The development of antiretroviral drugs (ARVs) was a great milestone in the management of HIV infection. ARVs suppress viral activity in the host cell, thus minimizing injury to the cells and prolonging life. However, an effective treatment has remained elusive for four decades due to the successful immune evasion mechanisms of the virus. A thorough understanding of the molecular interaction of HIV with the host cell is essential in the development of both preventive and curative therapies for HIV infection. This review highlights several inherent mechanisms of HIV that promote its survival and propagation, such as the targeting of CD4+lymphocytes, the downregulation of MHC class I and II, antigenic variation and an envelope complex that minimizes antibody access, and how they collaboratively render the immune system unable to mount an effective response.