In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells.

Two major protein-binding sites within the negative regulatory element of the human immunodeficiency virus type 1 long terminal repeat have been identified. One (site B) contained a palindromic sequence with homology to steroid/thyroid hormone response elements but was distinct from previously described binding sites of this class. A novel T-cell protein recognized the palindromic sequence within site B and also bound estrogenor thyroid hormone-response elements with lower affinity. A 7-base-pair mutation in the site B palindrome, which destroyed protein binding, resulted in increased expression from the human immunodeficiency virus type 1 long terminal repeat in T cells.

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Apolipoprotein E (apoE) is a 34 kDa glycoprotein with multiple actions that help protect against the development of atherosclerosis. Here, we have assessed the atheroprotective potential of an [E1(-), E3(-), polymerase(-)] adenovirus vector expressing human apoE, comparing intramuscular and intravenous (liver-directed) injections in hypercholesterolaemic apoE-deficient mice (apoE(-/-)). Intramuscular injections resulted in low expression of apoE and afforded no protection against atherogenesis. In contrast, 3 and 7 days after intravenous injections into young (6-8-week-old) apoE(-/-) mice, plasma levels of apoE were elevated and were accompanied by reductions in plasma cholesterol and normalization of lipoprotein profiles. Thereafter, plasma apoE was still detectable up to day 70, but gradually declined, although no humoral immune response was evoked, and there was a return to dyslipoproteinaemia. High levels of the vector genome were still present in livers of treated animals at 70 days, implying that decrease in apoE expression was due to cellular shutdown of the cytomegalovirus promoter. Importantly, liver-directed apoE gene transfer to these young mice retarded progression of atherosclerosis by 38% (treated, 8.21 +/- 1.05%; untreated, 13.26 +/- 0.98%, P < 0.05), during the 70 day study period. Moreover, when 10-month-old apoE(-/-) mice with advanced atherosclerosis were treated with the adenovirus vector, there was clear regression of aortic lesion area by 1 month [24.3 +/- 1.7% compared to 40.7 +/- 2.6% in baseline controls (P < 0.002)]. We conclude that the stability of the adenovirus vector genome in the livers of intravenously treated animals provides an ideal platform to evaluate liver-specific promoters for sustained transgene expression and control of atherosclerotic lesion pathology.

Apolipoprotein E (apoE) is a multifunctional plasma glyco-