The thalidomide analogue CC-3052 inhibits HIV-1 and tumour necrosis factor-alpha (TNF-alpha) expression in acutely and chronically infected cells in vitro

We investigated the in vitro effect of the water-soluble, highly stable tha lidomide analogue CC-3052 on HIV-1 expression and TNF-alpha production in l atently infected promonocytic U1 cells, acutely infected T cells and monocy te-derived human macrophages (MDM), and in mitogen-stimulated ex vivo cultu res from patients with primary acute HIV-1 infection. HIV-1 expression was assessed by Northern blot analysis of RNAs, and ELISA for p24 antigen relea se and reverse transcriptase (RT) activity. TNF-alpha expression was evalua ted by RT-polymerase chain reaction (PCR)-ELISA for mRNA and ELISA for prot ein secretion. We demonstrated that CC-3052 is able to inhibit HIV-1 expres sion, as evaluated by mRNA, p24 release and RT activity, in phorbol myrista te acetate (PMA)- and cytokine-stimulated U1 cells. Furthermore, CC-3052 in hibited HIV-1 expression, as evaluated by p24 and RT activity, in acutely i nfected MDM and T cells. As far as TNF-alpha is concerned, CC-3052 signific antly reduced TNF-alpha mRNA and protein secretion in PMA-stimulated U937 a nd U1 cells, and in PMA-stimulated uninfected and acutely infected MDM. Con sistently, the addition of CC-3052 reduced TNF-alpha production in phytohae magglutinin (PHA) and lipopolysaccharide (LPS)-stimulated whole blood cultu res from patients during the primary acute phase of HIV-1 infection. Since TNF-alpha is among the most potent enhancers of HIV-1 expression, the effec t of CC-3052 on TNF-alpha may account for its inhibitory activity on HIV-1 expression. Given the well documented immunopathological role of TNF-alpha and its correlation with viral load, advanced disease and poor prognosis, C C-3052 could be an interesting drug for the design of therapeutic strategie s in association with anti-retroviral agents.