Publications by authors named "Sarah Joseph"

85 Publications

A Novel Sample Selection Approach to Aid the Identification of Factors That Correlate With the Control of HIV-1 Infection.

Front Immunol 2021 11;12:634832. Epub 2021 Mar 11.

IAVI Human Immunology Laboratory, Imperial College London, London, United Kingdom.

Individuals infected with HIV display varying rates of viral control and disease progression, with a small percentage of individuals being able to spontaneously control infection in the absence of treatment. In attempting to define the correlates associated with natural protection against HIV, extreme heterogeneity in the datasets generated from systems methodologies can be further complicated by the inherent variability encountered at the population, individual, cellular and molecular levels. Furthermore, such studies have been limited by the paucity of well-characterised samples and linked epidemiological data, including duration of infection and clinical outcomes. To address this, we selected 10 volunteers who rapidly and persistently controlled HIV, and 10 volunteers each, from two control groups who failed to control (based on set point viral loads) from an acute and early HIV prospective cohort from East and Southern Africa. A propensity score matching approach was applied to control for the influence of five factors (age, risk group, virus subtype, gender, and country) known to influence disease progression on causal observations. Fifty-two plasma proteins were assessed at two timepoints in the 1st year of infection. We independently confirmed factors known to influence disease progression such as the B57 HLA Class I allele, and infecting virus Subtype. We demonstrated associations between circulating levels of MIP-1α and IL-17C, and the ability to control infection. IL-17C has not been described previously within the context of HIV control, making it an interesting target for future studies to understand HIV infection and transmission. An in-depth systems analysis is now underway to fully characterise host, viral and immunological factors contributing to control.
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http://dx.doi.org/10.3389/fimmu.2021.634832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991997PMC
March 2021

HIV-1 infection and the lack of viral control are associated with greater expression of interleukin-21 receptor on CD8+ T cells.

AIDS 2021 Mar 11. Epub 2021 Mar 11.

IAVI Human Immunology Laboratory, Imperial College London, London, UK.

Objectives: Interleukin-21 (IL-21) has been linked with the generation of virus-specific memory CD8+ T cells following acute infection with HIV and reduced exhaustion of CD8+ T cells. IL-21 has also been implicated in the promotion of CD8+ T cell effector functions during viral infection. Little is known about the expression of interleukin-21 receptor (IL-21R) during HIV-1 infection or its role in HIV-1-specific CD8+ T cell maintenance and subsequent viral control.

Methods: We compared levels of IL-21R expression on total and memory subsets of CD8+ T cells from HIV-1-ve and HIV-1+ve donors. We also measured IL-21R on antigen specific CD8+ T cells in volunteers who were positive for HIV-1 and had CMV responding T cells. Finally, we quantified plasma IL-21 in treatment naïve HIV+ individuals and compared this with IL-21R expression.

Results: IL-21R expression was significantly higher on CD8+ T cells (p= 0.0256), and on central memory (p = 0.0055) and effector memory (p = 0.0487) CD8+ T cell subsets from HIV-1+ve individuals relative to HIV-1-ve individuals. For those infected with HIV-1, the levels of IL-21R expression on HIV-1-specific CD8+ T cells correlated significantly with visit viral load (r  =  0.6667, p  =  0.0152, n = 13) and inversely correlated with plasma IL-21 (r  =  0.6273, p  =  0.0440, n = 11). Lastly, CD8+ T cells from individuals with lower set point viral load who demonstrated better viral control had the lowest levels of IL-21R expression and highest levels of plasma IL-21.

Conclusions: Our data demonstrates significant associations between IL-21R expression on peripheral CD8+ T cells and viral load, as well as disease trajectory. This suggests that the IL-21 receptor could be a novel marker of CD8+ T cell dysfunction during HIV-1 infection.
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http://dx.doi.org/10.1097/QAD.0000000000002864DOI Listing
March 2021

Furin is not required for processing of mesothelin precursor protein.

Biochim Biophys Acta Mol Cell Res 2021 Apr 19;1868(5):118967. Epub 2021 Jan 19.

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.bbamcr.2021.118967DOI Listing
April 2021

Frequent Anti-V1V2 Responses Induced by HIV-DNA Followed by HIV-MVA with or without CN54rgp140/GLA-AF in Healthy African Volunteers.

Microorganisms 2020 Nov 4;8(11). Epub 2020 Nov 4.

Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden.

Antibody responses that correlated with reduced risk of HIV acquisition in the RV144 efficacy trial were assessed in healthy African volunteers who had been primed three times with HIV-DNA (subtype A, B, C) and then randomized into two groups; group 1 was boosted twice with HIV-MVA (CRF01_AE) and group 2 with the same HIV-MVA coadministered with subtype C envelope (Env) protein (CN54rgp140/GLA-AF). The fine specificity of plasma Env-specific antibody responses was mapped after the final vaccination using linear peptide microarray technology. Binding IgG antibodies to the V1V2 loop in CRF01_AE and subtype C Env and Env-specific IgA antibodies were determined using enzyme-linked immunosorbent assay. Functional antibody-dependent cellular cytotoxicity (ADCC)-mediating antibody responses were measured using luciferase assay. Mapping of linear epitopes within HIV-1 Env demonstrated strong targeting of the V1V2, V3, and the immunodominant region in gp41 in both groups, with additional recognition of two epitopes located in the C2 and C4 regions in group 2. A high frequency of V1V2-specific binding IgG antibody responses was detected to CRF01_AE (77%) and subtype C antigens (65%). In conclusion, coadministration of CN54rgp140/GLA-AF with HIV-MVA did not increase the frequency, breadth, or magnitude of anti-V1V2 responses or ADCC-mediating antibodies induced by boosting with HIV-MVA alone.
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http://dx.doi.org/10.3390/microorganisms8111722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693996PMC
November 2020

The HIV-1 latent reservoir is largely sensitive to circulating T cells.

