Objectives: Recombinant Human IL-7 (rhIL-7) therapy allows reconstituting systemic and tissue-associated CD4 + T-cell populations in HIV-infected poor immunological responder (PIR) patients. However, in-vitro studies suggest that the impact of rhIL-7 treatment on HIV-DNA loads in vivo remains questionable. Design: We assessed the dynamics of circulating HIV-DNA loads in IL-7-treated HIV-infected PIR individuals. Methods: Forty-one rhIL-7-treated and 16 control participants from the INSPIRE-3 clinical trial were included. Participants received three weekly subcutaneous injections of rhIL-7. HIV-DNA was quantified by nested quantitative PCR in white blood cells sampled at D0, D28 and M3 and expressed as per milliliters and per CD4 + T-cell. Changes in HIV-DNA loads in the CD4 + compartment at M3 were confirmed on sorted CD4 + cells. Results: Together with rhIL-7-induced T-cell expansion, we observed a significant raise in both infected cell frequencies and counts during the first 28 days of follow-up. During this period, HIV-DNA load per CD4 + T-cell also increased, to a lower extent. Three months post-therapy, both the frequencies and counts of infected cells diminished in blood as compared with D28 but remained significantly higher than before IL-7 therapy. In contrast, infection frequencies strongly diminished within CD4 + cells, reaching slightly but significantly lower levels than at baseline. Conclusion: rhIL-7 treatment initially drives an expansion of HIV reservoir in PIR patients by D28. This expansion is probably not only because of infected cell proliferation, but also to possible enhanced neoinfection, despite highly active antiretroviral therapy. In contrast, subsequent reduction in HIV-DNA load per CD4 + T-cell argues for partial elimination of infected cells between D28 and M3. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.