12 research outputs found
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria
Comprehensive transcriptome of the maize stalk borer, Busseola fusca, from multiple tissue types, developmental stages, and parasitoid wasp exposures
International audienc
Identifying Risk Factors for Recent HIV Infection in Kenya Using a Recent Infection Testing Algorithm: Results from a Nationally Representative Population-Based Survey
<div><p>Introduction</p><p>A recent infection testing algorithm (RITA) that can distinguish recent from long-standing HIV infection can be applied to nationally representative population-based surveys to characterize and identify risk factors for recent infection in a country.</p><p>Materials and Methods</p><p>We applied a RITA using the Limiting Antigen Avidity Enzyme Immunoassay (LAg) on stored HIV-positive samples from the 2007 Kenya AIDS Indicator Survey. The case definition for recent infection included testing recent on LAg and having no evidence of antiretroviral therapy use. Multivariate analysis was conducted to determine factors associated with recent and long-standing infection compared to HIV-uninfected persons. All estimates were weighted to adjust for sampling probability and nonresponse.</p><p>Results</p><p>Of 1,025 HIV-antibody-positive specimens, 64 (6.2%) met the case definition for recent infection and 961 (93.8%) met the case definition for long-standing infection. Compared to HIV-uninfected individuals, factors associated with higher adjusted odds of recent infection were living in Nairobi (adjusted odds ratio [AOR] 11.37; confidence interval [CI] 2.64–48.87) and Nyanza (AOR 4.55; CI 1.39–14.89) provinces compared to Western province; being widowed (AOR 8.04; CI 1.42–45.50) or currently married (AOR 6.42; CI 1.55–26.58) compared to being never married; having had ≥ 2 sexual partners in the last year (AOR 2.86; CI 1.51–5.41); not using a condom at last sex in the past year (AOR 1.61; CI 1.34–1.93); reporting a sexually transmitted infection (STI) diagnosis or symptoms of STI in the past year (AOR 1.97; CI 1.05–8.37); and being aged <30 years with: 1) HSV-2 infection (AOR 8.84; CI 2.62–29.85), 2) male genital ulcer disease (AOR 8.70; CI 2.36–32.08), or 3) lack of male circumcision (AOR 17.83; CI 2.19–144.90). Compared to HIV-uninfected persons, factors associated with higher adjusted odds of long-standing infection included living in Coast (AOR 1.55; CI 1.04–2.32) and Nyanza (AOR 2.33; CI 1.67–3.25) provinces compared to Western province; being separated/divorced (AOR 1.87; CI 1.16–3.01) or widowed (AOR 2.83; CI 1.78–4.45) compared to being never married; having ever used a condom (AOR 1.61; CI 1.34–1.93); and having a STI diagnosis or symptoms of STI in the past year (AOR 1.89; CI 1.20–2.97). Factors associated with lower adjusted odds of long-standing infection included using a condom at last sex in the past year (AOR 0.47; CI 0.36–0.61), having no HSV2-infection at aged <30 years (AOR 0.38; CI 0.20–0.75) or being an uncircumcised male aged <30 years (AOR 0.30; CI 0.15–0.61).</p><p>Conclusion</p><p>We identified factors associated with increased risk of recent and longstanding HIV infection using a RITA applied to blood specimens collected in a nationally representative survey. Though some false-recent cases may have been present in our sample, the correlates of recent infection identified were epidemiologically and biologically plausible. These methods can be used as a model for other countries with similar epidemics to inform targeted combination prevention strategies aimed to drastically decrease new infections in the population.</p></div
HIV-antibody-positive specimens in the 2007 Kenya AIDS Indicator Survey.
<p>HIV-antibody-positive specimens in the 2007 Kenya AIDS Indicator Survey.</p
Factors associated with recent and long-term infection among persons aged 15–64 years in Kenya, 2007 Kenya AIDS Indicator Survey.
<p>Factors associated with recent and long-term infection among persons aged 15–64 years in Kenya, 2007 Kenya AIDS Indicator Survey.</p
Frequencies and weighted proportions of select demographic, behavioral, and biologic variables among HIV-infected women and men aged 15–64 years by recent and long-standing infection status, 2007 Kenya AIDS Indicator Survey.
<p>Frequencies and weighted proportions of select demographic, behavioral, and biologic variables among HIV-infected women and men aged 15–64 years by recent and long-standing infection status, 2007 Kenya AIDS Indicator Survey.</p
Frequencies and weighted proportions of select demographic, behavioral, and biologic variables among HIV-uninfected women and men aged 15–64 years, 2007 Kenya AIDS Indicator Survey.
<p>Frequencies and weighted proportions of select demographic, behavioral, and biologic variables among HIV-uninfected women and men aged 15–64 years, 2007 Kenya AIDS Indicator Survey.</p
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria