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1.
AIDS. 2019 Aug 2. doi: 10.1097/QAD.0000000000002325. [Epub ahead of print]

The use of molecular markers for cervical screening of women living with hiv in South Africa.

Author information

1
Amsterdam UMC, Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam, Amsterdam, the Netherlands.
2
Department of Obstetrics and Gynaecology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa.
3
Department of Medical Virology, University of Pretoria and Lancet Laboratories, Pretoria, South Africa.

Abstract

OBJECTIVE:

To determine the performance of molecular screening strategies for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in comparison with cytology screening in women living with HIV (WLHIV).

DESIGN:

post-hoc analysis using data from a South African study cohort.

METHODS:

Cytology and human papillomavirus (HPV) based strategies were evaluated, including single test and FAM19A4/miR124-2 methylation triage strategies. Participants underwent cytology screening and a colposcopy-directed biopsy. Valid results on cytology, HPV status, 16/18 genotyping, and histology were available for 318 women. Detection of HPV and FAM19A4/miR124-2 hypermethylation was performed on DNA from cervical scrapes. Histological diagnosis of CIN3+ was used as outcome.

RESULTS:

Cytology provided highest specificity (91.6%), but lowest sensitivity (59.3%), whereas a single HPV test provided highest sensitivity (83.1%), but lowest specificity (66.4%). Combining cytology with methylation did not improve the performance compared with cytology alone: a slight increase in sensitivity was seen, at the cost of a decrease in specificity. Triage of high-risk HPV positive women with methylation increased specificity (76.1%) compared with a single HPV or cytology test, while maintaining acceptable sensitivity (72.9%). Similar performance was observed for HPV16/18 with methylation triage (sensitivity 79.7%, specificity 74.8%). The number of women needed to refer to detect one CIN3+ ranged from 1.5 (cytology) to 2.6 (single HPV test).

CONCLUSIONS:

Molecular screening strategies using HPV, with or without HPV16/18 genotyping, and FAM19A4/miR124-2 methylation have higher sensitivity with an acceptable loss in specificity compared with current cytology screening and are efficient for the detection of CIN3+ in South African WLHIV.

2.
AIDS. 2019 Aug 2. doi: 10.1097/QAD.0000000000002324. [Epub ahead of print]

Estimating and projecting the number of new HIV diagnoses and incidence in Spectrum's case surveillance and vital registration tool.

Author information

1
Center for Modeling and Analysis, Avenir Health, Glastonbury, Connecticut, USA.
2
Strategic Information and Monitoring Division, UNAIDS, Geneva, Switzerland.
3
Department of Infectious Disease Epidemiology, Imperial College London, London, UK.

Abstract

OBJECTIVE:

The United Nations Program on HIV/AIDS-supported Spectrum software package is used by most countries worldwide to monitor the HIV epidemic. In Spectrum, HIV incidence trends among adults (aged 15-49 years) are derived by either fitting to seroprevalence surveillance and survey data or generating curves consistent with case surveillance and vital registration data, such as historical trends in the number of newly diagnosed infections or AIDS-related deaths. This article describes development and application of the case surveillance and vital registration (CSAVR) tool for United Nations Program on HIV/AIDS' 2019 estimate round.

METHODS:

Incidence in CSAVR is either estimated directly using single logistic, double logistic, or spline functions, or indirectly via the 'r-logistic' model, which represents the (log-transformed) per-capita transmission rate using a logistic function. The propensity to get diagnosed is assumed to be monotonic, following a Gamma cumulative distribution function and proportional to mortality as a function of time since infection. Model parameters are estimated from a combination of historical surveillance data on newly reported HIV cases, mean CD4 at HIV diagnosis and estimates of AIDS-related deaths from vital registration systems. Bayesian calibration is used to identify the best fitting incidence trend and uncertainty bounds.

