Recent progress in antiretrovirals--lessons from resistance

Abstract

Recent failures in efforts to develop an effective vaccine against HIV-1 infection have emphasized the importance of antiretroviral therapy in treating HIV-1-infected patients. Thus far, inhibitors of two viral enzymes, reverse transcriptase and protease, have had a profoundly positive impact on the survival of HIV-1-infected patients. However, new inhibitors that act at diverse steps in the viral replication cycle are urgently needed because of the development of resistance to currently available antiretrovirals. This review summarizes recent progress in antiretroviral drug discovery and development by specifically focusing on novel inhibitors of three phases of replication: viral entry, integration of the viral DNA into the host cell genome and virus particle maturation.

FIGURE 1

Schematic depiction of Env-mediated membrane fusion. (1) The Env complex (gp120 and gp41), CD4 and coreceptor (CXCR4 or CCR5) before Env/CD4 engagement. The viral membrane is at the top and the target cell membrane at the bottom. (2) gp120 binding to CD4. (3) Interaction between gp120 and coreceptor after CD4 binding. (4) Conformational changes in gp120 and gp41 triggered by CD4 and coreceptor engagement induce gp41 to extend and insert the N-terminal fusion peptide into the target cell membrane. In this conformation, the heptat repeats 1 and 2 (HR1 and HR2) are extended in a rod-like fashion. (5 and 6) HR1 and HR2 form a six-helix bundle and membrane fusion takes place. Peptides derived from HR1 or HR2 (e.g. T20) prevent six-helix bundle formation. Reprinted with permission from Freed and Martin [94] (5th Edition, Chapter 57).

FIGURE 2

Integration pathway. The IN enzyme cleaves the viral DNA ends after a CA dinucleotide (3′ processing) and integration occurs in the nucleus (strand transfer). Viral DNA integration leads to a signature duplication of a short stretch of cellular DNA, represented as ‘VWXYZ’. After integration, cellular enzymes repair and ligate the viral/cellular DNA junction. Reprinted with permission from Freed and Martin [94] (5th Edition, Chapter 57).

FIGURE 3

(a) HIV-1 Gag processing cascade, indicating the major Gag domains matrix (MA), capsid (CA), nucleocapsid (NC), and p6 and spacer peptides SP1 and SP2. The order of processing events is depicted by vertical flow diagram, with arrows indicating sites of cleavage by PR. The red arrow denotes the cleavage event blocked by 3-O-(3′,3′-dimethylsuccinyl)betulinic acid (PA-457 or bevirimat). (b) Immature HIV-1 particle showing ‘doughnut-like’ morphology (i); mature virion with condensed, conical core (ii); virion produced in the presence of bevirimat, showing aberrant core and crescent of electron density inside the viral lipid bilayer (iii).