COMBINATION OF A DRUG TARGETING THE CELL WITH A DRUG TARGETING THE VIRUS CONTROLS HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 RESISTANCE

Combinations of drugs targeting viral proteins have been used to limit or control drug resistance, which is the most important cause of trea tment failure in HIV-l-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 inhibit ion 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 mechan ism to explain this lack of rebound: although the combination of the t wo drugs did not prevent the emergence of mutant viral strains resista nt to didanosine (ddI) in these patients, the mutants were still sensi tive to standard doses of ddI in the presence of hydroxyurea. These in vivo results were consistent with our in vitro observations: HIV-1 mo lecular clones resistant to ddI were rendered sensitive to this drug ( at concentrations routinely achievable in vivo) after addition of hydr oxyurea. This phenomenon can be explained by the observation that hydr oxyurea 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 efficac y of a treatment that is well tolerated, simple, and inexpensive.