CD 4 + T‐cell depletion in HIV infection: mechanisms of immunological failure

Summary The hallmark of acquired immunodeficiency syndrome ( AIDS ) pathogenesis is a progressive depletion of CD 4 + T‐cell populations in close association with progressive impairment of cellular immunity and increasing susceptibility to opportunistic infections ( OI ). Disease progression in untreated human immunodeficiency virus ( HIV ) infection can take many years, and it was originally hypothesized to be a consequence of slow, viral‐mediated CD 4 + T‐cell destruction. However, massive CD 4 + memory T‐cell destruction is now known to occur quite early in infection, almost always without overt immunodeficiency. In most individuals, this initial destruction is countered by CD 4 + memory T‐cell regeneration that preserves CD 4 + T‐cell numbers and functions above the threshold associated with overt immunodeficiency. This regeneration, which occurs in the setting of chronic immune activation and immune dysregulation does not, however, restore all functionally important CD 4 + T‐cell populations and is not stable over the long term. Ultimately, CD 4 + memory T‐cell homeostasis fails and critical effector populations decline below the level necessary to prevent OI . Thus, the onset of overt immune deficiency appears to be intimately linked with CD 4 + memory T‐cell dynamics and reflects the complex interplay of direct viral cytopathogenicity and the indirect effects of persistent immune activation on CD 4 + memory T‐cell proliferation, differentiation, and survival.