Elife 2020 10 6;9. Epub 2020 Oct 6.

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, United States.

HIV-1-specific CD8+ T cells are an important component of HIV-1 curative strategies. Viral variants in the HIV-1 reservoir may limit the capacity of T cells to detect and clear virus-infected cells. We investigated the patterns of T cell escape variants in the replication-competent reservoir of 25 persons living with HIV-1 (PLWH) durably suppressed on antiretroviral therapy (ART). We identified all reactive T cell epitopes in the HIV-1 proteome for each participant and sequenced HIV-1 outgrowth viruses from resting CD4+ T cells. All non-synonymous mutations in reactive T cell epitopes were tested for their effect on the size of the T cell response, with a≥50% loss defined as an escape mutation. The majority (68%) of T cell epitopes harbored no detectable escape mutations. These findings suggest that circulating T cells in PLWH on ART could contribute to control of rebound and could be targeted for boosting in curative strategies.
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http://dx.doi.org/10.7554/eLife.57246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593086PMC
October 2020

Macrophage Tropism in Pathogenic HIV-1 and SIV Infections.

Viruses 2020 09 25;12(10). Epub 2020 Sep 25.

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Most myeloid lineage cells express the receptor and coreceptors that make them susceptible to infection by primate lentiviruses (SIVs and HIVs). However, macrophages are the only myeloid lineage cell commonly infected by SIVs and/or HIVs. The frequency of infected macrophages varies greatly across specific host and virus combinations as well as disease states, with infection rates being greatest in pathogenic SIV infections of non-natural hosts (i.e., Asian nonhuman primates (Asian NHPs)) and late in untreated HIV-1 infection. In contrast, macrophages from natural SIV hosts (i.e., African NHPs) are largely resistant to infection due to entry and/or post-entry restriction mechanisms. These highly variable rates of macrophage infection may stem from differences in the host immune environment, entry and post-entry restriction mechanisms, the ability of a virus to adapt to efficiently infect macrophages, and the pleiotropic effects of macrophage-tropism including the ability to infect cells lacking CD4 and increased neutralization sensitivity. Questions remain about the relationship between rates of macrophage infection and viral pathogenesis, with some evidence suggesting that elevated levels of macrophage infection may contribute to greater pathogenesis in non-natural SIV hosts. Alternatively, extensive infection of macrophages may only emerge in the context of high viral loads and immunodeficiency, making it a symptom of highly pathogenic infections, not a primary driver of pathogenesis.
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http://dx.doi.org/10.3390/v12101077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601331PMC
September 2020

Time for remodeling: SNF2-family DNA translocases in replication fork metabolism and human disease.

DNA Repair (Amst) 2020 11 15;95:102943. Epub 2020 Aug 15.

Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. Electronic address:

Over the course of DNA replication, DNA lesions, transcriptional intermediates and protein-DNA complexes can impair the progression of replication forks, thus resulting in replication stress. Failure to maintain replication fork integrity in response to replication stress leads to genomic instability and predisposes to the development of cancer and other genetic disorders. Multiple DNA damage and repair pathways have evolved to allow completion of DNA replication following replication stress, thus preserving genomic integrity. One of the processes commonly induced in response to replication stress is fork reversal, which consists in the remodeling of stalled replication forks into four-way DNA junctions. In normal conditions, fork reversal slows down replication fork progression to ensure accurate repair of DNA lesions and facilitates replication fork restart once the DNA lesions have been removed. However, in certain pathological situations, such as the deficiency of DNA repair factors that protect regressed forks from nuclease-mediated degradation, fork reversal can cause genomic instability. In this review, we describe the complex molecular mechanisms regulating fork reversal, with a focus on the role of the SNF2-family fork remodelers SMARCAL1, ZRANB3 and HLTF, and highlight the implications of fork reversal for tumorigenesis and cancer therapy.
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http://dx.doi.org/10.1016/j.dnarep.2020.102943DOI Listing
November 2020

Improved killing of HIV-infected cells using three neutralizing and non-neutralizing antibodies.

J Clin Invest 2020 10;130(10):5157-5170

Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.

The correlation of HIV-specific antibody-dependent cellular cytotoxicity (ADCC) responses with protection from and delayed progression of HIV-1 infection provides a rationale to leverage ADCC-mediating antibodies for treatment purposes. We evaluated ADCC mediated by different combinations of 2 to 6 neutralizing and non-neutralizing anti-HIV-1 Envelope (Env) mAbs, using concentrations ≤ 1 μg/mL, to identify combinations effective at targeting latent reservoir HIV-1 viruses from 10 individuals. We found that within 2 hours, combinations of 3 mAbs mediated more than 30% killing of HIV-infected primary CD4+ T cells in the presence of autologous NK cells, with the combination of A32 (C1C2), DH511.2K3 (MPER), and PGT121 (V3) mAbs being the most effective. Increasing the incubation of target and effector cells in the presence of mAb combinations from 2 to 24 hours resulted in increased specific killing of infected cells, even with neutralization-resistant viruses. The same combination eliminated reactivated latently HIV-1-infected cells in an ex vivo quantitative viral outgrowth assay. Therefore, administration of a combination of 3 mAbs should be considered in planning in vivo studies seeking to eliminate persistently HIV-1-infected cells.
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http://dx.doi.org/10.1172/JCI135557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524508PMC
October 2020

Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study.

Lancet Glob Health 2020 08 15;8(8):e1003-e1017. Epub 2020 Jun 15.

Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

Background: The risk of severe COVID-19 if an individual becomes infected is known to be higher in older individuals and those with underlying health conditions. Understanding the number of individuals at increased risk of severe COVID-19 and how this varies between countries should inform the design of possible strategies to shield or vaccinate those at highest risk.

Methods: We estimated the number of individuals at increased risk of severe disease (defined as those with at least one condition listed as "at increased risk of severe COVID-19" in current guidelines) by age (5-year age groups), sex, and country for 188 countries using prevalence data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 and UN population estimates for 2020. The list of underlying conditions relevant to COVID-19 was determined by mapping the conditions listed in GBD 2017 to those listed in guidelines published by WHO and public health agencies in the UK and the USA. We analysed data from two large multimorbidity studies to determine appropriate adjustment factors for clustering and multimorbidity. To help interpretation of the degree of risk among those at increased risk, we also estimated the number of individuals at high risk (defined as those that would require hospital admission if infected) using age-specific infection-hospitalisation ratios for COVID-19 estimated for mainland China and making adjustments to reflect country-specific differences in the prevalence of underlying conditions and frailty. We assumed males were twice at likely as females to be at high risk. We also calculated the number of individuals without an underlying condition that could be considered at increased risk because of their age, using minimum ages from 50 to 70 years. We generated uncertainty intervals (UIs) for our estimates by running low and high scenarios using the lower and upper 95% confidence limits for country population size, disease prevalences, multimorbidity fractions, and infection-hospitalisation ratios, and plausible low and high estimates for the degree of clustering, informed by multimorbidity studies.

Findings: We estimated that 1·7 billion (UI 1·0-2·4) people, comprising 22% (UI 15-28) of the global population, have at least one underlying condition that puts them at increased risk of severe COVID-19 if infected (ranging from <5% of those younger than 20 years to >66% of those aged 70 years or older). We estimated that 349 million (186-787) people (4% [3-9] of the global population) are at high risk of severe COVID-19 and would require hospital admission if infected (ranging from <1% of those younger than 20 years to approximately 20% of those aged 70 years or older). We estimated 6% (3-12) of males to be at high risk compared with 3% (2-7) of females. The share of the population at increased risk was highest in countries with older populations, African countries with high HIV/AIDS prevalence, and small island nations with high diabetes prevalence. Estimates of the number of individuals at increased risk were most sensitive to the prevalence of chronic kidney disease, diabetes, cardiovascular disease, and chronic respiratory disease.

Interpretation: About one in five individuals worldwide could be at increased risk of severe COVID-19, should they become infected, due to underlying health conditions, but this risk varies considerably by age. Our estimates are uncertain, and focus on underlying conditions rather than other risk factors such as ethnicity, socioeconomic deprivation, and obesity, but provide a starting point for considering the number of individuals that might need to be shielded or vaccinated as the global pandemic unfolds.

Funding: UK Department for International Development, Wellcome Trust, Health Data Research UK, Medical Research Council, and National Institute for Health Research.
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http://dx.doi.org/10.1016/S2214-109X(20)30264-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295519PMC
August 2020

MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage.

Nat Commun 2020 06 11;11(1):2948. Epub 2020 Jun 11.

Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.

Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. Here we characterize C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a DNA repair factor involved in HR. MCM8IP-deficient cells exhibit HR defects, especially in long-tract gene conversion, occurring downstream of RAD51 loading, consistent with a role for MCM8IP in HR-dependent DNA synthesis. Moreover, loss of MCM8IP confers cellular sensitivity to crosslinking agents and PARP inhibition. Importantly, we report that MCM8IP directly associates with MCM8-9, a helicase complex mutated in primary ovarian insufficiency, and RPA1. We additionally show that the interactions of MCM8IP with MCM8-9 and RPA facilitate HR and promote replication fork progression and cellular viability in response to treatment with crosslinking agents. Mechanistically, MCM8IP stimulates the helicase activity of MCM8-9. Collectively, our work identifies MCM8IP as a key regulator of MCM8-9-dependent DNA synthesis during DNA recombination and replication.
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http://dx.doi.org/10.1038/s41467-020-16718-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290032PMC
June 2020

Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation.

J Med Chem 2020 05 22;63(10):5242-5256. Epub 2020 Apr 22.

Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.

Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to discover a new class of orally bioavailable BRD4-selective inhibitors. Two potent BRD4 bromodomain 1 (BD1)-selective inhibitors (ZL0513) and (ZL0516) have been discovered with high binding affinity (IC values of 67-84 nM) and good selectivity over other BRD family proteins and distant BD-containing proteins. Both compounds significantly inhibited the expression of Toll-like receptor-induced inflammatory genes in vitro and airway inflammation in murine models. The cocrystal structure of in complex with human BRD4 BD1 at a high resolution of 2.0 Å has been solved, offering a solid structural basis for its binding validation and further structure-based optimization. These BRD4 BD1 inhibitors demonstrated impressive in vivo efficacy and overall promising pharmacokinetic properties, indicating their therapeutic potential for the treatment of inflammatory diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989030PMC
May 2020

Curing HIV: Seeking to Target and Clear Persistent Infection.

Cell 2020 04 26;181(1):189-206. Epub 2020 Mar 26.

International Center for the Advancement of Translational Science, Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Center for AIDS Research, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.

Human immunodeficiency virus type 1 (HIV-1) infection persists despite years of antiretroviral therapy (ART). To remove the stigma and burden of chronic infection, approaches to eradicate or cure HIV infection are desired. Attempts to augment ART with therapies that reverse viral latency, paired with immunotherapies to clear infection, have advanced into the clinic, but the field is still in its infancy. We review foundational studies and highlight new insights in HIV cure research. Together with advances in ART delivery and HIV prevention strategies, future therapies that clear HIV infection may relieve society of the affliction of the HIV pandemic.
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http://dx.doi.org/10.1016/j.cell.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896558PMC
April 2020

What can characterization of cerebrospinal fluid escape populations teach us about viral reservoirs in the central nervous system?

