A paradox is presented by HIV-1 infected injection drug users (IDU): although the practice of injection of psychoactive drugs is known to cause significant alterations of the immune system, and despite the intense immunodeficiency caused by HIV-1 infection, HIV-1 infected IDU, one of the main at-risk populations in the HIV / AIDS world wide epidemic, do not progress faster to AIDS than individuals from other exposure categories. It would be expected that HIV infection in IDU causes a specially progressive disease, but no difference in disease progression between HIV infected IDU and individuals infected sexually has been reported. One hypothesis that could explain this paradox could be a better immune response in individuals with chronic immune activation, such as described for IDU, associated to a direct immune response to the highly diverse HIV-1 population directly injected into the blood stream without the “selection bottleneck” that occurs after sexual transmission of HIV-1. Analyses of HIV specific immune response in IDU is limited, but has indicated a high titered broad anti-HIV seroreactivity, and an analysis of the effective humoral immune response has indicated that IDU have HIV-1 neutralizing antibodies as effective as detected in sexually infected individuals.