Immune deficiency in HIV-1 infection: novel therapeutic approaches targeting innate and adaptive responses

HIV-1 is a lentivirus capable of infecting CD4(+) T-lymphocytes and CD4-expressing innate immune cells. Infection with HIV-1 leads to rapid and early depletion of mucosal CD4(+) T-cells, and to the establishment of viral reservoirs that are resistant to the most potent antiretroviral therapy currently available. Commonly observed virus-induced adaptive immune defects consist of weak-to-absent HIV-specific CD4 T-cell responses and of inappropriate or inefficient CD8(+) cytotoxic T-lymphocyte activity. Moreover, the virus establishes early and long-lasting deficits in innate immunity characterized by reduced numbers or/and disrupted functions of antigen-presenting cells, natural killer cells and natural-kiiller T-lymphocytes. Therapeutic approaches have long been oriented toward restoration of adaptive immunity in HIV-1 patients. This is exemplified by the use, in antiretrovial treated subjects, of interleukin-2 to increase and expand CD4(+) lymphocytes, and of structured treatment interruptions or therapeutic vaccination to restore HIV-specific responses. More recently, approaches aimed at correcting the deficits in innate immune responses have been explored. The most advanced of these strategies include synthetic immunomodulators targeting antigen presentation and human recombinant cytokines capable of regulating the functions of natural-killer cells. Today, in addition to the combined use of different classes of antiretrovirals, a highly active immune therapy, with components targeting both innate and adaptive responses, appears to be absolutely necessary to formulate immune control of the virus. Current and future clinical protocols will eventually define the timing, composition and formulations of combined HIV-specific and nonspecific immunotherapy that could be safely administered to HIV patients to restore immune homeostasis.