Chronic immune activation: a lethal factor in HIV infection?

The theory that HIV causes T-cell dysfunction and T-cell loss by chronic immune activation has gained ground with the publication of a study that shows that persistent immune stimulation can cause immunodeficiency.

“Chronic immune activation contributes to the depletion of the naive T-cell compartment and results in fatal opportunistic infections,” reports senior researcher René van Lier (Academic Medical Centre, Amsterdam, Netherlands).

Van Lier and colleagues studied the effects of chronic immune activation using CD70 transgenic mice, which constitutively express CD70 – the ligand for the tumour necrosis factor receptor family member CD27 – on B cells. Transgenic expression of CD70 on B cells promoted effector T-cell formation, and mice showed progressive conversion of naive T cells into effector-memory cells, which led to a depletion of naive T cells from the lymph nodes and spleen. Despite having a hyperactive immune system, CD70 transgenic mice died aged six to eight months from Pneumocystis carinii infection, a hallmark of T-cell immunodeficiency (Nat Immunol; published online 9 December). “The persistent delivery of co-stimulatory signals was able to exhaust the T-cell pool and induced lethal immunodeficiency, in the absence of an active infection”, explains van Lier.

“This is an elegant study”, comments Lena Al-Harthi (Rush Medical College, Chicago, IL, USA), “that highlights the critical role played by immune over-stimulation in the progression of HIV”. It is particularly interesting, notes Al-Harthi, that chronic immune activation leads to thymic accelularity, perhaps through induction of steroid hormones that lead to thymic involution. “This is especially relevant to paediatric HIV disease, where paediatric patients tend to progress much faster to AIDS than adult patients”, she says.

Van Lier stresses that the cornerstone of the treatment of HIV-seropositive individuals remains reduction of virus replication, but adds that new and perhaps more effective drugs will be included in HAART cocktails. “The study suggests that treatment of hyper-immune activation may be beneficial in patients with viruses resistant to the current regimens. One option would be to target co-stimulatory molecules like CD70 that are up-regulated in HIV-infected people,” he says.

The researchers are now doing two follow-up studies. One deals with the role of antigen in naive T-cell depletion. “We are testing if repetitive exposure to antigens together with excessive co-stimulation leads to depletion of antigen-specific T cells (CD4 and CD8),” explains van Lier. The second is investigating mechanisms of reconstitution – ie, role of thymus, peripheral homeostatic proliferation – and possible ways of influencing recovery.