RESULTS:

We used CSAVR to estimate HIV incidence, number of new diagnoses, mean CD4 at diagnosis and the proportion undiagnosed in 31 European, Latin American, Middle Eastern, and Asian-Pacific countries. The spline model appeared to provide the best fit in most countries (45%), followed by the r-logistic (25%), double logistic (25%), and single logistic models. The proportion of HIV-positive people who knew their status increased from about 0.31 [interquartile range (IQR): 0.10-0.45] in 1990 to about 0.77 (IQR: 0.50-0.89) in 2017. The mean CD4 at diagnosis appeared to be stable, decreasing from 410 cells/μl (IQR: 224-567) in 1990 to 373 cells/μl (IQR: 174-475) by 2017.

CONCLUSION:

Robust case surveillance and vital registration data are routinely available in many middle-income and high-income countries while HIV seroprevalence surveillance and survey data may be scarce. In these countries, the CSAVR offers a simpler, improved approach to estimating and projecting trends in both HIV incidence and knowledge of HIV status.

3.
AIDS. 2019 Aug 2. doi: 10.1097/QAD.0000000000002342. [Epub ahead of print]

The proportion of CD57+ cells among effector CD8+ T cells is lower HIV controllers compared to ART treated patients.

Author information

1
CEA - Université Paris Sud 11 - INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, IBFJ, Fontenay-aux-Roses, France.
2
Universite[Combining Acute Accent] Paris Descartes, Faculté de Médecine, Sorbonne Paris Cite[Combining Acute Accent], Paris, France.
3
INSERM, U1016, Institut Cochin, Paris, France.
4
CNRS, UMR8104, Paris, France.
5
Assistance Publique - Hôpitaux de Paris, Laboratoire de Microbiologie clinique, Hôpital Necker-Enfants Malades, France.
6
Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Groupe Hospitalier Universitaire Paris Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
7
INSERM CESP U1018, Université Paris Sud, Paris Saclay, Le Kremlin-Bicêtre, France.
8
Université Paris Sud, Le Kremlin Bicêtre, France.
9
Institut Pasteur, HIV Inflammation et Persistance, Paris, France.
10
Assistance Publique-Hôpitaux de Paris, Service de Santé Publique, Groupe Hospitalier Universitaire Paris Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

Abstract

BACKGROUND:

HIV infection has often been linked to faster immune aging. We sought to determine whether or not treatment-naïve spontaneous HIV-1 controllers (HICs) and ART-exposed patients differ with regard to the expression of cell senescence markers.

METHODS:

Eighty-eight chronically infected HICs and ART-exposed patients (median time since infection: 15 years) with an undetectable plasma HIV RNA load (for at least the previous two years) were included. We used flow cytometry to measure immunosenescence markers (KLRG-1 and CD57) expression in fresh blood samples collected from patients and healthy donors.

RESULTS:

For the CD8 T cell population as a whole, the ART-exposed but not the HIC patients exhibited a much higher proportion of KLRG-1 and CD57 CD8 T cells than HDs. For the CD8 T cell subsets, HICs had a lower proportion of CD57 effector CD8 T cells than ART patients or HDs, whereas the proportions of KLRG-1 effector were similar. A similar trend was observed for terminal effectors. No impact of age, gender or standard parameters of infection (CD4 percentage, protective HLA allele, viral blips) was observed. The difference in the proportion of CD57 cells between HIC and ART was observed more specifically in long-term infected patients (>20 years). However, when considering the CD57 effector memory and effector subsets, the cytotoxic granule content was greater in HICs than in ART.

CONCLUSION:

The proportion of CD57 effector CD8 T cells is lower in HICs than in ART-exposed patients. This profile may be beneficial by ensuring limited senescence associated with consistent cytotoxic potential.

4.
AIDS. 2019 Aug 2. doi: 10.1097/QAD.0000000000002335. [Epub ahead of print]

Mycoplasma genitalium infection among HIV-infected pregnant African women and implications for mother-to-child transmission of HIV.

