Pharmacological intervention of HIV-1 maturation

Abstract

Despite significant advances in antiretroviral therapy, increasing drug resistance and toxicities observed among many of the current approved human immunodeficiency virus (HIV) drugs indicate a need for discovery and development of potent and safe antivirals with a novel mechanism of action. Maturation inhibitors (MIs) represent one such new class of HIV therapies. MIs inhibit a late step in the HIV-1 Gag processing cascade, causing defective core condensation and the release of non-infectious virus particles from infected cells, thus blocking the spread of the infection to new cells. Clinical proof-of-concept for the MIs was established with betulinic acid derived bevirimat, the prototype HIV-1 MI. Despite the discontinuation of its further clinical development in 2010 due to a lack of uniform patient response caused by naturally occurring drug resistance Gag polymorphisms, several second-generation MIs with improved activity against viruses exhibiting Gag polymorphism mediated resistance have been recently discovered and are under clinical evaluation in HIV/AID patients. In this review, current understanding of HIV-1 MIs is described and recent progress made toward elucidating the mechanism of action, target identification and development of second-generation MIs is reviewed.

Keywords: BMS, Bristol-Myers Squibb; Bevirimat; CA, capsid; GSK, GlaxoSmithKline; Gag processing; Gag-drug interaction; HIV, human immunodeficiency virus; HIV-1 maturation inhibitors; MA, matrix; MI, maturation inhibitor; PI, protease inhibitor; PR, protease; SIV, Simian immunodeficiency virus; SP1, spacer protein 1.

Graphical abstract

Figure 1

The chemical structures of betulinic acid (top panel) and its derivative bevirimat, 3-O-(3′,3′-dimethylsuccinyl) betulinic acid (bottom panel).

Figure 2

The processing cascade of HIV-1 Gag polyprotein precursor. The proteolytic cleavage of HIV-1 Gag polyprotein precursor via the viral protease is a sequential and high-order event. The numbers indicated underneath the various precursors show the cleavage rates of each individual cleavage step relative to that of CA-SP1 precursor cleavage, the final step with the slowest rate of cleavage in the Gag processing cascade. CA-SP1 cleavage is a primary target of the HIV-1 maturation inhibitor bevirimat.

Figure 3

Mechanism of action of HIV-1 maturation inhibitor Bevirimat. In panel A, HeLa cells were transfected with pNL4-3 and cultured in the absence or presence of indicated concentrations of bevirimat. Two days posttransfection, cells were metabolically labeled for 2 h with [³⁵S]Met/Cys. Virus lysates were immunoprecipitated with anti-HIV antibody. The positions of virally encoded proteins p25 and p24 are indicated. Note the accumulation of p25 in the presence of bevirimat. Panel B is the thin section electron microscope analysis of virions produced from bevirimat-treated or -untreated HeLa cells following transfection with pNL4-3 proviral DNA plasmid. Panel C schematically shows that bevirimat disrupts the CA-SP1 cleavage and blocks the release of mature CA protein.

Figure 4

The clustering of bevirimat-resistance-conferring mutation at the CA-SP1 cleavage site.

Figure 5

Gag CA-SP1 polymorphisms that are associated with bevirimat resistance in HIV/AIDS patients. Two polymorphism sites found in patients (Gag 362 position in CA and SP1 6-8 positions QVT) are highlighted with the underlined black letters. Among them, SP1 V7A polymorphism is a primary determinant of non-responsiveness in patients to bevirimat treatment in clinical trials.