evaporation method and characterized for size and zeta potential. The average size and surface charge of RAL-EFV-NP were 81.8±6.4nm and -23.18±7.18mV respectively. The average encapsulation efficiency of raltegravir and efavirenz was 55.5% and 98.2% respectively. Thermosensitive vaginal gel containing RAL-EFV-NPs was successfully prepared using a combination of Pluronic F127 (20% w/v) and Pluronic F68 (1% w/v). Incorporation RAL-EFV-NPs in the gel did not result in nanoparticle aggregation and RAL-EFV-NPs containing gel showed thermogelation at 32.5°C. The RAL-EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC(90) of RAL-EFV-NPs was lower than raltegravir+efavirenz (RAL-EFV) solution but did not reach significance. Compared to control HeLa cells without any treatment, RAL-EFV-NPs or blank gel were not cytotoxic for 14days in vitro. The intracellular levels of efavirenz in RAL-EFV-NPs treated HeLa cells were above the EC(90) for 14days whereas raltegravir intracellular concentrations were eliminated within 6days. Transwell experiments of NPs-in-gel demonstrated rapid transfer of fluorescent nanoparticles from the gel and uptake in HeLa cells within 30min. These data demonstrate the potential of antiretroviral NP-embedded vagina gels for long-term vaginal pre-exposure prophylaxis of heterosexual HIV-1 transmission.Antiviral research 10/2012; 96(3). DOI:10.1016/j.antiviral.2012.09.015 · 3.43 Impact Factor
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ABSTRACT: An HIV vaccine capable of providing sterilizing immunity from vaginal infection would reduce the spread of HIV to women. Unfortunately, only one of the four HIV-1 vaccine clinical trials has demonstrated any level of protection (31%) against HIV-1 transmission. Additionally, only one topical microbicide clinical trial has reported an overall reduction in HIV transmission (39%). Developing even more effective vaccines and microbicides will require a better understanding of the key events involved in HIV infection and dissemination at the site of exposure. Novel immunodeficient mice capable of being systemically reconstituted with human hematopoietic stem cells have provided new systems where HIV transmission studies can be performed. Specifically, a humanized mouse model of vaginal HIV transmission has been developed that utilizes the humanized bone marrow-liver-thymus (BLT) mouse. The female reproductive tract (FRT) of humanized BLT mice is reconstituted with functional human immune cells rendering them susceptible to vaginal HIV-1 infection. In this review we focus on four aspects of BLT mice for the study of vaginal HIV-1 transmission: (1) we discuss methods for creating humanized BLT mice and their reconstitution with human hematopoietic cells, (2) we describe reconstitution of the BLT mouse FRT with human immune cells, (3) we highlight the work done regarding vaginal HIV-1 transmission and (4) we summarize the efficacy of systemic pre-exposure prophylaxis (PrEP) to prevent vaginal HIV-1 transmission in BLT mice. BLT mice are a highly relevant small animal model for studying vaginal HIV-1 transmission, prevention and therapy.Journal of Reproductive Immunology 03/2011; 88(2):195-203. DOI:10.1016/j.jri.2010.11.005 · 2.37 Impact Factor
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ABSTRACT: Pre-exposure prophylaxis (PrEP) with daily Truvada [a combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)] is a novel HIV prevention strategy recently found to prevent HIV transmission among men who have sex with men and heterosexual couples. Acute infection in adherent persons who fail PrEP will inevitably occur under concurrent antiretroviral therapy, thus raising questions regarding the potential impact of PrEP on early viral dynamics. We investigated viral evolution dynamics in a macaque model of PrEP consisting of repeated rectal exposures to SHIV162P3 in the presence of PrEP. Four macaques were infected during daily or intermittent PrEP with FTC or FTC/TDF, and five were untreated controls. SHIV env sequence evolution was monitored by single genome amplification with phylogenetic and sequence analysis. Mean nucleotide divergence from transmitted founder viruses calculated 17 weeks (range = 12-20) post peak viremia was significantly lower in PrEP failures than in control animals (7.2 × 10-3 compared to 1.6 × 10-2 nucleotide substitutions per site per year, respectively, p < 0.0001). Mean virus diversity was also lower in PrEP failures after 17 weeks (0.13% vs. 0.53% in controls, p < 0.0001). Our results in a macaque model of acute HIV infection suggest that infection during PrEP limits early virus evolution likely because of a direct antiviral effect of PrEP and/or reduced target cell availability. Reduced virus diversification during early infection might enhance immune control by slowing the selection of escape mutants.Retrovirology 05/2012; 9:40. DOI:10.1186/1742-4690-9-40 · 4.77 Impact Factor