Author information

1
Departments of Medicine.
2
Departments of Global Health.
3
Departments of Epidemiology.
4
Departments of Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
5
Departments of Centre for Public Health Research, Kenya Medical Research Institute (KEMRI), Nairobi, Kenya.
6
Departments of UNICEF, New York, NY.
7
Departments of Biostatistics, University of Washington, Seattle, Washington, USA.
8
Departments of Pediatrics.

Abstract

OBJECTIVE:

Many sexually transmitted infections (STIs) increase risk of mother-to-child transmission (MTCT) of HIV, but the effect of Mycoplasma genitalium (MG) is not known. We hypothesized that MG infection would be common among HIV-infected pregnant women and could be associated with in utero and intrapartum MTCT.

DESIGN:

Observational case-cohort study METHODS:: This study used specimens from a Kenyan perinatal MTCT cohort (1999-2005) involving HIV-infected women and their infants, who received short-course zidovudine for prevention of MTCT. Vaginal swabs collected at 32 weeks gestation were tested for MG using a transcription-mediated amplification assay. Infant perinatal HIV infection was determined at birth and 4 weeks of age by DNA PCR. Using a case-cohort design, a random sample was generated with 3:1 control: case ratio; prevalence and correlates of MG were assessed with Chi-squared and t-tests; predictors of infant outcomes were analyzed using logistic regression.

RESULTS:

Among 220 HIV-infected pregnant women evaluated, 47 women (21.4%) had MG. Antenatal MG infection was associated with higher HIV RNA in plasma (5.0 vs. 4.6 log10 copies/ml in MG-positive vs. MG-negative women, p = 0.02) at 32 weeks. Women with MG were less likely to report prior STIs and genital ulcers (both p = 0.05). There was no association found between exposure to MG and perinatal MTCT (OR = 0.72, 95% CI 0.35, 1.51, p = 0.39).

CONCLUSIONS:

Vaginal MG infection was frequently detected among Kenyan HIV-infected pregnant women and was associated with higher plasma HIV levels, but was not associated with perinatal transmission of HIV.

5.
AIDS. 2019 Aug 2. doi: 10.1097/QAD.0000000000002331. [Epub ahead of print]

Serious clinical events in HIV-positive persons with chronic kidney disease (CKD).

Author information

1
Department of Infectious Diseases, CHIP, Section 2100, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
2
The Kirby Institute, University of New South Wales, Sydney, Australia.
3
ICAP-Columbia University and Harlem Hospital, New York, USA.
4
Université Bordeaux, INSERM U 897, CHU de Bordeaux, Bordeaux, France.
5
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
6
Public Health department, CHU Nice, Nice, France.
7
Dipartimento di Scienze della Salute, Clinica di Malattie Infectitive e Tropicali, Azienda Ospedaliera-Polo Universitario San Paolo, Milan, Italy.
8
Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, UCL, London, United Kingdom.
9
Amsterdam University Medical Centers (location AMC), Department of Global Health and Div. of Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands.
10
HIV Monitoring Foundation, Amsterdam, The Netherlands.
11
CHU Saint-Pierre, Department of Infectious Diseases, Brussels, Belgium.

Abstract

OBJECTIVES:

Predictors of chronic kidney disease (CKD) amongst HIV-positive persons are well established, but insights into the prognosis after CKD including the role of modifiable risk factors are limited.

DESIGN:

Prospective cohort study METHODS:: D:A:D participants developing CKD (confirmed, >3 months apart, eGFR ≤ 60 mL/min/1.73 m or 25% eGFR decrease when eGFR ≤ 60) were followed to incident serious clinical events (SCE); end stage renal (ESRD) and liver disease, cardiovascular disease (CVD), AIDS- and non-AIDS defining malignancies (NADM), other AIDS or death, 6 months after last visit or 02.01.2016. Poisson regression models considered associations between SCE and modifiable risk factors.

