CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure

Abstract

The hallmark of acquired immunodeficiency syndrome (AIDS) pathogenesis is a progressive depletion of CD4(+) 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 CD4(+) T-cell destruction. However, massive CD4(+) 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 CD4(+) memory T-cell regeneration that preserves CD4(+) 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 CD4(+) T-cell populations and is not stable over the long term. Ultimately, CD4(+) 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 CD4(+) memory T-cell dynamics and reflects the complex interplay of direct viral cytopathogenicity and the indirect effects of persistent immune activation on CD4(+) memory T-cell proliferation, differentiation, and survival.

Fig. 1. CCR5⁺CD4⁺ memory T cells are primary targets for HIV/SIV

The figure shows CD28 versus CCR5 or CCR7 on gated CD4⁺ memory (CD95⁺) T cells from the peripheral blood of a healthy normal RM (SIV⁻) and the same animal during chronic infection with the CCR5-tropic SIVmac239. CCR7 downregulation and CCR5 upregulation are key phenotypic markers of T_TrM and T_EM differentiation and therefore constitute prime HIV/SIV targets. In contrast, CD4⁺ T_N and T_CM are CCR7⁺ and CCR5⁻, making them inefficient targets for CCR5-tropic HIV and SIV. Regeneration of depleted CD4⁺ T_EM compartments is dependent on continuous recruitment of new cells from their CD4⁺ T_CM precursors.

Fig. 2. CD4⁺ TCM homeostasis is dysregulated in progressive HIV/SIV infection

In normal (healthy uninfected) individuals, proliferating cells are predominantly long-lived, while effector site CD4⁺ T_EM populations are stable and maintained at levels required for effective immune function. In progressive HIV/SIV infection, immune activation drives a high turnover process that produces short-lived cells. As the regenerative CD4⁺ T_CM cell population slowly diminishes over time, it precipitates the decline in production and influx of new CD4⁺ T_EM cells below a crucial threshold required to keep OIs at bay. Thus, progressive failure of CD4⁺ T_CM homeostasis and its consequent inability to produce new T_EM cells plays a major role in setting the tempo of disease progression and the timing to overt immunodeficiency and AIDS.

Fig. 3. CD4⁺ memory T-cell regenerative capacity can be restored with ART even at end-stage disease

At end-stage disease, the total CD4⁺ memory T-cell proliferative response declines below a crucial threshold that typically signals the failure of the CD4⁺ T_CM regenerative potential and subsequent effector site CD4⁺ T_EM population collapse. (A) Administration of ART leads to a robust proliferative burst in CD4⁺ T_CM cells in the peripheral blood of an RM at end-stage disease. (B) This proliferative response is also observed in secondary lymphoid tissues (spleen, axillary and mesenteric lymph nodes) and results in the influx of new CD4⁺ T_EM cells into extra-lymphoid effector sites (such as the BAL). (C) Administration of partially suppressive ART to chronically SIVmac239-infected RMs induces proliferative responses in both CD4⁺ T_CM and CD8⁺ T_CM cells in the peripheral blood.