Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, ID, United States.
Institute for Modeling Collaboration and Innovation, University of Idaho, Moscow, ID, United States.
Front Cell Infect Microbiol. 2020 Nov 26;10:600112. doi: 10.3389/fcimb.2020.600112. eCollection 2020.
Antifolate resistance is significant in Kenya and presumed to result from extensive use and cross-resistance between antifolate antimalarials and antibiotics, including cotrimoxazole/Bactrim used for HIV-1 chemotherapy. However, little is known about antifolate-resistant malaria in the context of newly diagnosed HIV-1 co-infection prior to administration of HIV-1 chemotherapy. Blood samples from a cross-sectional study of asymptomatic adult Kenyans enrolled during voluntary HIV testing were analyzed by PCR for spp. More than 95% of volunteers with identifiable parasite species (132 HIV-1 co-infected) were infected with alone or with and/or . Deep sequencing was used to screen for mutations in (N51I, C59R, S108N, I164L) and (S436H, A437G, K540E, A581G) from 1133 volunteers. Individual mutations in DHPS but not DHFR correlated with HIV-1 status. DHFR haplotype diversity was significantly different among volunteers by gender and HIV-1 status. DHPS haplotype diversity by HIV-1 status was significantly different between volunteers paired by age and gender, indicating that patterns of resistance were independent of these variables. Molecular simulations for a novel DHPS mutation (I504T) suggested that the mutated protein has increased affinity for the endogenous ligand DHPPP and decreased affinity for drug binding. A sub-group of monoclonal infections revealed that age and parasitemia were not correlated and enabled identification of a rare septuple-mutant haplotype (IRNL-HGEA). In our study, adult Kenyans newly diagnosed with HIV-1 infection were predominantly infected with moderately resistant , with patterns of infecting parasite genotypes significantly associated with HIV-1 status. Together with the discovery of DHPS I504T, these data indicate that antifolate resistance continues to evolve in Kenya. Further, they highlight the need to understand the effects of associated mutations on both fitness and resistance of in the context of HIV-1 co-infection to better inform treatment for asymptomatic malaria.
抗叶酸耐药性在肯尼亚很常见，据推测是由于抗叶酸抗疟药物和抗生素（包括用于 HIV-1 化疗的复方新诺明/复方磺胺甲噁唑）的广泛使用和交叉耐药导致的。然而，在开始 HIV-1 化疗之前，对于新诊断的 HIV-1 合并感染中的抗叶酸耐药性疟疾，人们知之甚少。通过 PCR 对在自愿 HIV 检测期间招募的无症状肯尼亚成年志愿者的血液样本进行分析，以确定 spp. 在可识别寄生虫物种的志愿者中（132 名 HIV-1 合并感染），超过 95%的志愿者单独感染 或 与 和/或 感染。对来自 1133 名志愿者的 1133 名志愿者进行深度测序，以筛选 （N51I、C59R、S108N、I164L）和 （S436H、A437G、K540E、A581G）的突变。DHPS 中的个体突变，但不是 DHFR，与 HIV-1 状态相关。DHFR 单倍型多样性在志愿者中因性别和 HIV-1 状态而异。志愿者的 DHPS 单倍型多样性因 HIV-1 状态而异，年龄和性别配对的志愿者之间差异显著，表明耐药模式与这些变量无关。对一种新的 DHPS 突变（I504T）的分子模拟表明，突变蛋白对内源性配体 DHPPP 的亲和力增加，对药物结合的亲和力降低。一组单克隆感染表明，年龄和寄生虫血症没有相关性，并能够识别罕见的七重突变单倍型（IRNL-HGEA）。在我们的研究中，新诊断为 HIV-1 感染的肯尼亚成年患者主要感染中度耐药的 ，感染寄生虫基因型的模式与 HIV-1 状态显著相关。与 DHPS I504T 的发现一起，这些数据表明抗叶酸耐药性在肯尼亚仍在继续演变。此外，它们强调需要了解相关突变对 HIV-1 合并感染中 的适应性和耐药性的影响，以便更好地为无症状疟疾的治疗提供信息。