RESULTS:

During 2.7 (IQR 1.1-5.1) years median follow-up 595 persons with CKD (24.1%) developed a SCE (incidence rate 68.9/1000 PYFU [95%CI 63.4-74.4]) with 8.3% [6.9-9.0] estimated to experience any SCE at one year. The most common SCE was death (12.7%), followed by NADM (5.8%), CVD (5.6%), other AIDS (5.0%) and ESRD (2.9%). Crude SCE ratios were significantly higher in those with vs. without CKD, strongest for ESRD (65.9 [43.8-100.9]) and death (4.8 [4.3-5.3]). Smoking was consistently associated with all CKD-related SCE. Diabetes predicted CVD, NADM and death, while dyslipidaemia was only significantly associated with CVD. Poor HIV-status predicted other AIDS and death, eGFR < 30 mL/min/1.73m predicted CVD and death and low BMI predicted other AIDS and death.

CONCLUSION:

In an era where many HIV-positive persons require less monitoring due to efficient antiretroviral treatment, persons with CKD carry a high burden of SCE. Several potentially modifiable risk factors play a central role for CKD-related morbidity and mortality.

6.
AIDS Res Hum Retroviruses. 2019 Aug 8. doi: 10.1089/AID.2019.0091. [Epub ahead of print]

HIV DNA measurement and improved detection of HIV infection among MSM: a strategic implication.

Author information

1
National Center for AIDS/STD Control and Prevention, China CDC, Beijing, China; kaichencool@163.com.
2
National Center for AIDS/STD Control and Prevention, China CDC, Beijing, China; 383445472@qq.com.
3
National Center for AIDS/STD Control and Prevention, China CDC, Beijing, Beijing, China; 124945608@qq.com.
4
National Center for AIDS/STD Control and Prevention, China CDC, Beijing, China; yaojun@chinaaids.cn.
5
Beijing Center for Disease Control and Prevention, Beijing, China; hbxdy@126.com.
6
Beijing Center for Disease Control and Prevention, Institute for AIDS/STD Control and Prevention, No.16 HePingLi Middle Street,Dongcheng District, Beijing, China, 100013; hongyan_lu@sina.com.
7
National Center for AIDS/STD Control and Prevention, China CDC, Beijing, China; jiangyan@chinaaids.cn.

Abstract

Rapid test (RT) is the principal screening method in the human immunodeficiency virus (HIV) control practice. However, this method may lead to inaccurate detection, primarily due to the more than 4 weeks' window phase. In the present study, we performed a HIV DNA screening method to show its application prospects in men who have sex with men (MSM). From July 2017 to April 2018, we recruited 1301 MSM from Beijing who were not previously diagnosed as HIV positive. Both HIV DNA detection and RT were performed. In total, 141 and 135 HIV positive results were detected by DNA detection and RT, respectively. By repetitive and confirmative tests (western blot), we verified that DNA detection detected 10 more true positives than RT and 4 false positives were corrected from RT. This represents 14 inaccurate RT results that were corrected by DNA measurement. Therefore, DNA measurement should be fully considered as a screening method in the detection of HIV among MSM in the future.

7.
AIDS Res Hum Retroviruses. 2019 Aug 6. doi: 10.1089/AID.2019.0023. [Epub ahead of print]

Prevalence of Subclinical Atherosclerosis and Risk of Atherosclerotic Cardiovascular Disease in Older Adults Living with HIV.

Author information

1
Chiang Mai University, 26682, Research Institute for Health Sciences, Chiang Mai, Thailand; lindaa@rihes.org.
2
Chiang Mai University, 26682, Research Institute for Health Sciences, Chiang Mai, Thailand.
3
Chiang Mai University, 26682, Faculty of medicine, Chiang Mai, Thailand; ksrithanaviboonchai@gmail.com.
4
Chiang Mai University, 26682, Faculty of medicine, Chiang Mai, Thailand; rerkase@gmail.com.
5
Chiang Mai University, 26682, Research Institute for Health Sciences, Chiang Mai, United States; arunrat@rihes.org.
6
Chiang Mai University, 26682, Research Institute for Health Sciences, Chiang Mai, Thailand; wathee@rihes.org.
7
Kyoto University Graduate School of Medicine Department of Public Health, 222815, Department of Global Health and Socio-epidemiology, Kyoto, Japan; patoumus@yahoo.fr.

