The chemokine receptor CCR5 is a key target for HIV-1 infection, playing a critical role in the virus's ability to enter and infect cells. This review discusses the structural diversity of CCR5 and how HIV-1 exploits this diversity to infect its target cells. CCR5 is a G protein-coupled receptor (GPCR) that binds to chemokine ligands and is involved in various biological processes, including immune cell activation and migration. HIV-1 uses CCR5 and CXCR4 as co-receptors to enter CD4+ T cells, with CCR5 being particularly important for R5-tropic HIV-1 strains. The structural variability of CCR5, including post-translational modifications, lipid environment, and conformational changes, influences its interaction with HIV-1 and affects the efficiency of infection. Additionally, the presence of CCR5 on the cell surface is crucial for viral entry, and mutations such as the delta-32 mutation can lead to resistance to HIV-1 by reducing CCR5 expression. Therapeutic strategies targeting CCR5 include the use of CCR5 ligands, antibodies, and gene editing to modify or eliminate CCR5 expression. These approaches aim to block HIV-1 entry and prevent infection. Despite these strategies, challenges remain due to the structural diversity of CCR5 and the need for effective, long-term treatments. The review highlights the importance of understanding CCR5's structural and functional diversity in developing new antiretroviral therapies for HIV-1.The chemokine receptor CCR5 is a key target for HIV-1 infection, playing a critical role in the virus's ability to enter and infect cells. This review discusses the structural diversity of CCR5 and how HIV-1 exploits this diversity to infect its target cells. CCR5 is a G protein-coupled receptor (GPCR) that binds to chemokine ligands and is involved in various biological processes, including immune cell activation and migration. HIV-1 uses CCR5 and CXCR4 as co-receptors to enter CD4+ T cells, with CCR5 being particularly important for R5-tropic HIV-1 strains. The structural variability of CCR5, including post-translational modifications, lipid environment, and conformational changes, influences its interaction with HIV-1 and affects the efficiency of infection. Additionally, the presence of CCR5 on the cell surface is crucial for viral entry, and mutations such as the delta-32 mutation can lead to resistance to HIV-1 by reducing CCR5 expression. Therapeutic strategies targeting CCR5 include the use of CCR5 ligands, antibodies, and gene editing to modify or eliminate CCR5 expression. These approaches aim to block HIV-1 entry and prevent infection. Despite these strategies, challenges remain due to the structural diversity of CCR5 and the need for effective, long-term treatments. The review highlights the importance of understanding CCR5's structural and functional diversity in developing new antiretroviral therapies for HIV-1.