Targeting Cellular Cofactors in HIV Therapy

Abstract

Besides viral proteins cellular factors play a key role in the replication of the human immunodeficiency virus HIV-1. The outcome of virus replication is determined by the balance between the activity of a number of cellular dependency factors and restriction factors. Whereas the first are essential cofactors for diverse steps in the viral replication cycle, the latter counteract virus replication by sensing particular viral components as non-self, often as mediators of the innate immune system. Cellular cofactors include receptors for HIV-1 entry, LEDGF as cofactor for the viral integrase, the RNA helicase DDX3 involved in the nuclear export of unspliced viral RNAs, and diverse cellular kinases that promote viral replication. Cellular restriction factors are often antagonized by HIV-1 accessory proteins in order to counteract their restrictive function on viral replication. Although cellular cofactors in the HIV field are understood as factors promoting viral replication, we add a subchapter on the most important restriction factors (Trim5α, APOBEC3G, SAMHD1, and tetherin/BST-2). Today highly active antiretroviral therapy (HAART) mostly targets HIV proteins like reverse transcriptase, protease, or integrase to specifically interfere with virus replication. However, the identification of cellular cofactors and the increasing knowledge on their mode of action at R. Dürr and U. Dietrich (*) Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, 60596 Frankfurt, Germany e-mail: duerr@gsh.uni-frankfurt.de; ursula.dietrich@gsh.uni-frankfurt.de O. Keppler Institute of Medical Virology, Goethe University, Frankfurt, Germany e-mail: oliver.keppler@kgu.de F. Christ Laboratory for Molecular Virology and Gene Therapy, K.U. Leuven, Leuven, Belgium e-mail: frauke.christ@med.kuleuven.be E. Crespan, A. Garbelli, and G. Maga Institute of Molecular Genetics, IGM-CNR, Pavia, Italy e-mail: emmanuelecrespan@gmail.com; agarbelli@gmail.com; maga@igm.cnr.it defined steps in the HIV-1 replication cycle have opened new avenues towards the development of HIV-1 inhibitors. Here we summarize the most important cellular factors involved in HIV-1 replication along with therapeutic approaches developed to target them, preferentially without harming their normal cellular function.

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

“…The exact mechanisms of interaction of this protein with individual pathogens are still poorly understood (26). Nonetheless, DDX3 is being regarded as an interesting target for the development of novel antiviral compounds (27,28).…”

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

“…The HIV-1 genome codes for nine viral genes (gag, pol, env, vif, vpr, vpu, tat, rev, nef) encoding 19 proteins. Besides the structurally and functionally necessary gag, pol, and env genes, the regulatory and accessory tat, rev, nef, vif, vpr, and vpu modulate HIV-1 infection, replication, viral release, and immune recognition [98]. The SARS-CoV-2 genome codes for 14 open-reading frames (ORFs) encoding 29 proteins [99].…”

Small Molecules Solving Big Problems: Present and Future of Drug Discovery

“…A different approach in the attempt of avoiding resistance problems in anti-HIV drug design is to use host cellular cofactors instead of viral proteins as molecular targets. [20][21][22] By targeting host cellular cofactors essential for HIV replication drug resistance is less likely to occur. DDX3 is one of the essential host cofactors in HIV replication because it shuttles viral nucleic acids between the cytoplasm and the nucleus.…”