Variants of HCMV UL18 Sequenced Directly from Clinical Specimens Associate with Antibody and T-Cell Responses to HCMV

Around 80% of adults worldwide carry human cytomegaloviris (HCMV). The HCMV gene UL18 is a homolog of HLA class I genes and encodes a protein with high affinity for the NK and T-cell cytotoxicity inhibitor LIR-1. UL18 was deep sequenced from blood, saliva or urine from Indonesian people with HIV (PWH) (n = 28), Australian renal transplant recipients (RTR) (n = 21), healthy adults (n = 7) and neonates (n = 4). 95% of samples contained more than one variant of HCMV UL18, as defined by carriage of nonsynonymous variations. When aligned with immunological markers of the host’s burden of HCMV, the S318N variation associated with high levels of antibody reactive with HCMV lysate in PWH over 12 months on antiretroviral therapy. The A107T variation associated with HCMV antibody levels and inflammatory biomarkers in PWH at early timepoints. Variants D32G, D248N, V250A and E252D aligned with elevated HCMV antibody levels in RTR, while M191K, E196Q and F165L were associated with HCMV-reactive T-cells and proportions of Vδ2⁻ γδ T-cells—populations linked with high burdens of HCMV. We conclude that UL18 is a highly variable gene, where variation may alter the persistent burden of HCMV and/or the host response to that burden.     

二酮酸类HIV整合酶抑制剂研究进展

为了开发高效、低毒、生物利用度好的HIV整合酶抑制剂,对几种重要的二酮酸类HIV整合酶抑制剂做了介绍,为寻找新的有效的抗艾滋病药物提供理论依据.对此类化合物的药效团、与HIV整合酶的作用机理和靶点设计、临床研究进展等方面进行分析比较,探讨了进一步的研究和发展方向.对二酮酸类HIV整合酶抑制剂的研究和开发具有借鉴意义.     

Timing HIV infection with a simple and accurate population viral dynamics model

Clinical trials for HIV prevention can require knowledge of infection times to subsequently determine protective drug levels. Yet, infection timing is difficult when study visits are sparse. Using population nonlinear mixed-effects (pNLME) statistical inference and viral loads from 46 RV217 study participants, we developed a relatively simple HIV primary infection model that achieved an excellent fit to all data. We also discovered that Aptima assay values from the study strongly correlated with viral loads, enabling imputation of very early viral loads for 28/46 participants. Estimated times between infecting exposures and first positives were generally longer than prior estimates (average of two weeks) and were robust to missing viral upslope data. On simulated data, we found that tighter sampling before diagnosis improved estimation more than tighter sampling after diagnosis. Sampling weekly before and monthly after diagnosis was a pragmatic design for good timing accuracy. Our pNLME timing approach is widely applicable to other infections with existing mathematical models. The present model could be used to simulate future HIV trials and may help estimate protective thresholds from the recently completed antibody-mediated prevention trials.     

Unified model of short- and long-term HIV viral rebound for clinical trial planning

Antiretroviral therapy (ART) effectively controls HIV infection, suppressing HIV viral loads. Typically suspension of therapy is rapidly followed by rebound of viral loads to high, pre-therapy levels. Indeed, a recent study showed that approximately 90% of treatment interruption study participants show viral rebound within at most a few months of therapy suspension, but the remaining 10%, showed viral rebound some months, or years, after ART suspension. Some may even never rebound. We investigate and compare branching process models aimed at gaining insight into these viral dynamics. Specifically, we provide a theory that explains both short- and long-term viral rebounds, and post-treatment control, via a multitype branching process with time-inhomogeneous rates, validated with data from Li et al. (Li et al. 2016 AIDS 30, 343–353. (doi:10.1097/QAD.0000000000000953)). We discuss the associated biological interpretation and implications of our best-fit model. To test the effectiveness of an experimental intervention in delaying or preventing rebound, the standard practice is to suspend therapy and monitor the study participants for rebound. We close with a discussion of an important application of our modelling in the design of such clinical trials.     

Viral Interactions with Adaptor-Protein Complexes: A Ubiquitous Trait among Viral Species

Numerous viruses hijack cellular protein trafficking pathways to mediate cell entry or to rearrange membrane structures thereby promoting viral replication and antagonizing the immune response. Adaptor protein complexes (AP), which mediate protein sorting in endocytic and secretory transport pathways, are one of the conserved viral targets with many viruses possessing AP-interacting motifs. We present here different mechanisms of viral interference with AP complexes and the functional consequences that allow for efficient viral propagation and evasion of host immune defense. The ubiquity of this phenomenon is evidenced by the fact that there are representatives for AP interference in all major viral families, covered in this review. The best described examples are interactions of human immunodeficiency virus and human herpesviruses with AP complexes. Several other viruses, like Ebola, Nipah, and SARS-CoV-2, are pointed out as high priority disease-causative agents supporting the need for deeper understanding of virus-AP interplay which can be exploited in the design of novel antiviral therapies.     

Intergenerational benefits of family-based HIV interventions.

The longitudinal impact of a family-based intervention on grandchildren of parents with HIV (PWH) is evaluated. Because PWH and their daughters demonstrated gains over 6 years when randomized to a coping skills intervention compared with a control condition, the adjustment of the PWH's grandchildren was also compared across conditions. Grandchildren in the intervention condition reported significantly fewer internalizing and externalizing behavioral symptoms compared with grandchildren in the control condition. There is weak evidence that grandchildren in the intervention condition had higher scores on measures of cognitive development and more positive home environments. These results suggest that there are possibly long-term, intergenerational benefits of an intervention for families coping with HIV. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conceptualizing the influence of social agents of behavior change: A meta-analysis of the effectiveness of HIV-prevention interventionists for different groups.

A meta-analysis of 166 HIV-prevention interventions tested theoretical predictions about the effects of experts, lay community members, and similar and dissimilar others, as agents of change. In general, expert interventionists produced greater behavior change than lay community members, and the demographic and behavioral similarity between the interventionist and the recipients facilitated behavioral change. Equally importantly, there were differences across groups in the efficacy of various sources, especially among populations of low status and/or power. These findings support the hypothesis that unempowered populations are more sensitive to characteristics of the interventionists who can facilitate access to various resources. In addition, they suggest the need to ensure the availability of health professionals from diverse demographic and behavioral backgrounds. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Target groups for preventing AIDS among intravenous drug users: II. The "hard" data studies.

Studies were reviewed with respect to three different target groups for preventing AIDS among intravenous (IV) drug users by (a) providing drug abuse treatment for those who want to stop injecting drugs, (b) providing "safer" injection for those who are likely to continue injecting, and (c) preventing drug injection among those who are at high risk for beginning to inject. The studies reviewed were limited to those that include "hard" data: validated self-reports, seroprevalence outcomes, or self-reports of behavior that is opposed to any of the demand characteristics generated by the research setting. For two groups of current IV drug users—those entering drug treatment and those continuing to inject—these hard data studies show rapidly induced AIDS risk reduction but suggest a need for large-scale change maintained over long time periods. In terms of preventing initial injection, alternative forms of intense drug use have emerged but have not supplanted drug injection, and basic knowledge of AIDS does not appear to deter initial drug injection. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

一类HIV／AIDS传播模型的T-S模糊控制

为抑制疾病的发展,构造了针对艾滋病传播相应的T-S模糊模型。利用T-S模糊控制方法,设计基于疫情发展的模糊控制器,使艾滋病传播模型在平衡点达到稳定状态。数值模拟结果验证了模糊控制器的合理性。