Twelve years after the introduction of potent combination antiretroviral therapy (ART) for HIV infection, it remains unclear whether suppressive ART that drives plasma viral RNA below 50 copies/mL also results in complete inhibition of HIV replication. The issue is not merely of academic interest; resolving this controversy could help guide future strategies aimed at eradicating HIV and inform novel management approaches such as induction-maintenance. In this issue of the Journal, Chun and colleagues [1] uncover new evidence for persistent, cryptic HIV replication by showing that cells in gut-associated lymphoid tissues (GALT) are disproportionately infected with HIV, despite the fact that the study patients had been receiving continuous suppressive therapy for up to 10 years. These findings raise new questions, such as:(1) how lowlevel replication in the gut, if it occurs, might qualitatively differ from replication at other sites;(2) why replication persists despite potent antiretroviral therapy;(3) how therapies could better inhibit HIV replication in the gut; and (4) whether further reductions of HIV replication in the gut will translate into new clinical benefits.

Within weeks of starting ART, the plasma viral RNA level often drops to 50 copies/mL, the level of detection of most commercial assays. With the use of more sensitive assays, it is possible to show that HIV RNA often persists at low levels in the peripheral blood [2–5]. Although some studies show a slow decline of plasma HIV RNA levels over several years, most studies suggest that the plasma HIV RNA level reaches an equilibrium level after 1–2 years of treatment [5, 6]. It is unclear whether this residual viral expression in patients who receive ART reflects the incomplete suppression of ongoing viral replication, intermittent production from stable reservoirs of chronically infected cells, or viral expression from self-limited reactivation of latently infected cells. HIV DNA is readily detectable in peripheral blood mononuclear cells (PBMCs), a subset of which constitutes a reservoir of latently infected, resting memory CD4 lymphocytes whose stability has been attributed to varying degrees of replenishment by ongoing replication [7–12]. These latently infected cells likely represent a barrier to eradication that is distinct from incomplete inhibition of viral replication.