During all the steps of HIV-1 replication in the main target cells (activated CD4 T cells and macrophages) the virus takes advantages of the functions of cellular proteins to accomplish efficiently its infection or to hide its replication from the immune system response and restriction factors. The identification of the molecular mechanisms by which HIV-1 uses the host proteins is a perquisite for the design of new therapeutic strategies that are able to target specifically viral-cellular interfaces and inhibit the infection. In this seminar I will present a summary of my PhD and Post-doc research studies focused on the identification and characterization of cellular factors involved in HIV-1 early infection steps. I will present the role of KAP1, a TRIM family protein identified during my PhD studies in Cereseto’s laboratory (Scuola Normale Superiore Pisa, Italy). KAP1 inhibits HIV-1 infection by counteracting HIV-1 integrase and inducing its deacetylation through HDAC-1 (Allouch et al., Cell Host and Microbes, 2011). I will also present the molecular mechanisms contributing to the inhibition of HIV-1 reverse transcription in macrophages by p21 cellular factor (Allouch et al., PNAS, 2013), determined during my first Post-doc studies in Pancino’s Laboratory (Institut Pasteur, France). Finally, I will present the recent findings of my second Post-doc studies in Perfettini’s laboratory (INSERM U1030, Institut Gustave Roussy, France) focused on the characterization of the role of SUGT1 in HIV-1 cytoplasmic trafficking (Allouch et al., Cell Death and Differentiation, 2020) and NLRP3 in viral entry (Allouch*, Paoletti* et al, Cell Reports, 2019). At the end a brief summary, on my actual research work in immuno-oncology field mainly on tumor-associated macrophages (TAMs) will be presented.