Preventing virological failure following HIV treatment remains a difficult task that is further complicated by the emergence of drug resistance. We have developed a mathematical model able to explain and predict HIV virological outcomes for various compounds and patients' drug intake patterns. Compared to current approaches, this model considers, altogether, drug penetration into lymph nodes, a refined adherence representation accounting for the propensity for long drug holidays, population pharmacokinetic and pharmacodynamic variability, drug interaction, and crossresistance. In silico results are consistent with clinical observations for treatment with efavirenz, efavirenz in association with tenofovir DF and emtricitabine, or boosted darunavir. Our findings indicate that limited lymph node drug penetration can account for a large proportion of cases of virological failure and drug resistance. Since a limited amount of information is required by the model, it can be of use in the process of drug discovery and to guide clinical treatment strategies.