Similar Changes in Proviral Landscapes Over 10 Years in 40 Individuals With Diverging HIV Reservoir Dynamics and Viral Load Kinetics

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Background: People with human immunodeficiency virus type 1 (HIV-1; PWH) on antiretroviral therapy (ART) and suppressed viremia usually experience a decrease in HIV DNA over time, but about 25% experience an increase. Some also experience intermittent viremia. The reasons for and potential clinical implications of increases in the HIV reservoir remain unclear and a major concern. Methods: In this study, we longitudinally characterized the proviral landscape in 4 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 DNA levels and experiencing or not experiencing intermittent viremia, by intact proviral DNA assay and near-full-length HIV proviral sequencing in bulk and on the single proviral level. Results: A decrease in intact proviruses was observed in all groups, independent of total HIV DNA level dynamics and viral load kinetics by both intact proviral DNA assay and 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. Conclusions: Our results show that the increase in HIV DNA levels is driven by an increase in defective proviruses, also in PWH experiencing intermittent viremia. Furthermore, we did not see evidence of evolution of the HIV reservoir, regardless of HIV reservoir size dynamics and viral load kinetics over a follow-up period of 10 years with ART. Nevertheless, PWH with intermittent viremia should be monitored frequently.

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