We accrue somatic mosaicism with age in many tissues. In the blood system, this is called clonal hematopoiesis (CH). CH is a premalignant condition in which hematopoietic stem cells (HSCs) accrue 1-2 mutations among ~20 genes such as DNMT3A, TET2, and ASXL1. The CH clone size and the rate at which clones expand, which are promoted by external factors such as inflammation, are strong predictors of malignant transformation of CH into hematologic malignancies. Consistently, inflammation has been shown to promote the progression of CH to hematologic malignancies. HIV-infected patients exhibit signatures of enhanced inflammation, such as activated immune cells and cytokine expression, even when the patients are treated with antiretroviral therapies (ART). Indeed, people living with HIV (PLWH) have higher incidence of CH, particularly those with ASXL1 mutations, than HIV negative population. Notably, PLWH have a higher risk of developing hematologic malignancies such as non-Hodgkin lymphoma (NHL) and myelodysplastic syndromes (MDS), suggesting an association between the elevated CH prevalence among PLWH and its malignant transformation. The fact that PLWH treated with ART have high incidence of CH raises a possibility that HIV infection promotes CH independently of viral load or inflammation. HIV-infected human hematopoietic stem cells (HSCs) have been found in PLWH, further supporting the possibility that HIV infection may alter HSC function cell intrinsically to confer competitive advantages to mutant HSCs. The objective of this project is to elucidate the molecular mechanisms underpinning the increased prevalence of CH and its transformation to malignancies among PLWH. In Aim 1, we will study whether Asxl1 mutant HSCs expands upon HIV infection. In Aim 2, we will examine whether HIV infection transforms Asxl1 mutant HSCs to myeloid neoplasms. Completion of this study will provide novel insights into the effects of HIV infection on clonal expansion and subsequent transformation of Asxl1 mutant HSCs.