HIV is a disease in which the original clinical observations of severe opportunistic infections gave the first clues regarding the underlying pathology, namely that HIV is essentially an infection of the immune system. HIV infects and deletes CD4⁺ T cells that normally coordinate the adaptive T- and B-cell response to defend against intracellular pathogens. The immune defect is immediate and profound: At the time of acute infection with an AIDS virus, typically more than half of the gut-associated CD4⁺ T cells are depleted, leaving a damaged immune system to contend with a life-long infection.