Please use this identifier to cite or link to this item: http://hdl.handle.net/10451/34145
Title: New prevention and treatment strategies for HIV infection
Author: Costa, Ana Rita Ramos Diniz de Quadros e, 1988-
Advisor: Taveira, Nuno, 1964-
Pereira, J. Moniz, 1949-
Keywords: Teses de doutoramento - 2018
Defense Date: 2018
Abstract: To successfully control the global spread of HIV, it is crucial to combine effective prevention and treatment strategies. The aims of this thesis are: a) to characterize the antiviral activity of dolutegravir (DTG) against HIV-2 primary isolates; b) to develop dendrimers as topical anti-HIV-2 microbicides; c) to evaluate P3 peptide as a potential microbicide to prevent HIV transmission in women. In Chapter 2, we observed that DTG had potent activity against all raltegravir (RAL)-resistant HIV-2 isolates, indicating its usefulness as second line therapy for patients failing RAL. Mutation Q148K was responsible for high-level of resistance to RAL, however, it did not affect the activity of DTG. Importantly, we described for the first time primary resistance to DTG and we propose a new mechanism of resistance: mutations K221Q and D222K increase the activity of reverse transcriptase, thus increasing viral replication, leading to indirect resistance to DTG. In Chapter 3, we showed that dendrimers G2-S16, G2-NS16 and G3-Sh16 inhibited HIV-2 infection acting in the early steps of the HIV-2 lifecycle. They blocked HIV-2 cell-free and cell-to-cell fusion and had synergistic effects with tenofovir and RAL. Vaginal application of 3% HEC-G2-S16 gel formulation in mice did not affect mucosa integrity, further confirming that these dendrimers are promising candidates for future topical microbicides. In Chapter 4, we proved that the fusion inhibitor peptide P3 was stable and active in the presence of body fluids and at different temperatures. P3 was also active in the acidic environment of the vagina, was not be affected by the H2O2 produced by Lactobacillus and did not have spermicidal activity. Importantly, we showed that a P3-1.5% HEC gel was very effective at blocking HIV-1 infection. These findings suggest that dendrimers and P3 are good microbicide candidates to prevent vaginal HIV transmission in humans.
Description: Tese de doutoramento, Farmácia (Microbiologia), Universidade de Lisboa, Faculdade de Farmácia, 2018
URI: http://hdl.handle.net/10451/34145
Designation: Doutoramento em Farmácia
Appears in Collections:FF - Teses de Doutoramento

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