HIV entry inhibitors: Mechanisms of action and resistance pathway

Introduction

Viral entry currently represents one of the most attractive targets in the search for new drugs to treat HIV infection. Thanks to the advances in the knowledge of the molecular basis of the mechanisms involved in the entry process, it has been possible to split it into several steps and design molecules to block each one of them. The main steps in the viral entry process are (i) attachment of the viral gp120 to the CD4 T cell receptor, (ii) binding of the gp120 to CCR5 or CXCR4 co-receptors and (iii) fusion of the viral and cellular membranes (Figure 1).

Entry inhibitors are a new family of antiretrovirals presently represented only by one drug, enfuvirtide, the first fusion inhibitor,¹ but many other compounds are in the process of clinical development and certainly will be part of the therapeutic armamentarium within the next few months or years. These compounds are eagerly awaited and may prove beneficial for the growing number of HIV-infected individuals who have developed resistance to the currently available reverse transcriptase (RT) and protease inhibitors.

The threat of resistance is always present in HIV therapeutics, and there is no doubt that HIV will develop resistance to entry inhibitors also. However, the good news is that no cross-resistance with the currently available antiretrovirals is expected given their distinct mechanisms of action. Herein, we review in detail how HIV entry inhibitors block each stage of the entry process and which are the mechanisms by which resistance may develop (Table)

 

Table

HIV entry inhibitors: mechanisms of action and resistance pathways

Drug	Mechanism of action	Resistance pathway
CD4–gp120 inhibitors		Changes within gp120 surrounding the Phe-43 cavity
PRO-542	Tetravalent recombinant antibody (IgG2–CD4)
TNX-355	Monoclonal antibody against CD4
BMS-806	Binds to gp120, blocking conformational changes after CD4 binding
CADA	Decreases CD4 expression on the cell surface
CCR5 antagonists		Changes within gp120 (V3, C2, V2, C4) Co-receptor shift to CXCR4 use
SCH-C, Vicriviroc, SCH-D	Binds to transmembrane domains of CCR5
Aplaviroc (GW-873140)a	Binds to ECL2 of CCR5
Maraviroc (UK-427,857)	Binds to transmembrane domains of CCR5
TAK-220, TAK-652	Binds to transmembrane domains of CCR5
PRO-140	Monoclonal antibody against CCR5
CXCR4 antagonists		Changes within gp120 (V3, V1, V2, V4) Co-receptor shift to CCR5 use
AMD070	Binds to CXCR4
KRH-1636, KRH-2731	Binds to second and third extracellular loops of CXCR4
Fusion inhibitors
Enfuvirtide (T-20)b	Synthetic peptide which mimics a HR2 fragment and blocks the formation of the six-helix bundle	Changes at residues 36–45 in the HR1 region of gp41