In the absence of a HIV vaccine, and with inconsistent use of condoms, the AIDS pandemic continues to gather momentum. Sexual exposure is the primary route of infection with women becoming disproportionately affected. In this setting, there is an urgent need to develop new female controlled prevention technologies including microbicides. Ideally, microbicides should provide protection against HIV-1 and other common sexually transmitted infections (STIs) such as herpes simplex virus (HSV) and human papilloma virus (HPV). These products should be safe, effective, acceptable and cheap to manufacture. They should also be able to be used in both the vaginal and rectal compartments. The purpose of this grant is to use aptamer technology to generate individual candidate microbicides with activity against HIV-1, HSV-2 and HPV-16. HSV-2 and HPV-16 have been chosen because they are known to increase the risk of HIV-1 transmission (HSV-2) or are linked to the development of cervical and anal cancer (HPV-16). Aptamers are nucleic acid ligands derived from massively complex combinatorial libraries by a process of in vitro evolution, often referred to as systematic evolution of ligands by exponential enrichment (SELEX). Aptamers have the capacity to bind to important protein targets with high affinity and biological consequences including reducing viral infectivity. In this proposal we will test the following hypotheses: (1) Individual antiviral aptamers can be developed that demonstrate efficacy against HIV-1, HSV-2, and HPV-16 using in-vitro cell challenge experiments, (2) Antiviral efficacy can be demonstrated in cervico-vaginal, intestinal, and anal tissue explant systems and is not altered when aptamers are given as single agents or in combination, and (3) Combinations of antiviral aptamers can prevent infection of explant systems when multiple viruses are used in challenge experiments. The study will be undertaken by a consortium based at Oxford University (aptamer discovery), RNA-Tec (aptamer optimization and scale-up) and UCLA (tissue explant studies). ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI066734-02
Application #
7079266
Study Section
Special Emphasis Panel (ZAI1-HSD-M (M2))
Program Officer
Deal, Carolyn D
Project Start
2005-06-15
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$640,181
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Chiu, Wai Kan; Brand, Rhonda M; Camp, Danielle et al. (2017) The Safety of Multiple Flexible Sigmoidoscopies with Mucosal Biopsies in Healthy Clinical Trial Participants. AIDS Res Hum Retroviruses 33:820-826
Mufhandu, Hazel Tumelo; Alexandre, Kabamba Bankoledi; Gray, Elin Solomonovna et al. (2016) UCLA1 aptamer inhibition of human immunodeficiency virus type 1 subtype C primary isolates in macrophages and selection of resistance. Biochem Biophys Rep 7:408-414
Riddler, Sharon A; Husnik, Marla; Gorbach, Pamina M et al. (2016) Long-term follow-up of HIV seroconverters in microbicide trials - rationale, study design, and challenges in MTN-015. HIV Clin Trials 17:204-11
Lopes de Campos, Walter R; Chirwa, Nthato; London, Grace et al. (2014) HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-Gp120 aptamer. PLoS One 9:e110930
Mufhandu, Hazel T; Gray, Elin S; Madiga, Maphuti C et al. (2012) UCLA1, a synthetic derivative of a gp120 RNA aptamer, inhibits entry of human immunodeficiency virus type 1 subtype C. J Virol 86:4989-99
Moore, Michael D; Cookson, Jonathan; Coventry, Veronica K et al. (2011) Protection of HIV neutralizing aptamers against rectal and vaginal nucleases: implications for RNA-based therapeutics. J Biol Chem 286:2526-35
McGowan, Ian (2011) Rectal microbicides: can we make them and will people use them? AIDS Behav 15 Suppl 1:S66-71
Moore, M D; Bunka, D H J; Forzan, M et al. (2011) Generation of neutralizing aptamers against herpes simplex virus type 2: potential components of multivalent microbicides. J Gen Virol 92:1493-9
Rudy, Bret J; Kapogiannis, Bill G; Lally, Michelle A et al. (2010) Youth-specific considerations in the development of preexposure prophylaxis, microbicide, and vaccine research trials. J Acquir Immune Defic Syndr 54 Suppl 1:S31-42
McGowan, Ian (2010) Microbicides for HIV prevention: reality or hope? Curr Opin Infect Dis 23:26-31

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