HIV infection is multi-faceted and a multi-step process. The virus-induced pathogenicmechanisms are manifold and mediated through a range of positive and negative feedbackregulations of immune and physiological processes engaged in virus-host interactions. Thefundamental questions towards understanding the pathogenesis of HIV infection are nowshifting to ‘dynamic’ categories: (i) why is the HIV-immune response equilibrium finallydisrupted? (ii) can one modify the dynamic equilibrium for host benefit? (iii) can onepredict the outcome of a system perturbation via antiviral drugs or drugs modulating thehost immune response dynamics? Answering these questions requires a majorinterdisciplinary effort, and in particular, the development of novel mathematicalapproaches for a coherent quantitative description and prediction of intra-patient HIVevolution, the immunological responses to HIV infection, and the systems level homeostaticregulation of specific effector and regulatory lymphocyte populations in correlation withdisease status. Here we summarized fundamental biological features of HIV infection andcurrent mathematical modelling attempts to understand HIV pathogenesis.