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The present review summarizes the current challenges for the design of new therapeutic strategies toward HIV eradication in individuals receiving suppressive highly active antiretroviral therapy (HAART). We will focus on the experimental evidence suggesting that immunological mechanisms involved in the generation and maintenance of memory CD4+ T cells are also responsible for the establishment and persistence of a stable reservoir for HIV.Recent studies performed on clinical samples obtained from virally suppressed HIV-infected individuals indicate that T-cell survival and homeostatic proliferation, two major mechanisms involved in the maintenance of immunological memory, contribute to the persistence of latently infected memory CD4+ T cells. Thus, the long lifespan characteristic of the HIV reservoir is likely a consequence of the capacity of the immune system to generate and maintain memory CD4+ T cells for a long period.These findings suggest that strategies aimed at reducing the pool of latently infected cells should interfere with the survival pathways responsible for the long-term maintenance of memory CD4+ T cells. Because memory CD4+ T cells are critical for appropriate immune defense, targeted approaches are needed to interfere only with the long-term survival of discrete fractions of memory T cells carrying proviral DNA.