ABSTRACT
BACKGROUND: The transmembrane subunit of the HIV envelope protein, gp41 is a vulnerable target to inhibit HIV entry. There is one fusion inhibitor T20 (brand name: Fuzeon, generic name: enfuvirtide) available by prescription. However, it has several drawbacks such as a high level of development of drug resistance, a short-half life in vivo, rapid renal clearance, low oral bioavailability, and it is only used as a salvage therapy. Therefore, investigators have been studying a variety of different modalities to attempt to overcome these limitations. METHODS: Comprehensive literature searches were performed on HIV gp41, inhibition mechanisms, and inhibitors. The latest structural information was collected, and multiple inhibition strategies targeting gp41 were reviewed. RESULTS: Many of the recent advances in inhibitors were peptide-based. Several creative modification strategies have also been performed to improve inhibitory efficacy of peptides and to overcome the drawbacks of T20 treatment. Small compounds have also been an area of intense research. There is a wide variety in development from those identified by virtual screens targeting specific regions of the protein to natural products. Finally, broadly neutralizing antibodies have also been important area of research. The inaccessible nature of the target regions for antibodies is a challenge, however, extensive efforts to develop better neutralizing antibodies are ongoing. CONCLUSION: The fusogenic protein, gp41 has been extensively studied as a promising target to inhibit membrane fusion between the virus and target cells. At the same time, it is a challenging target because the vulnerable conformations of the protein are exposed only transiently. However, advances in biochemical, biophysical, structural, and immunological studies are coming together to move the field closer to an understanding of gp41 structure and function that will lead to the development of novel drugs and vaccines.
Subject(s)
HIV Envelope Protein gp41/antagonists & inhibitors , HIV Fusion Inhibitors/pharmacology , HIV Fusion Inhibitors/therapeutic use , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/drug effects , HIV-1/physiology , Animals , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/therapeutic use , Drug Discovery , HIV Antibodies/pharmacology , HIV Antibodies/therapeutic use , HIV Envelope Protein gp41/chemistry , HIV Envelope Protein gp41/metabolism , HIV Fusion Inhibitors/chemistry , Humans , Molecular Structure , Peptides/chemistry , Peptides/pharmacology , Peptides/therapeutic use , Protein Interaction Domains and Motifs , Protein Subunits/antagonists & inhibitors , Virus Internalization/drug effectsABSTRACT
The effect of human cytomegalovirus (HCMV) infection on the viability of the cells in the monocyte/myeloid lineage was investigated. Two cell lines at different stages in the differentiation pathway, the less differentiated promyeloid HL-60 and the more differentiated promonocyte THP-1 cells, were used in this study. While the viability of THP-1 cells was significantly impaired by HCMV infection, the viability of HL-60 cells was not affected. The decrease in the viability of THP-1 cells appears to result from the increase in apoptosis following HCMV infection. Interestingly, HL-60 cells were more sensitive than THP-1 cells to the apoptotic effect of other apoptogenic agents such as ultraviolet irradiation and hydrogen peroxide. When HL-60 cells were induced to differentiate by treating cells with 12-O-tetradecanoyl-phorbol 13-acetate (TPA), HCMV infection induced an increase in apoptosis of the differentiated HL-60 cells by TPA. Therefore, HCMV-induced apoptosis in the cells of the myeloid/monocyte lineage appears to depend on the degree of cell differentiation.