Abstract

BACKGROUND:

Cardiovascular disease is one among leading causes of mortality in people living with HIV on antiretroviral treatment (ART) worldwide. We examined the prevalence of subclinical atherosclerosis, associated factors, and risk of cardiovascular disease in older adults living with HIV(OALHIV).

METHODS:

A cross-sectional study in patients aged ≥ 50 years with HIV infection receiving ART at community hospitals in Chiang Mai, Thailand. Age- and sex-matched patients without documented HIV-infection who visited the general outpatient department were enrolled for comparison. Cardio-ankle vascular index(CAVI) and ankle-brachial index(ABI) were measured using the vascular screening system, VaSera SystemTM (Fukuda Denshi Co., ltd., Japan) to determine subclinical atherosclerosis (defined as CAVI ≥ 9.0) and peripheral arterial disease (defined as ABI < 0.9), respectively. The Ramathibodi-Electric Generating Authority of Thailand (RAMA-EGAT) score to predict the risk of coronary stenosis and the 10-year risk for ASCVD by pooled cohort equation were calculated.

RESULTS:

155 patients were enrolled (107 HIV/ 48 comparison). The mean age was 59.0 years (SD 6.1); 67 (43%) were male. Participants in the HIV and comparison group were similar with respect to abnormal CAVI (57% vs. 58%, p=0.88), abnormal ABI (6% vs 8%, p=0.50), and the risk of coronary stenosis (34% vs 44%, p=0.23). However, the 10-year risk of ASCVD was lower in HIV than the comparison group (29% vs. 48%, p=0.02). In OALHIV, diabetes mellitus was the only factor associated with abnormal CAVI.

CONCLUSIONS:

The cardiovascular risk of OALHIV in this study was similar to non-HIV population. More than a half of them had abnormal CAVI, and approximately one-third was at ≥ 10% 10-year risk of ASCVD.

8.
AIDS Res Hum Retroviruses. 2019 Aug 4. doi: 10.1089/AID.2019.0122. [Epub ahead of print]

Perspectives from the Front Lines: Encouraging Community Engagement in the Performance of Research at the Intersection of HIV and Aging.

Author information

1
University of California San Diego, 8784, Medicine, San Diego, California, United States; m1young@ucsd.edu.
2
Johns Hopkins University, 1466, Nursing, Baltimore, Maryland, United States; dbaker4@jhu.edu.
3
Test Positive Aware Network, Chicago, United States; Jmichael.Berry@ucsf.edu.
4
University of California Riverside, 8790, Riverside, California, United States; brandon.brown@medsch.ucr.edu.
5
AIDS Community Research Initiative of America , New York , United States; stephenk@gmhc.org.
6
National AIDS Treatment Advocacy Project, 33646, New York, New York, United States; jules@natap.org.
7
Older Women Embracing Life , Baltimore, Maryland, United States; me2umar@gmail.com.
8
The Reunion Project, Berkeley, California, United States; mattsharpster@gmail.com.
9
HIV + Aging Research Project, Palm Springs , California, United States; jefftaylorps@gmail.com.

Abstract

In this letter we advocate for greater inclusion of community members in the performance of research at the intersection of HIV and aging.

9.
AIDS Res Hum Retroviruses. 2019 Aug 4. doi: 10.1089/AID.2019.0155. [Epub ahead of print]

Veterans Aging Cohort Study Index as a Marker of Bone Disease in HIV-Infected Patients.

