In the absence of antiretroviral treatment, HIV-1 establishes a chronic infection that is marked by the progressive depletion of CD4+ T-cells. Of all the viral infections that afflict humans, only HIV-1 is known to cause such profound and inevitable CD4+ T-cell loss. Yet the mechanisms by which this depletion arises remain a matter of controversy. This review will address what is exceptional about HIV-1 infection that sets it apart from other viral infections. Recent attempts to understand HIV-1 pathogenesis have set aside the view that CD4+ T-cell depletion is effected solely by HIV-1-mediated killing in favor of a more complete explanation that also includes T-cell dynamics and, more specifically, chronic immune activation as a central factor in HIV-1 pathogenesis. This review will address the contributions of the virus itself, T-cell activation, T-cell reconstitution, and target cell availability, in the shaping of these dynamics during the disease. The acute and chronic phases of HIV-1 disease will be addressed separately, as they manifest distinctive viral and T-cell dynamics and are the setting for different pathogenic mechanisms. New observations suggest that considerable damage is caused to the immune system during the acute phase of the infection, resulting in a substantial early lymphopenia of the memory CD4+ T-cell pool that may have a profound impact on the subsequent course of the infection. Other observations reveal a strategy in which HIV-1 induces immune activation to generate replaceable targets, activated CD4+ T-cells, which sustain its replication. Although the majority of these target cells are short-lived by physiological design, chronic activation can indirectly strain homeostasis of the naive and resting memory T-cell pools in a number of ways. In the context of virus-induced damage to the lymphoid tissues and cells that maintain these T-cell pools, and physiological limitations in peripheral CD4+ T-cell renewal, this homeostatic strain leads to the progressive depletion of the more vulnerable CD4+ T-cell pools.