The anti-infectives market is poised to experience considerable growth in the next few years, with a forecast market value that is expected to double in size to more than $44 billion by 2010. The HIV market is one particular example of this market phenomenon. The success of current HIV therapies has led to patients being treated over long time periods of time and clinical demands have correspondingly evolved to include molecules with reduced toxicity and susceptibility to drug resistance. This requirement is predicted to contribute to the 3-fold increase in the HIV market expected between 2001 and 2007, or in real terms an increase from $5 billion to over $13 billion in sales. Early HIV therapies have targeted proteases and reverse transcriptase, both of which are crucial viral proteins. Newer strategies have included the blockade of viral entry into host cells and the inhibition of integrase activity and therefore incorporation of the viral genome into host DNA. HIV entry is initiated by the attachment of the virus to the host cell membrane, which in some cases involves binding to attachment factors such as DC-SIGN. Subsequent interaction of the envelope protein with the CD4 receptor causes conformational changes that enable the envelope protein to interact with a coreceptor, generally the chemokine receptors CCR5 or CXCR4. Co-receptor engagement triggers the final conformational changes in the envelope protein, which mediate lipid mixing between the viral and cellular membranes. Hence the development of CCR5 or CXCR4 receptor antagonists has attracted considerable attention from the drug development sector. Another possibility is the use of approaches able to reduce gene expression. Duplexes of 21 base pair RNA, known as short-interfering RNA (siRNA), have been shown to inhibit gene expression by a sequence-specific RNA degradation mechanism termed RNA interference (RNAi). Researchers based at the University of Barcelona have turned this technology to the possible prevention of HIV-1 infection. This group found that siRNAs that target CXCR4 and CCR5 could effectively impede cell surface protein expression and their consequent function as HIV co-receptors. This effectively blocked the acute infection of CXCR4+ or CCR5+ cells by X4 (NL4-3) or R5 (BaL) HIV-1 strains. Inhibition of virus replication occurred regardless of the multiplicity of infection employed. These data demonstrate that RNAi may be used to block HIV entry and replication through the blockade of cellular gene expression. Gene silencing by siRNA may become a valid alternative to the development of CCR5 or CXCR4 receptor antagonists.

January, 2003

Adapted from Martinez et al, AIDS 2002 Dec 6;16(18):2385-90