We analyse mathematical models comparing the in vivo dynamics of macrophage-and T cell infection by HIV. Experiments suggest that HIV can only replicate in activated T cells whereas cell activation may not be required for successful replication in macrophages. These assumptions lead to fundamentally different conditions required to establish a persistent infection in the two cell types. While persistent replication in macrophages is achieved if the basic reproductive ratio of the virus, R 0 , exceeds unity, the establishment of T cell infection may depend on a complex balance between host and viral parameters as well as initial conditions. More specifically, the replication rate of HIV needs to lie above a threshold level and the immune responsiveness of the host below a certain threshold for persistent T cell infection to be possible. In addition, initial virus load has to be intermediate and the initial abundance of CTLs low. Mathematical models predict that macrophage infection may be essential for the successful establishment of HIV in the primary phase of the infection. Acting as a reservoir, they allow the virus to evolve towards increased replication kinetics as well as away from immune recognition, thus paving the way for the rise of exclusively T cell tropic strains using the CXCR4-coreceptor.