AIDS 2019 12;33 Suppl 2:S171-S179

Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Objective: To review the evidence that CSF (cerebrospinal fluid) escape populations are produced by viral reservoirs in the central nervous system (CNS).

Design: CSF escape is a rare phenomenon in which individuals on suppressive ART have well controlled systemic infections with elevated levels of HIV-1 RNA in their CSF. However, the rarity of CSF escape coupled with relatively low CSF viral loads has impeded detailed analyses of these populations. Here, and in a previous study, we performed genetic and phenotypic assessments of CSF escape populations to determine whether CSF escape is produced by CNS reservoirs or by cells trafficking through the CNS.

Methods: We report HIV-1 viral loads in the CSF and blood plasma of four individuals with CSF escape (one new example and three previously described examples). We performed phylogenetic analyses of the viral env gene to evaluate diversity within the CSF escape populations and performed entry analyses to determine whether Env proteins were adapted to entering macrophage/microglia.

Results: Two individuals had CSF escape produced by CNS reservoirs. In contrast, the remaining two cases were likely because of transient viral production from cells migrating into the CNS and releasing virus.

Conclusion: Together our analyses indicate that replication-competent HIV-1 can persist in the CNS during ART, but that not all cases of CSF escape are produced by CNS reservoirs. Our results also suggest that both CD4 T cells and macrophage/microglia can serve as persistent viral reservoirs in the CNS.
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http://dx.doi.org/10.1097/QAD.0000000000002253DOI Listing
December 2019

Measuring the contribution of γδ T cells to the persistent HIV reservoir.

AIDS 2020 03;34(3):363-371

Division of Infectious Diseases, Department of Medicine.

Objective: To study the contribution of γδ T cells to the persistent HIV reservoir.

Design: Fifteen HIV-seropositive individuals on suppressive ART were included. We performed parallel quantitative viral outgrowth assays (QVOA) of resting CD4 T (rCD4) cells in the presence or absence of γδ T cells.

Methods: Resting αβ+CD4 T cells were magnetically isolated from PBMCs using two different custom cocktails, only one kit contained antibodies to deplete γδ T cells, resulting in two populations: rCD4 cells and rCD4 cells depleted of γδ cells. Frequency of infection was analyzed by QVOA and DNA measurements.

Results: Recovery of replication-competent HIV from cultures of rCD4 cells was similar in 11 individuals despite the presence of γδ T cells. In four donors, HIV recovery was lower when γδ T cells were present. Expression of the cytotoxic marker CD16 on Vδ2 cells was the only variable associated with the lower HIV recovery. Our results highlight the potency of those responses since a mean of 10 000 γδ T cells were present within 2.5 million rCD4 cells. However, despite the low frequency of γδ T cells, the presence of cytotoxic Vδ2 cells correlated with lower HIV recovery from cultures of rCD4 cells.

Conclusion: Results of this study show that quantification of the contribution of γδ T cells to the reservoir is challenging because of their low numbers compared with conventional rCD4 cells and highlights the potent antiviral function of γδ T cells and the impact of their presence on the frequency of latent HIV infection.
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http://dx.doi.org/10.1097/QAD.0000000000002434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994336PMC
March 2020

The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation.

Sci Transl Med 2019 10;11(513)

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4 T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4 T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation.
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http://dx.doi.org/10.1126/scitranslmed.aaw5589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233356PMC
October 2019

Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure.

Front Immunol 2019 22;10:1966. Epub 2019 Aug 22.

Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Recent studies demonstrate that the stable HIV-1 reservoir in resting CD4 T cells is mostly formed from viruses circulating when combination antiretroviral therapy (ART) is initiated. Here we explore the immunological basis for these observations. Untreated HIV-1 infection is characterized by a progressive depletion of memory CD4 T cells which mostly express CD127, the α chain of the IL-7 receptor (IL-7R). Depletion results from both direct infection and bystander loss of memory CD4 T cells in part attributed to dysregulated IL-7/IL-7R signaling. While IL-7/IL7R signaling is not essential for the generation of effector CD4 T cells from naïve cells, it is essential for the further transition of effectors to memory CD4 T cells and their subsequent homeostatic maintenance. HIV-1 infection therefore limits the transition of CD4 T cells from an effector to long-lived memory state. With the onset of ART, virus load (VL) levels rapidly decrease and the frequency of CD127 CD4 memory T cells increases, indicating restoration of effector to memory transition in CD4 T cells. Collectively these data suggest that following ART initiation, HIV-1 infected effector CD4 T cells transition to long-lived, CD127 CD4 T cells forming the majority of the stable HIV-1 reservoir. We propose that combining ART initiation with inhibition of IL-7/IL-7R signaling to block CD4 T cell memory formation will limit the generation of long-lived HIV-infected CD4 T cells and reduce the overall size of the stable HIV-1 reservoir.
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http://dx.doi.org/10.3389/fimmu.2019.01966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714000PMC
September 2020

Precision Medicine Tools to Guide Therapy and Monitor Response to Treatment in a HER-2+ Gastric Cancer Patient: Case Report.

Front Oncol 2019 6;9:698. Epub 2019 Aug 6.

Department of Oncology, Lady Davis Institute, McGill University, Montreal, QC, Canada.