Author information

1
University of Texas John P and Katherine G McGovern Medical School Department of Psychiatry and Behavioral Sciences, 144383, 1941 East Road, Houston, Texas, United States, 77030-3406; lokesh.r.shahani@uth.tmc.edu.
2
Michael E. DeBakey VA Medical Center and Baylor Unviersity School of Medicine, Houston, Texas, United States; katherine.breaux@va.gov.
3
Baylor College of Medicine, 3989, Houston, Texas, United States; mlin@bcm.edu.
4
Michael E. DeBakey VA Medical Center and Baylor Unviersity School of Medicine, Houston, Texas, United States; marco.marcelli@va.gov.
5
Michael E. DeBakey VA Medical Center and Baylor Unviersity School of Medicine, Houston, Texas, United States; maria.Rodriguez-Barradas2@va.gov.

Abstract

Background People living with human immunodeficiency virus (HIV) infection have higher risk of low bone mineral density (BMD) and fragility fracture than general population. The aim of our retrospective study was to explore if HIV specific Veterans Aging Cohort Study (VACS) Index and its specific components could help identify patients at risk for low BMD.

METHODS:

195 HIV-infected patients with DXA scan between 2007 - 2014 were included and DXA scan results were used to classify patients with osteopenia. VACS Index was calculated for all patients using laboratory values closest to the date of DXA scan. Logistic regression was used to assess the association between VACS Index score or individual components of VACS Index with the presence of low BMD after adjusting for confounding variables.

RESULTS:

109 (56%) patients were diagnosed with low BMD. VACS Index score was significantly associated with low BMD, with the odds of low BMD increasing 1.21 times for each 10 unit increase in VACS Index score (95% confidence interval [CI], 1.03, 1.42; p=0.02). The two groups differed significantly on patient weights, proportion of white patients and Hepatitis C co-infected patients. After adjusting for white race and weight, Hepatitis C coinfection was significantly associated with increased risk of low BMD (OR, 24.4; 95% CI, 7.45-80.16).

CONCLUSION:

VACS Index score, previously demonstrated to be a marker of frailty in HIV infected patients; is significantly associated with risk of low BMD and could be used to develop a prediction tool to screen for low BMD in resource limited setting where DXA scans are not easily available.

10.
J Med Virol. 2019 Aug 7. doi: 10.1002/jmv.25564. [Epub ahead of print]

Antiviral activity of HIV-1 integrase strand-transfer inhibitors against mutants with integrase resistance-associated mutations and their frequency in treatment-naïve individuals.

Author information

1
Gilead Sciences, Inc., Clinical virology, Foster City, California.

Abstract

The development of resistance to human immunodeficiency virus 1 (HIV-1) integrase strand-transfer inhibitors (INSTI) has been documented; however, knowledge of the impact of pre-existing integrase (IN) mutations on INSTI resistance (INSTI-R) is still evolving. The frequency of HIV-1 IN mutations in 2177 treatment-naïve subjects was investigated, along with the INSTI susceptibility of site-directed mutant viruses containing major and minor INSTI-R mutations. Total 6 of 39 minor INSTI-R mutations (M50I, S119P/G/T/R, and E157Q) were found in >1% of IN-treatment-naïve subjects with no impact on INSTI susceptibility. When each combined with major INSTI-R mutation, M50I, S119P, and E157Q led to decreased susceptibility to elvitegravir but remained sensitive to dolutegravir and bictegravir.

KEYWORDS:

HIV-1; INSTI-resistance; bictegravir; dolutegravir; elvitegravir; integrase strand-transfer inhibitor; raltegravir

11.
J Virol. 2019 Aug 7. pii: JVI.01197-19. doi: 10.1128/JVI.01197-19. [Epub ahead of print]

Strain-dependent Activation and Inhibition of Human Immunodeficiency Virus (HIV-1) Entry by a Specific PF-68742 Stereoisomer.

Author information

1
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215.
2
Department of Microbiology, Harvard Medical School, Boston, MA 02115.
3
Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN 55455.
4
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104.
5
Department of Chemical and Biological Engineering, Drexel University, Philadelphia, PA 19104.
6
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215 joseph_sodroski@dfci.harvard.edu.
7
Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02215.

