Despite the efficient reduction of the HIV replication, the administration of combination antiretroviral therapy (c-ART) is not systematically accompanied by the restoration of the peripheral T CD4+ lymphocyte compartment. The life expectancy and quality are severely impacted in individuals with immunological failure. Together with peripheral abnormalities, an alteration of CD34+ hematopoietic progenitor may explain the frequency of the cytopenia observed in the latest stages of the disease. While a direct infection of CD34+ progenitors is thought to be extremely rare, quantitative studies performed in vitro have highlighted the impairment of the differentiation potential of these cells.We selected and matched individuals infected with HIV presenting extremely opposite immunological profile in response to c-ART as well as non-infected donors. The Immune Responders (IR) and Immune Non Responders (INR) treated since more than 8 years, presented similar characteristics for each parameter known to be involved in poor reconstitution of immune system. INR patients showed chronic immune activation, persistent inflammation and thymic regeneration failure. The frequency of circulating CD34 hematopoietic progenitors being not different between both groups of patients, we analyzed the differentiation potential of these cells at pre-thymic stages of lymphopoiesis.Using a co-culture system of hematopoietic progenitors with stromal cell lines OP9-DL1 (T-cell assay) or MS5 (B- and NK-cells assay) with appropriate cytokines, we highlighted an alteration of T-cell differentiation potential in INRs impacting their peripheral restoration. This was not observed in IRs who were similar to non-HIV donors. On the other hand, NK-cell differentiation potential was impaired in both groups of patients in comparison to non-HIV donors. Lastly, no abnormalities in B-cell potential were revealed.Studying molecular pathways involved in T-cell specification (Notch), proliferation (IL-7/IL7R) and survival (Fas/FasL, TNFR, caspase-1, P2X7) we observed the decreased viability of hematopoietic progenitors in HIV patients with increased caspase-1 activation involved in cellular death by pyroptosis. Moreover, expression of some Notch target genes was clearly Notch-independent. However, differences in transcriptional profile of BCL11B between IRs and INRs allowed us to postulate that T-cell differentiation is promoted over NK-cell differentiation in IR patients. Finally, CD34+ cells from INRs presented P2X7 overexpression (extracellular ATP receptor) and absence of CD73 ectonucleotidase (ATP hydrolysis) pointing out their increased susceptibility to extracellular nucleotides.Taken together our data, we postulate that highly inflammatory microenvironment of hematopoietic progenitor’s bone marrow niche disturbs their survival and differentiation in HIV patients. Thus, increased cellular death of CD34+ cells and probably neighboring cells amplifies the local inflammation. This is compensated in some patients by enhanced T-cell differentiation of CD34+ progenitors and results in immunological success. When it is not the case, the alteration of lymphopoiesis is important and the absence of reconstitution of peripheral T CD4+ lymphocyte compartment is noted. We believe have identified the population of HIV-infected individuals who will benefit from occasional administration of anti-inflammatory drugs (such as P2X7 antagonists).