Trastuzumab, has played a major role in improving treatment outcomes in HER-2 positive gastric cancer. However, once there is disease progression there is a paucity of evidence for second line therapy. Patient-derived xenografts (PDXs) in combination with liquid biopsies can help guide individual therapeutic decisions and have now started to be studied. In the present case we established a PDX model from a metastatic HER-2+ gastric cancer patient and after the first engraftment passage we performed a mouse clinical trial to test T-DM1 as an alternative therapy for the patient. The PDX tumor response served as a guide to administer T-DM1 therapy to the patient who responded to treatment before relapsing 6 months later. Throughout out the clinical follow up of the patient, ctDNA levels of HER-2 copy number and a PIK3CA mutation were monitored and we found their correlation with drug response and disease progression to outperform that of CEA levels. This study highlights the utility of applying precision medicine tools combining PDX models to guide therapy with circulating tumor DNA (ctDNA) to monitor treatment response and disease progression.
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http://dx.doi.org/10.3389/fonc.2019.00698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691136PMC
August 2019

Envelope-Specific Recognition Patterns of HIV Vaccine-Induced IgG Antibodies Are Linked to Immunogen Structure and Sequence.

Front Immunol 2019 24;10:717. Epub 2019 Apr 24.

Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany.

A better understanding of the parameters influencing vaccine-induced IgG recognition of individual antigenic regions and their variants within the HIV Envelope protein (Env) can help to improve design of preventive HIV vaccines. Env-specific IgG responses were mapped in samples of the UKHVC003 Standard Group (UK003SG, = 11 from UK) and TaMoVac01 (TMV01, = 17 from Tanzania) HIV vaccine trials. Both trials consisted of three immunizations with DNA, followed by two boosts with recombinant Modified Vaccinia Virus Ankara (MVA), either mediating secretion of gp120 (UK003SG) or the presentation of cell membrane bound gp150 envelopes (TMV01) from infected cells, and an additional two boosts with 5 μg of CN54gp140 protein adjuvanted with glucopyranosyl lipid adjuvant (GLA). Env immunogen sequences in UK003SG were solely based on the clade C isolate CN54, whereas in TMV01 these were based on clades A, C, B, and CRF01AE. The peptide microarray included 8 globally representative Env sequences, CN54gp140 and the MVA-encoded Env immunogens from both trials, as well as additional peptide variants for hot spots of immune recognition. After the second MVA boost, UK003SG vaccinees almost exclusively targeted linear, non-glycosylated antigenic regions located in the inter-gp120 interface. In contrast, TMV01 recipients most strongly targeted the V2 region and an immunodominant region in gp41. The V3 region was frequently targeted in both trials, with a higher recognition magnitude for diverse antigenic variants observed in the UK003SG ( < 0.0001). After boosting with CN54gp140/GLA, the overall response magnitude increased with a more comparable recognition pattern of antigenic regions and variants between the two trials. Recognition of most immunodominant regions within gp120 remained significantly stronger in UK003SG, whereas V2-region recognition was not boosted in either group. IgG recognition of linear antigenic Env regions differed between the two trials particularly after the second MVA boost. Structural features of the MVA-encoded immunogens, such as secreted, monomeric gp120 vs. membrane-anchored, functional gp150, and differences in prime-boost immunogen sequence variability most probably contributed to these differences. Prime-boosting with multivalent Env immunogens during TMV01 did not improve variant cross-recognition of immunodominant peptide variants in the V3 region.
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http://dx.doi.org/10.3389/fimmu.2019.00717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492543PMC
October 2020

Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion.

Nat Commun 2019 02 13;10(1):728. Epub 2019 Feb 13.

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA.

After initiating antiretroviral therapy (ART), a rapid decline in HIV viral load is followed by a long period of undetectable viremia. Viral outgrowth assay suggests the reservoir continues to decline slowly. Here, we use full-length sequencing to longitudinally study the proviral landscape of four subjects on ART to investigate the selective pressures influencing the dynamics of the treatment-resistant HIV reservoir. We find intact and defective proviruses that contain genetic elements favoring efficient protein expression decrease over time. Moreover, proviruses that lack these genetic elements, yet contain strong donor splice sequences, increase relatively to other defective proviruses, especially among clones. Our work suggests that HIV expression occurs to a significant extent during ART and results in HIV clearance, but this is obscured by the expansion of proviral clones. Paradoxically, clonal expansion may also be enhanced by HIV expression that leads to splicing between HIV donor splice sites and downstream human exons.
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http://dx.doi.org/10.1038/s41467-019-08431-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374386PMC
February 2019

Predicting Efavirenz Concentrations in the Brain Tissue of HIV-Infected Individuals and Exploring their Relationship to Neurocognitive Impairment.

Clin Transl Sci 2019 05 27;12(3):302-311. Epub 2019 Feb 27.

Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Sparse data exist on the penetration of antiretrovirals into brain tissue. In this work, we present a framework to use efavirenz (EFV) pharmacokinetic (PK) data in plasma, cerebrospinal fluid (CSF), and brain tissue of eight rhesus macaques to predict brain tissue concentrations in HIV-infected individuals. We then perform exposure-response analysis with the model-predicted EFV area under the concentration-time curve (AUC) and neurocognitive scores collected from a group of 24 HIV-infected participants. Adult rhesus macaques were dosed daily with 200 mg EFV (as part of a four-drug regimen) for 10 days. Plasma was collected at 8 time points over 10 days and at necropsy, whereas CSF and brain tissue were collected at necropsy. In the clinical study, data were obtained from one paired plasma and CSF sample of participants prescribed EFV, and neuropsychological test evaluations were administered across 15 domains. PK modeling was performed using ADAPT version 5.0 Biomedical Simulation Resource, Los Angeles, CA) with the iterative two-stage estimation method. An eight-compartment model best described EFV distribution across the plasma, CSF, and brain tissue of rhesus macaques and humans. Model-predicted median brain tissue concentrations in humans were 31 and 8,000 ng/mL, respectively. Model-predicted brain tissue AUC was highly correlated with plasma AUC (γ = 0.99, P < 0.001) but not CSF AUC (γ = 0.34, P = 0.1) and did not show any relationship with neurocognitive scores (γ < 0.05, P > 0.05). This analysis provides an approach to estimate PK the brain tissue in order to perform PK/pharmacodynamic analyses at the target site.
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http://dx.doi.org/10.1111/cts.12620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510381PMC
May 2019

HIV-1 detection in the olfactory mucosa of HIV-1-infected participants.