Abstract

Human immunodeficiency virus (HIV-1) entry into cells is mediated by the viral envelope glycoprotein (Env) trimer, which consists of three gp120 exterior glycoproteins and three gp41 transmembrane glycoproteins. When gp120 binds sequentially to the receptors, CD4 and CCR5, on the target cell, the metastable Env trimer is triggered to undergo entry-related conformational changes. PF-68742 is a small molecule that inhibits the infection of a subset of HIV-1 strains by interfering with an Env function other than receptor binding. Determinants of HIV-1 resistance to PF-68742 map to the disulfide loop and fusion peptide of gp41. Of the four possible PF-68742 stereoisomers, only one, MF275, inhibited the infection of CD4-positive, CCR5-positive cells by some HIV-1 strains. MF275 inhibition of these HIV-1 strains occurred after CD4 binding, but before the formation of the gp41 six-helix bundle. Unexpectedly, MF275 activated the infection of CD4-negative, CCR5-positive cells by several HIV-1 strains resistant to the inhibitory effects of the compound in CD4-positive target cells. In contrast to CD4 complementation by CD4-mimetic compounds, activation of CD4-independent infection by MF275 did not depend upon the availability of the gp120 Phe 43 cavity. Sensitivity to inhibitors indicates that MF275-activated virus entry requires formation/exposure of the gp41 heptad repeat (HR1) as well as CCR5 binding. MF275 apparently activates a virus entry pathway parallel to that triggered by CD4 and CD4-mimetic compounds. Strain-dependent divergence in Env conformational transitions allows different outcomes, inhibition or activation, in response to MF275. Understanding the mechanisms of MF275 activity should assist efforts to optimize its utility. IMPORTANCE Envelope glycoprotein (Env) spikes on the surface of human immunodeficiency virus (HIV-1) bind target cell receptors, triggering changes in the shape of Env. We studied a small molecule, MF275, that also induced shape changes in Env. The consequences of MF275 interaction with Env depended on the HIV-1 strain, with infection by some viruses inhibited and infection by other viruses enhanced. These studies reveal the strain-dependent diversity of HIV-1 Envs as they undergo shape changes in proceeding down the entry pathway. Appreciation of this diversity will assist attempts to develop broadly active inhibitors of HIV-1 entry.

12.
J Virol. 2019 Aug 7. pii: JVI.00653-19. doi: 10.1128/JVI.00653-19. [Epub ahead of print]

Attenuation of equine lentivirus alters mitochondrial protein expression profile from inflammation to apoptosis.

Author information

1
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
2
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China. wangxiaojun@caas.cn.

Abstract

Equine infectious anemia virus (EIAV) is an equine lentivirus similar to HIV-1, targets to host immune cells and causes life-long infection in horses. The Chinese live EIAV vaccine is attenuated from long-term passaging of a high virulent strain in vitro The parent pathogenic strain (EIAVDLV34) induces a host inflammatory storm to cause severe pathological injury of animals. However, the vaccine strain (EIAVDLV121) induces a high level of apoptosis to eliminate the infected cells. To investigate how these processes are regulated, we performed a comparative proteomics analysis and functional study in equine monocyte-derived macrophages (eMDMs), and found that divergent mitochondrial protein expression profiles caused by EIAV strains with different virulence lead to disparate mitochondrial function, morphology and metabolism. This in turn promoted distinct transformation of macrophage inflammatory polarization and intrinsic apoptosis. In EIAVDLV34 infected cells, a high level of glycolysis and increased mitochondrial fragmentation were induced, resulting in M1-polarized pro-inflammatory type transformation of macrophages and subsequently producing a strong inflammatory response. Following infection with EIAVDLV121, the infected cells were transformed into M2-polarized anti-inflammatory macrophages by inhibition of glycolysis. In this case, decrease of mitochondrial membrane potential and impairment of electronic respiratory chain led to increased levels of apoptosis and ROS. These results are correlated with the viral pathogenicity loss and may help to understand the key mechanism of lentiviral attenuation.IMPORTANCEFollowing viral infection, the working pattern and function of the cell can be transformed through the impact on mitochondria. It still unknown how mitochondrial response changes in the cells infected with viruses in the process of virulence attenuation. EIAVDLV121 is the only effective lentiviral vaccine for large-scale use in world. EIAVDLV34 is a parent pathogenic strain. Unlike EIAVDLV34-induced inflammation storms, EIAVDLV121 can induce high levels of apoptosis. For the first time, we found that, after altering mitochondrial protein expression profile, EIAVDLV34 infected cells are transformed into M1-polarized type macrophages to cause inflammatory injury and the intrinsic apoptosis pathway is activated in EIAVDLV121 infected cells. These studies shed light on how the mitochondrial protein expression profile change from cells infected by pathogenic or attenuated lentivirus strains to drive different cellular response, especially from inflammation to apoptosis.

