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The greatest obstacle to curing HIV-1 infection is a latent reservoir comprising resting CD4+ T cells that contain an unexpressed, replication-competent copy of the HIV-1 genome integrated into the host DNA. These latently infected cells are essentially indistinguishable from uninfected ones and therefore cannot be selectively targeted for elimination. The latent reservoir is characterized by a notable stability that explains why it is a lifelong barrier to a cure. Longitudinal studies in HIV-1–infected individuals measuring changes in the frequency of latently infected cells over time have estimated the half-life of reservoir decay to be ∼3.6 y (1, 2). At this rate, a reservoir containing 106 cells would take more than 70 y to decay naturally. Because even a single replication-competent latent virus can lead to rebound viremia, HIV-1–infected individuals must endure lifelong treatment with antiretroviral therapy (ART). The disturbing possibility that the clonal expansion of latently infected cells contributes to the stability of the latent reservoir is explored in an important paper by Simonetti et al. in PNAS (3). Current ART regimens are extremely effective and have far fewer side effects than their predecessors. The HIV treatment guidelines now recommend continuous ART for all infected individuals (4). However, variability in treatment access, the risks of inconsistent drug adherence, the unknown consequences of lifelong ART, and the unsustainable cost of lifelong treatment of all infected individuals have provided impetus to the search for a cure. The primary approach has been a “shock-and-kill” strategy in which expression of latent proviruses is induced (“shock”) by a latency reversing agent and then the infected cells are eliminated by viral cytopathic effects or by immune mechanisms (“kill”). In considering whether shock-and-kill is likely to be successful, the stability of the reservoir is germane. It is generally assumed that as long as …

Reservoir expansion by T-cell proliferation may be another barrier to curing HIV infection