AIDS 2019 03;33(4):665-674

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino.

Objective: HIV infection chronically affects the central nervous system (CNS). Olfactory mucosa is a unique site in the respiratory tract that is directly connected to the CNS; thus we wanted to evaluate olfactory mucosa as a surrogate of CNS sampling.

Design: We conducted a preliminary study examining HIV populations and susceptible cells in the olfactory mucosa.

Methods: Olfactory mucosa was sampled by minimally invasive brushing. Cerebrospinal fluid (CSF) analyses were performed as per routine clinical procedures. Olfactory marker protein, CD4+, CD8+, and trans-activator of transcription (TAT) expressions were assessed by immunohistochemistry. Plasma, CSF, and olfactory mucosa HIV-RNA were quantified using the Cobas AmpliPrep/Cobas TaqMan assay, whereas HIV proviral DNA was evaluated on peripheral blood mononuclear cell and olfactory mucosa. HIV-1 env deep sequencing was performed for phylogenetic analysis.

Results: Among ART-naive participants, 88.2% (15/17), and among ART-treated participants, 21.4% (6/28) had detectable HIV-RNA in samples from their olfactory mucosa; CSF escape was more common in patients with olfactory mucosa escape (50 vs. 7.9%; P = 0.010). Olfactory mucosa samples contained few cells positive for CD4, CD8, or HIV-DNA, and no HIV TAT-positive cells, indicating that this approach efficiently samples virions in the olfactory mucosa, but not HIV-infected cells. Yet, using a deep sequencing approach to phylogenetically compare partial HIV env genes in five untreated participants, we identified distinct viral lineages in the OM.

Conclusions: The results of this study suggest that nasal brushing is a well tolerated and useful technique for sampling the olfactory mucosa. HIV-RNA was detected in most naïve and in some treated patients, warranting larger longitudinal studies.
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http://dx.doi.org/10.1097/QAD.0000000000002102DOI Listing
March 2019

Human Immunodeficiency Virus Type 1 RNA Detected in the Central Nervous System (CNS) After Years of Suppressive Antiretroviral Therapy Can Originate from a Replicating CNS Reservoir or Clonally Expanded Cells.

Clin Infect Dis 2019 09;69(8):1345-1352

University of North Carolina Center for AIDS Research, University of North Carolina at Chapel Hill, San Francisco.

Background: Human immunodeficiency virus type 1 (HIV-1) populations are detected in cerebrospinal fluid (CSF) of some people on suppressive antiretroviral therapy (ART). Detailed analysis of these populations may reveal whether they are produced by central nervous system (CNS) reservoirs.

Methods: We performed a study of 101 asymptomatic participants on stable ART. HIV-1 RNA concentrations were cross-sectionally measured in CSF and plasma. In participants with CSF HIV-1 RNA concentrations sufficient for analysis, viral populations were genetically and phenotypically characterized over multiple time points.

Results: For 6% of participants (6 of 101), the concentration of HIV-1 RNA in their CSF was ≥0.5 log copies/mL above that of plasma (ie, CSF escape). We generated viral envelope sequences from CSF of 3 participants. One had a persistent CSF escape population that was macrophage-tropic, partially drug resistant, genetically diverse, and closely related to a minor macrophage-tropic lineage present in the blood prior to viral suppression and enriched for after ART. Two participants (1 suppressed and 1 not) had transient CSF escape populations that were R5 T cell-tropic with little genetic diversity.

Conclusions: Extensive analysis of viral populations in 1 participant revealed that CSF escape was from a persistently replicating population, likely in macrophages/microglia, present in the CNS over 3 years of ART. CSF escape in 2 other participants was likely produced by trafficking and transient expansion of infected T cells in the CNS. Our results show that CNS reservoirs can persist during ART and that CSF escape is not exclusively produced by replicating CNS reservoirs.
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http://dx.doi.org/10.1093/cid/ciy1066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938202PMC
September 2019

Optimizing the immunogenicity of HIV prime-boost DNA-MVA-rgp140/GLA vaccines in a phase II randomized factorial trial design.

PLoS One 2018 29;13(11):e0206838. Epub 2018 Nov 29.

Muhimbili University of Health and Allied Sciences (MUHAS), Department of Microbiology and Immunology, Dar es Salaam, Tanzania.

Background: We evaluated the safety and immunogenicity of (i) an intradermal HIV-DNA regimen given with/without intradermal electroporation (EP) as prime and (ii) the impact of boosting with modified vaccinia virus Ankara (HIV-MVA) administered with or without subtype C CN54rgp140 envelope protein adjuvanted with Glucopyranosyl Lipid A (GLA-AF) in volunteers from Tanzania and Mozambique.

Methods: Healthy HIV-uninfected adults (N = 191) were randomized twice; first to one of three HIV-DNA intradermal priming regimens by needle-free ZetaJet device at weeks 0, 4 and 12 (Group I: 2x0.1mL [3mg/mL], Group II: 2x0.1mL [3mg/mL] plus EP, Group III: 1x0.1mL [6mg/mL] plus EP). Second the same volunteers received 108 pfu HIV-MVA twice, alone or combined with CN54rgp140/GLA-AF, intramuscularly by syringe, 16 weeks apart. Additionally, 20 volunteers received saline placebo.

