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Combination of a drug targeting the cell with a drug targeting the virus controls human immunodeficiency virus type 1
1Research Institute for Genetic and Human Therapy, Georgetown University, Washington, DC 20007, USA.
Abstract:
Combinations of drugs targeting viral proteins have been used to limit or control drug resistance, which is the most important cause of treatment failure in HIV-1-infected individuals. We suggest an alternative approach, namely to target cellular proteins, which are less prone to mutations than viral proteins. Here we show that simultaneous inhibition of a cellular protein (by hydroxyurea) and a viral protein (by ddI) produces a consistent and sustained suppression of HIV-1 for as long as 40 weeks in the absence of virus rebound. We identified the mechanism to explain this lack of rebound: although the combination of the two drugs did not prevent the emergence of mutant viral strains resistant to didanosine (ddI) in these patients, the mutants were still sensitive to standard doses of ddI in the presence of hydroxyurea. These in vivo results were consistent with our in vitro observations: HIV-1 molecular clones resistant to ddI were rendered sensitive to this drug (at concentrations routinely achievable in vivo) after addition of hydroxyurea. This phenomenon can be explained by the observation that hydroxyurea decreases the level of dATP, the cellular competitor of ddI. A low level of dATP favors the incorporation of ddI, even if the viral reverse transcriptase is resistant to this nucleoside analog. This is a novel mechanism of control of resistance and it explains the efficacy of a treatment that is well tolerated, simple, and inexpensive.
Insights
Targeting cellular proteins with hydroxyurea alongside viral proteins with didanosine (ddI) offers a novel HIV-1 treatment. This combination prevents viral rebound and overcomes drug resistance by altering ddI
Area of Science:
- Virology
- Pharmacology
- Immunology
Background:
- Drug resistance is a primary cause of treatment failure in HIV-1 infections.
- Current strategies often combine drugs targeting viral proteins to mitigate resistance.
- An alternative approach involves targeting host cellular proteins, which are less susceptible to mutations.
Purpose of the Study:
- To investigate the efficacy of a combination therapy targeting both cellular and viral proteins in HIV-1 infected individuals.
- To elucidate the mechanism behind sustained viral suppression and the control of drug resistance.
Main Methods:
- Simultaneous administration of hydroxyurea (targeting a cellular protein) and didanosine (ddI, targeting a viral protein) in HIV-1 infected patients.
- Monitoring viral load and assessing the emergence of drug-resistant viral strains over 40 weeks.
- In vitro studies using HIV-1 molecular clones to confirm the mechanism of resistance modulation.
Main Results:
- The combination therapy achieved consistent and sustained suppression of HIV-1 for up to 40 weeks without viral rebound.
- Emergent didanosine-resistant viral strains remained sensitive to ddI in the presence of hydroxyurea.
- In vitro experiments confirmed that hydroxyurea restores sensitivity to ddI in resistant HIV-1 strains.
Conclusions:
- Simultaneous inhibition of cellular and viral targets represents a novel strategy for controlling HIV-1 and overcoming drug resistance.
- Hydroxyurea enhances ddI efficacy by reducing intracellular dATP levels, favoring ddI incorporation even with resistant viral reverse transcriptase.
- This well-tolerated, simple, and inexpensive treatment offers a promising approach for managing HIV-1 infection.