In this review, we discuss what persistent viremia has taught us about the biology of the HIV-1 reservoir during antiretroviral therapy (ART). We will also discuss the implications of this phenomenon for HIV-1 cure research and its clinical management.

While residual viremia (RV, 1-3 HIV-1 RNA copies/ml) can be detected in most of people on ART, some individuals experience non-suppressible viremia (NSV, > 20-50 copies/mL) despite optimal adherence. When issues of drug resistance and pharmacokinetics are ruled out, this persistent virus in plasma is the reflection of virus production from clonally expanded CD4 T cells carrying proviruses. Recent work has shown that a fraction of the proviruses source of NSV are not infectious, due to defects in the 5'-Leader sequence. However, additional viruses and host determinants of NSV are not fully understood. The study of NSV is of prime importance because it represents a challenge for the clinical care of people on ART, and it sheds light on virus-host interactions that could advance HIV-1 remission research.