Results: Vaccinations and electroporation did not raise safety concerns. After the last vaccination, the overall IFN-γ ELISpot response rate to either Gag or Env was 97%. Intradermal electroporation significantly increased ELISpot response rates to HIV-DNA-specific Gag (66% group I vs. 86% group II, p = 0.026), but not to the HIV-MVA vaccine-specific Gag or Env peptide pools nor the magnitude of responses. Co-administration of rgp140/GLA-AF with HIV-MVA did not impact the frequency of binding antibody responses against subtype B gp160, C gp140 or E gp120 antigens (95%, 99%, 79%, respectively), but significantly enhanced the magnitude against subtype B gp160 (2700 versus 300, p<0.001) and subtype C gp140 (24300 versus 2700, p<0.001) Env protein. At relatively low titers, neutralizing antibody responses using the TZM-bl assay were more frequent in vaccinees given adjuvanted protein boost.

Conclusion: Intradermal electroporation increased DNA-induced Gag response rates but did not show an impact on Env-specific responses nor on the magnitude of responses. Co-administration of HIV-MVA with rgp140/GLA-AF significantly enhanced antibody responses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206838PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264478PMC
April 2019

Melatonin supplementation for the prevention of hospital-associated delirium.

Ment Health Clin 2017 Jul 26;7(4):143-146. Epub 2018 Mar 26.

PGY-1 Pharmacy Practice Resident, Greenville Health System, Greenville, South Carolina,

Characterized by acute alterations in cognition or consciousness, delirium is a transient neuropsychiatric syndrome that develops in a large percentage of hospitalized patients. Delirium is a robust predictor of increased morbidity, mortality, and health care costs, especially when diagnosed in the critical care setting. Although the exact pathogenesis behind delirium has yet to be defined, disturbances in the sleep-wake cycle are a core feature. Currently, no pharmacologic interventions are recommended for delirium prophylaxis. Due to the role of melatonin in regulating the sleep-wake cycle, its use in delirium has been investigated in recent years. Objective data has shown altered serum levels of melatonin and its precursor, tryptophan, in patients with delirium, further suggesting a correlation between melatonin and delirium. This article examines the available evidence and discusses considerations surrounding melatonin supplementation for the prevention of hospital-associated delirium.
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http://dx.doi.org/10.9740/mhc.2017.07.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007528PMC
July 2017

Editorial: The HIV/SIV Envelope Protein: From Structure To Function To Host Evasion.

Curr HIV Res 2018 ;16(1):3-4

Department of Microbiology and Immunology University of North Carolina at Chapel Hill Chapel Hill, NC, United States.

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http://dx.doi.org/10.2174/1570162X1601180419095704DOI Listing
April 2019

Differences in nicotine dependence, smoke exposure and consumer characteristics between smokers of machine-injected roll-your-own cigarettes and factory-made cigarettes.

Drug Alcohol Depend 2018 06 7;187:109-115. Epub 2018 Apr 7.

Department of Public Health Sciences, Penn State College of Medicine, 500 University Dr., Hershey, PA 17033, USA. Electronic address:

Background: Consumption of machine-injected roll-your-own (RYO) filtered cigarettes made from pipe tobacco increased almost 7-fold from 2008 to 2011 in the United States.

Methods: We used data from the Pennsylvania Adult Smoking Study to compare the differences in sociodemographic, smoking topography, nicotine dependence, and cotinine levels between 280 smokers using factory made (FM) cigarettes and 68 smokers using RYO cigarettes.

Results: RYO smokers were older (41 vs. 37, P = 0.053), had significantly lower levels of income (P < 0.001) and education (P = 0.007), and were less likely to be fully employed (P = 0.009). RYO smokers consumed more cigarettes per day [CPD] (21 vs. 15, P < 0.001), and had a higher mean score on the Fagerström Test for Cigarette/Nicotine Dependence (5.2 vs. 4.1, P < 0.001). The main reasons for choosing RYO cigarettes were the lower cost (68%) and believed they are less harmful (12%). The average cost per pack of FM cigarettes was $5.74 vs. $1.13 for RYO. In multiple regression analyses, RYO smokers had significantly lower cotinine levels across all levels of CPD. Among smokers of king-size cigarettes, mean interpuff interval (P < 0.05) and total smoke duration (P < 0.01) per cigarette was significantly greater in RYO smokers. In laboratory measurements, RYO cigarettes contained more tobacco by weight than FM cigarettes, but weight varied by both tobacco and cigarette tube brands.

Conclusions: Machine-injected RYO cigarettes made from pipe tobacco are cheaper than FM cigarettes but may have higher abuse liability. Smokers who might otherwise reduce their cigarette consumption or quit altogether may continue to smoke RYO cigarettes due to their affordability.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959786PMC
June 2018

The evolution of HIV-1 entry phenotypes as a guide to changing target cells.

J Leukoc Biol 2018 03 1;103(3):421-431. Epub 2018 Feb 1.

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Through a twist of fate the most common form of HIV-1, as defined by entry phenotype, was not appreciated until recently. The entry phenotype is closely linked to the target cell and thus to virus-host interactions and pathogenesis. The most abundant form of HIV-1 uses CCR5 as the coreceptor and requires a high density of CD4 for efficient entry, defining its target cell as the CD4+ memory T cell. This is the transmitted form of the virus, the form that is found in the blood, and the form that rebounds from the latent reservoir. When CD4+/CCR5+ T cells become limiting the virus evolves to use alternative target cells to support viral replication. In the CNS, the virus can evolve to use a cell that displays only a low density of CD4, while maintaining the use of CCR5 as the coreceptor. When this evolutionary variant evolves, it must be sustaining its replication in either macrophages or microglial cells, which display only a low density of CD4 relative to that on T cells. In the blood and lymphoid system, the major switch late in disease is from T cells expressing CD4 and CCR5 to T cells expressing CD4 and CXCR4, with a change in coreceptor specificity. Thus the virus responds in two different ways to different environments when its preferred target cell becomes limiting.
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http://dx.doi.org/10.1002/JLB.2RI0517-200RDOI Listing
March 2018

Multiple Sclerosis Mortality by Race/Ethnicity, Age, Sex, and Time Period in the United States, 1999-2015.

