Similar Changes in Proviral Landscapes over 10 Years in 40 Individuals with Diverging HIV-1 Reservoir Dynamics and Viral Load Kinetics

Abstract Background People with HIV (PWH) under antiretroviral therapy (ART) and suppressed viremia usually experience a decrease in HIV-1 DNA over time, but about 25% of PWH experience an increase. Some of those PWH also experience intermittent viremia. Reasons for and potential clinical implications of HIV-1 reservoir increases remain unclear and a major concern. Methods In this study, we longitudinally characterized the proviral landscape in four distinct groups of PWH (n=40) successfully treated with ART over 10.4 years without any viral failure, presenting either an increase or decrease of total HIV-1 DNA levels and experiencing or not experiencing intermittent viremia, by IPDA (intact proviral DNA assay) and near full-length HIV-1 proviral sequencing in bulk and on single proviral level. Findings A decrease of intact proviruses was observed in all groups, independent of total HIV-1 DNA level dynamics and viral load kinetics both by IPDA and by single proviral sequencing. Genetic distances and diversities of individuals’ proviral sequences did not increase over time in any group. Although new drug resistance mutations were occasionally observed in proviral DNA, numbers did not differ significantly between the groups. Interpretation Our results show that the increase in HIV-1 DNA levels is driven by an increase of defective proviruses, also in PWH experiencing intermittent viremia. Furthermore, we did not observe evidence of evolution of the HIV-1 reservoir, regardless of HIV-1 reservoir size dynamics and viral load kinetics over a follow-up period of 10 years on ART. Nevertheless, PWH with intermittent viremia should be monitored frequently.