Targeting chemokine receptors for HIV
Past present and future
The significant discovery in 1996 that HIV needs to bind to one of two chemokine receptors, CCR5 or CXCR4, to infect host cells energized the search for chemokine receptor antagonists as a novel approach to HIV therapy. However, in spite of intensive research efforts there are only two clinically approved chemokine receptor inhibitors. One is the CCR5 inhibitor maraviroc for HIV. However use is restricted to adult patients with virus that use CCR5 as a co-receptor, and it comes with a warning of potential hepatotoxicity. The other is the CXCR4 inhibitor plerixafor which is approved as a mobilizer of hematopoietic stem cells (HSC) from the bone marrow for autologous HSC transplant in patients with non-Hodgkin’s lymphoma and multiple myeloma. Though clinical trials with plerixafor validated CXCR4 inhibition as a target for HIV no CXCR4 inhibitor was subsequently successfully developed for HIV.
With new 21st century initiatives in HIV research aimed at total viral eradication and vaccines the article poses the question, has the time and opportunity for chemokine receptor inhibition in HIV come and gone? Important lessons learnt from this period of research are discussed such as insights into the biology of HIV gained by studying the role of co-receptors in HIV infectivity, and the significant advances in structural biology for drug discovery targeted at seven transmembrane receptors (chemokine receptors belong to this class). Furthermore the recent successful cure of a leukemia patient with HIV by HSC transplant with cells from a donor with a mutant non-functional CCR5 raises the question of novel approaches to targeting chemokine receptors.
Read more in: Fricker SP. Targeting chemokine receptors for HIV: past, present and future. Future Med. Chem. DOI: 10.4155/FMC.15.153 (In Press) (2015).