Neuroepidemiology 2018 16;50(1-2):35-40. Epub 2018 Jan 16.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

Background: Multiple sclerosis (MS) carries high morbidity and shortens life span. While there is recent recognition of other US minority populations such as blacks and Hispanics being affected with MS, examination of MS-specific mortality trends by race/ethnicity has been lacking.

Objective: To investigate MS mortality rates and trends in the United States by sex, age, and race/ethnicity.

Methods: We used the Compressed Mortality data file for 1999-2015 in the Wide-ranging online Data for Epidemiological Research system developed by the Center for Disease Control and Prevention to calculate the age-adjusted (US 2000 standard population) and age-specific MS mortality rate (per 100,000) by race/ethnicity and sex over time. Five mutually exclusive racial/ethnic groups were included in the analysis: non-Hispanic (NH) white, NH black, NH Asian or Pacific Islander (API), NH American Indian or Alaska Native, and Hispanic.

Results: The average annual age-adjusted MS mortality rate was highest among NH whites (0.90 for males and 1.50 for females) immediately followed by NH blacks (0.75 for males and 1.42 for females), and lowest among APIs (0.05 for males and 0.12 for females). Statistically significant, increasing trend in age-adjusted MS mortality was observed during 1999-2015 among NH whites and NH blacks regardless of sex, more substantially in the latter. Age-specific MS mortality patterns showed NH blacks had the highest rate under age 55 and NH whites had the highest rate after that age point. For these 2 groups, MS mortality increased with age in both sexes and peaked at ages 55-64 for NH blacks and 65-74 for NH whites before declining substantially, while for Hispanic and API groups the risk plateaued after age 55.

Conclusion: MS-specific mortality trends demonstrate distinctive differences by race/ethnicity and age. The observations that whites and females are more likely to die from MS is in line with the overall understanding that these groups are affected more by MS. However, the findings of blacks dying at an earlier age and having more substantially increasing mortality trends than whites suggest that MS burden weighs unequally by race. Further investigation into these trends may provide additional evidence into risk or protective factors within each group.
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http://dx.doi.org/10.1159/000484213DOI Listing
September 2019

Evolution of Host Target Cell Specificity During HIV-1 Infection.

Curr HIV Res 2018 ;16(1):13-20

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Background: Many details of HIV-1 molecular virology have been translated into lifesaving antiviral drugs. Yet, we have an incomplete understanding of the cells in which HIV-1 replicates in untreated individuals and persists in during antiretroviral therapy.

Methods: In this review we discuss how viral entry phenotypes have been characterized and the insights they have revealed about the target cells supporting HIV-1 replication. In addition, we will examine whether some HIV-1 variants have the ability to enter cells lacking CD4 (such as astrocytes) and the role that trans-infection plays in HIV-1 replication.

Results: HIV-1 entry into a target cell is determined by whether the viral receptor (CD4) and the coreceptor (CCR5 or CXCR4) are expressed on that cell. Sustained HIV-1 replication in a cell type can produce viral lineages that are tuned to the CD4 density and coreceptor expressed on those cells; a fact that allows us to use Env protein entry phenotypes to infer information about the cells in which a viral lineage has been replicating and adapting.

Conclusion: We now recognize that HIV-1 variants can be divided into three classes representing the primary target cells of HIV-1; R5 T cell-tropic variants that are adapted to entering memory CD4+ T cells, X4 T cell-tropic variants that are adapted to entering naïve CD4+ T cells and Mtropic variants that are adapted to entering macrophages and possibly other cells that express low levels of CD4. While much progress has been made, the relative contribution that infection of different cell subsets makes to viral pathogenesis and persistence is still being unraveled.
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http://dx.doi.org/10.2174/1570162X16666171222105721DOI Listing
April 2019

Symptomatic cerebrospinal fluid HIV-1 escape with no resistance-associated mutations following low-level plasma viremia.

J Neurovirol 2018 02 14;24(1):132-136. Epub 2017 Dec 14.

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Ospedale Amedeo di Savoia, C.so Svizzera 164, 10144, Torino, Italy.

The majority of neurologically symptomatic cerebrospinal fluid HIV-1 escape cases are connected with resistance-associated mutations and potentially explained by low cerebrospinal fluid antiretroviral concentrations. However, there are still significant knowledge gaps regarding the physiopathology and long-term management of neurosymptomatic viral escape. We report a case of Parkinson-like syndrome following cerebrospinal fluid HIV-1 escape in a 40-year-old female patient with an history of persistent low-level plasma viremia under treatment. No resistance-associated mutations, high viral diversity (env deep sequencing), adequate pharmacokinetics, atypical CD3-CD14-CD4+CD5-CD2-/+CD7-/+ lymphocytes, low-level Epstein-Barr virus replication, and white matter autoimmune reactivity were observed in the cerebrospinal fluid. Antiretroviral regimen modification led to rapid clinical and radiological improvements. This case may increase the current uncertain knowledge on the origin of cerebrospinal fluid HIV-1 and illustrates the consequences of uncontrolled compartmental viral replication; it also highlights the relevance and persistence of immune activation and the possibility of various detrimental mechanisms underlying neurosymptomatic viral escape.
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http://dx.doi.org/10.1007/s13365-017-0605-1DOI Listing
February 2018