Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457)

Abstract

Because BVM likely will be used clinically in patients harboring viruses resistant to PR inhibitors (PIs), in this study we evaluated the interplay between a PI-resistant (PIR) PR and the BVM resistance mutations in Gag. As expected, the PIR mutations had no effect on inhibition by BVM; however, we observed general processing defects and a slight delay in viral replication in Jurkat T cells associated with the PIR mutations, even in the absence of compound. When combined, most BVM resistance and PIR mutations acted additively to impair viral replication, particularly in the presence of BVM. The BVM-resistant mutant SP1-A1V was an exception, as it supported robust replication in the context of either wild-type (WT) or PIR PR, even at high BVM concentrations. Significantly, the emergence of BVM resistance was delayed in the context of the PIR PR, and the SP1-A1V mutation was acquired most frequently with either WT or PIR PR. These results suggest that resistance to BVM is less likely to emerge in patients who have failed PIs than in patients who are PI naïve. We predict that the SP1-A1V substitution is the most likely to emerge in vivo, as this mutant replicates robustly independently of PR mutations or BVM. These findings offer insights into the effect of PIR mutations on the evolution of BVM resistance in PI-experienced patients.

HIV-1 Maturation Inhibitor Bevirimat Stabilizes the Immature Gag Lattice

“…1D). Levels of the unprocessed CA-SP1 polypeptide in both BVM-treated and CA5 virus particles were as expected from previous studies (2,5,7,19), with a CA-SP1/CA ratio of ϳ75%/25% for BVMtreated preparations compared to ϳ99%/1% for CA5 preparations. Detection of viral proteins also confirmed that pNL4-3 PR Ϫ particles were arrested in an immature state as they contained only uncleaved Gag.…”

Identification of anti-HIV and anti-Reverse Transcriptase activity from Tetracera scandens

“…Currently, therapeutic treatment of AIDS has mainly relied on the four types of anti-HIV/AIDS drugs: the viral reverse transcriptase (RTase) inhibitors that include nucleoside and non-nucleoside type RTase inhibitors (1,2), protease inhibitors (3), integrase inhibitors (4), and entry inhibitors (5). However, as the current drugs encounter problems such as the emergence of drug-resistant viruses and unexpected side effects, new types of antiviral inhibitors are being developed such as attachment inhibitors (6), a virion maturation inhibitor (7,8), and CCR5 inhibitors (9). An alternative effort to solve these problems has also been to actively seek novel antiviral agents from various natural sources such as traditionally used medicinal herbs and plants (10).…”

Poly(lactic-<em>co</em>-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations

“…[4][5][6] B has anticarcinogenic properties that generally trigger the apoptosis signaling cascade through the activation of caspase-3 and caspase-8. 7,8 In addition, B induces direct mitochondrial damage and thereby overcomes the resistance that a tumor cell generally acquires. [9][10][11][12][13][14][15][16][17][18] Hepatocellular carcinoma (HCC) is considered as the sixth most common malignancy and third most frequent leading cause of death worldwide.…”

“…47,48 It is also evidenced by the fact that the apoptosis is probably due to the activation of caspase-3 and -8 signaling cascade. 7,8 To investigate further, we performed in vivo antitumor activity of B and BNP in the NDEA-induced HCC model to investigate the underlying mechanism associated with the anticancer effects of these compounds and accumulated some noteworthy evidence in favor of the enhanced efficacy of BNP compared to that of B, which is discussed further.…”

“…56 B generally exerts anticancer action either by triggering the mitochondrial pathway of apoptosis or by inducing cellular stress, such as cytokine withdrawal and DNA damage. [7][8][9][10][11][12][13][14][15][16][17][18] Thus, we investigated the altered levels of cytokines and caspases among different groups through ELISA and screened the effects of B and BNP treatments over the carcinogen control group. All these inflammatory cytokines were elevated in NDEA-exposed rats and were decreased to a certain extent after B and BNP treatments.…”