15.
Virology. 2019 Jul 30;536:16-19. doi: 10.1016/j.virol.2019.07.024. [Epub ahead of print]

Expression of PD-1 and PD-Ls in Kaposi's sarcoma and regulation by oncogenic herpesvirus lytic reactivation.

Author information

1
Departments of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA.
2
Departments of Pathology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA.
3
Departments of Biostatistics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA.
4
Departments of Medicine, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, 1700 Tulane Ave, New Orleans, LA, 70112, USA.
5
Microbiology & Immunology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA.
6
Departments of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA. Electronic address: zqin@uams.edu.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several cancers such as Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). PD-1/PD-Ls immune checkpoint molecules play important roles in cancer cell immune escape. The expression of PD-1/PD-Ls and their regulation by oncogenic viruses, in particular KSHV, remain largely undefined. Here we demonstrate strong PD-1/PD-L1/PD-L2 expression in KS tissues from a cohort of HIV + patients. We found that induction of KSHV lytic reactivation significantly upregulates PD-L1 expression on infected tumor cells, potentially through several major cellular signaling pathways and IL-1β, which may represent a novel mechanism for virus-associated tumor cell immune escape.

KEYWORDS:

KSHV; Kaposi's sarcoma; PD-1; PD-L1; PD-L2

16.
BMJ. 2019 Aug 5;366:l4479. doi: 10.1136/bmj.l4479.

Unmasking the vulnerabilities of uninfected children exposed to HIV.

Author information

1
Health Systems Research Unit, South African Medical Research Council, South Africa vundli.ramokolo@mrc.ac.za.
2
Health Systems Research Unit, South African Medical Research Council, South Africa.
3
Department of Paediatrics, University of Pretoria, South Africa.
4
HIV Prevention Research Unit, South African Medical Research Council, South Africa.
5
Department of Paediatrics and Child Health and Ukwanda Centre for Rural Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Worcester, South Africa.
6
Massachusetts General Hospital, Departments of Medicine and Pediatrics, USA.
7
Harvard T H Chan School of Public Health, Department of Immunology and Infectious Diseases, USA.
8
Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
PMID:
31383646
DOI:
10.1136/bmj.l4479
[Indexed for MEDLINE]
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Conflict of interest statement

Competing interests: We have read and understood BMJ policy on declaration of interests and declare no competing interests. This article was funded by the South African Medical Research Council and Unicef. Research reported in this publication was also supported by the Fogarty International Center of the National Institutes of Health under Award Number 1K43TW010683 to ALS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development under Award Number 1R21HD093531 to KMP. ALS receives salary support through the CIPHER Grantee Programme of the International AIDS Society (2017/518-SLO) while VR receives support from the SAMRC Intramural Postdoctoral Fellowship Programme. The content of this paper is the sole responsibility of the authors and does not necessarily represent the official views of the organisations and funders.

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