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A number studies are currently underway to develop new drugs aimed at reducing the HIV reservoir or achieving ART-free control of HIV infection. Many markers of HIV reservoirs have been proposed, each one having a different meaning. Total HIV DNA dynamics during the course of HIV infection and its predictive value are now well known. This marker allowed to estimate the size of HIV reservoir at different stages of HIV infection in blood, cell subsets and tissues. Therefore, the purpose of this review is timely and relevant, with the objective to discuss how total HIV DNA might be helpful in the clinical settings.Among the markers, it appears that HIV DNA is the most well studied, and recent articles confirmed that this marker is easy to use and is precise, specific, practical, robust and reproducible. All these characteristics correspond to what is expected from a helpful clinical marker.HIV DNA level could be considered as a global marker, and it is usually included in current clinical studies to describe the persistence and dynamics of the HIV reservoir, mainly in treated patients. HIV DNA might be helpful in designing clinical trials and personalized medication for HIV patients in the future.