Search

Objectives: To determine natural phenotypic susceptibility of non-group M HIV-1 to integrase strand transfer inhibitors (INSTIs) in a large panel of 39 clinical strains from groups O, N and P and to identify genotypic polymorphisms according to susceptibility levels.Methods: Susceptibility to raltegravir, elvitegravir and dolutegravir was evaluated in 36 HIV-1/O, 2 HIV-1/N and 1 HIV-1/P strains plus an HIV-1/M reference strain. IC50 values were determined after 3 days, and fold changes (FCs) were calculated relative to the HIV-1/M strain. Genotypic polymorphism was determined by amplification of codons 19-263 of the integrase; the natural occurrence of resistance-associated mutations was analysed using the main resistance algorithms and the IAS-USA list. VESPA analysis of the strain sequences was used to determine a signature pattern associated with higher FC.Results: Similar IC50 results were observed for the three drugs. Based on the value for the HIV-1/M reference strain, the data showed FC values <2.5 for raltegravir and dolutegravir, whereas the distribution for elvitegravir was heterogeneous, with FC > 10 for six strains (15%). Analysis of the non-M integrase sequences showed a high level of polymorphism without a major genotypic impact; it also revealed mutations that may be associated with the highest FC values obtained for elvitegravir.Conclusions: Our phenotypic data showed that non-M strains are globally susceptible to the three currently used INSTIs, but the impact of the high FC values observed for some strains with elvitegravir needs to be explored. Clinical data are now needed to confirm these phenotypic results. [ABSTRACT FROM AUTHOR]

Background: Single low-dose primaquine (PQ) reduces Plasmodium falciparum infectivity before it impacts gametocyte density. Here, we examined the effect of PQ on gametocyte sex ratio as a possible explanation for this early sterilizing effect.Methods: Quantitative reverse-transcription polymerase chain reaction assays were developed to quantify female gametocytes (targeting Pfs25 messenger RNA [mRNA]) and male gametocytes (targeting Pf3D7_1469900 mRNA) in 2 randomized trials in Kenya and Mali, comparing dihydroartemisinin-piperaquine (DP) alone to DP with PQ. Gametocyte sex ratio was examined in relation to time since treatment and infectivity to mosquitoes.Results: In Kenya, the median proportion of male gametocytes was 0.33 at baseline. Seven days after treatment, gametocyte density was significantly reduced in the DP-PQ arm relative to the DP arm (females: 0.05% [interquartile range {IQR}, 0.0-0.7%] of baseline; males: 3.4% [IQR, 0.4%-32.9%] of baseline; P < .001). Twenty-four hours after treatment, gametocyte sex ratio became male-biased and was not significantly different between the DP and DP-PQ groups. In Mali, there was no significant difference in sex ratio between the DP and DP-PQ groups (>0.125 mg/kg) 48 hours after treatment, and gametocyte sex ratio was not associated with mosquito infection rates.Conclusions: The early sterilizing effects of PQ may not be explained by the preferential clearance of male gametocytes and may be due to an effect on gametocyte fitness. [ABSTRACT FROM AUTHOR]

Background: The anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is 'vessel co-option,' ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents.Methods: To study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology.Results: While sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic 'rebound' effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option.Conclusions: This is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling. [ABSTRACT FROM AUTHOR]

Objectives: The resistance development, cross-resistance to other NNRTIs and the impact of resistance on viral replicative fitness were studied for the new and potent NNRTI UAMC01398.Methods: Resistance was selected by dose escalation and by single high-dose selection against a comprehensive panel of NNRTIs used as therapeutics and NNRTIs under investigation for pre-exposure prophylaxis of sexual HIV transmission. A panel of 27 site-directed mutants with single mutations or combinations of mutations involved in reverse transcriptase (RT) inhibitor-mediated resistance was developed and used to confirm resistance to UAMC01398. Cross-resistance to other NNRTIs was assessed, as well as susceptibility of UAMC01398-resistant HIV to diarylpyrimidine-resistant viruses. Finally, the impact of UAMC01398 resistance on HIV replicative fitness was studied.Results: We showed that UAMC01398 has potent activity against dapivirine-resistant HIV, that at least four mutations in the RT are required in concert for resistance and that the resistance profile is similar to rilpivirine, both genotypically and phenotypically. Resistance development to UAMC01398 is associated with a severe fitness cost.Conclusions: These data, together with the enhanced safety profile and good solubility in aqueous gels, make UAMC01398 an excellent candidate for HIV topical prevention. [ABSTRACT FROM AUTHOR]

Physical training has been shown to be important to the control of muscle mass during aging, through the activation of several pathways including, IGF1-AKT and PGC-1α. Also, it was demonstrated that LRP130, a component of the PGC-1α complex, is important for the PGC-1α-dependent transcription of several mitochondrial genes in vivo. To explore the role of physical training during aging, we investigated the effects on muscle recovery after short-term immobilization followed by 3 or 7 days with aerobic or resistance training. Using morphological (myofibrillar adenosine triphosphatase activity, to assess the total muscle fiber cross-sectional area (CSA) and the frequency of specific fiber types), biochemical (myosin heavy chain), and molecular analyses (quantitative real-time PCR, functional pathways analyses, and Western blot), our results indicated that after an atrophic stimulus, only animals subjected to aerobic training showed entire recovery of cross-sectional area; aerobic training reduced the ubiquitin-proteasome system components involved in muscle atrophy after 3 days of recovery, and the upregulation in PGC-1α expression enhanced the process of muscle recovery by inhibiting the FoxO pathway, with the possible involvement of LRP130. These results suggest that aerobic training enhanced the muscle regeneration process after disuse-induced atrophy in aged rats possibly through of the LRP130/PGC-1α complex by inhibiting the ubiquitin-proteasome system. [ABSTRACT FROM AUTHOR]

Long-term treatment with interferon (IFN) alfa plus ribavirin decreases the proviral human immunodeficiency virus type 1 (HIV) DNA level. However, the short-term impact of IFN alfa on persistent HIV and its effects on immune activation after antiretroviral therapy remain unknown. Our study showed that the cell-associated HIV RNA level and CD4(+) T-cell activation decreased in the IFN group (n = 10). No changes were detected in levels of residual plasma viremia, replication-competent reservoirs, proviral DNA, or 2-long-terminal repeat circles, although APOBEC3G, TRIM5α, BST2, and TRIM22 were upregulated in the IFN group. These data suggest that short-term treatment with IFN alfa combined with RBV decreases HIV expression, in part through inhibition of HIV transcription by TRIM22 and decrease in T-cell activation. [ABSTRACT FROM AUTHOR]