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Development of an HIV-1 Rev-dependent post-transcriptional regulatory system as a tool for selective therapeutic elimination of latently infected cells
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Orientador(es)
Resumo(s)
Latent viral reservoirs represent the major challenge in curing HIV-1 infection. Despite considerable
progress through the introduction of antiretroviral therapy, complete viral eradication remains elusive
due to the presence of latently infected cells. Treatment interruptions often result in viral rebound,
emphasizing the urgency for innovative antiretroviral strategies. Targeting the Rev protein, which plays
a crucial role in HIV-1 gene expression, holds substantial promise. Rev binds to a Rev Response Element
(RRE) and mediates the nuclear export of unprocessed viral RNAs, thereby enabling the production of
the viral progeny.
This study aimed to develop a Rev-dependent switch system for the targeted elimination of latently
infected cells. To achieve this, reporter vectors were engineered with an RRE and IRES sequence within
the intronic element of a splicing unit. The underlying hypothesis states that in the presence of Rev, the
RRE within the intronic element would support the nuclear export of unspliced mRNAs, thereby
establishing a functional switch system enabling the expression of a second coding region. Despite
successfully generating and validating a primary construct containing a splicing unit coupled to an RRE,
the system did not respond to the accumulation of Rev as expected. Instead, the presence of Rev
exhibited a negative influence on gene expression and failed to support the cytoplasmic accumulation
of unspliced mRNA. The addition of the IRES into the reporter vector yielded a different result: a
reduction of transcript production was not observed in the presence of Rev, suggesting that the context
in which an RNA sequence is integrated affects how it influences gene expression. While the outcomes
diverged from expectations, potentially due to Rev-RRE complex formation inefficiencies and
experimental limitations, addressing these challenges could lay the foundation for innovative therapeutic
strategies for the effective eradication of latently infected cells among HIV-1 infected individuals.
Descrição
Tese de Mestrado, Bioquímica e Biomedicina, 2024, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Células latentes Proteína Rev Exportação nuclear Terapia génica Teses de mestrado - 2024