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1.
AIDS Res Hum Retroviruses. 2017 Nov 17. doi: 10.1089/AID.2017.0140. [Epub ahead of print]

Immunization with Clinical HIV-1 Env Proteins Induces Broad Antibody Dependent Cellular Cytotoxicity-Mediating Antibodies in a Rabbit Vaccination Model.

Author information

1
1 Department of Virology and Special Microbial Diagnostic, Statens Serum Institut , Copenhagen, Denmark .
2
2 Infectious Disease Research Unit, Clinical Institute, University of Southern Denmark , Odense, Denmark .
3
3 Biomedical Department, Virology Unit, Institute of Tropical Medicine , Antwerp, Belgium .
4
4 Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford , Oxford, United Kingdom .
5
5 Viral Evolution and Transmission Unit, San Raffaele Scientific Institute , Milan, Italy .

Abstract

The induction of both neutralizing antibodies and non-neutralizing antibodies with effector functions, for example, antibody-dependent cellular cytotoxicity (ADCC), is desired in the search for effective vaccines against HIV-1. In the pursuit of novel immunogens capable of inducing an efficient antibody response, rabbits were immunized with selected antigens using different prime-boost strategies. We immunized 35 different groups of rabbits with Env antigens from clinical HIV-1 subtypes A and B, including immunization with DNA alone, protein alone, and DNA prime with protein boost. The rabbit sera were screened for ADCC activity using a GranToxiLux-based assay with human peripheral blood mononuclear cells as effector cells and CEM.NKRCCR5 cells coated with HIV-1 envelope as target cells. The groups with the highest ADCC activity were further characterized for cross-reactivity between HIV-1 subtypes. The immunogen inducing the most potent and broadest ADCC response was a trimeric gp140. The ADCC activity was highest against the HIV-1 subtype corresponding to the immunogen. The ADCC activity did not necessarily reflect neutralizing activity in the pseudovirus-TZMbl assay, but there was an overall correlation between the two antiviral activities. We present a rabbit vaccination model and an assay suitable for screening HIV-1 vaccine candidates for the induction of ADCC-mediating antibodies in addition to neutralizing antibodies. The antigens and/or immunization strategies capable of inducing antibodies with ADCC activity did not necessarily induce neutralizing activity and vice versa. Nevertheless, we identified vaccine candidates that were able to concurrently induce both types of responses and that had ADCC activity that was cross-reactive between different subtypes. When searching for an effective vaccine candidate, it is important to evaluate the antibody response using a model and an assay measuring the desired function.

KEYWORDS:

ADCC; antibody mediated immunity; neutralizing antibody; vaccine development

2.
AIDS Res Hum Retroviruses. 2018 Feb;34(2):185-192. doi: 10.1089/AID.2017.0107. Epub 2017 Dec 14.

Heterogeneity of HIV-1 Replication in Ectocervical and Vaginal Tissue Ex Vivo.

Author information

1
1 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania.
2
2 Magee-Womens Research Institute , Pittsburgh, Pennsylvania.
3
3 Department of Medicine Bio Statisics, and Clinical and Translational Science, University of Pittsburgh , Pittsburgh, Pennsylvania.
4
4 University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.

Abstract

In clinical trials evaluating HIV-1 prevention products, ex vivo exposure of mucosal tissue to HIV-1 is performed to inform drug levels needed to suppress viral infection. Understanding assay and participant variables that influence HIV-1 replication will help with assay implementation. Demographic and behavioral data were obtained from 61 healthy women aged 21-45. Paired cervical tissue (CT) and vaginal tissue (VT) biopsies were collected and treated with HIV-1BaL or HIV-1JR-CSF, washed, and cultured. On days 3, 7, and/or 11, culture supernatant was collected, and viral replication was monitored by p24 ELISA. Tissue was extracted at study end, and HIV-1 relative RNA copies were determined by polymerase chain reaction. Cumulative p24 and RNA were log-transformed and analyzed using a linear mixed model, t-test, and an intraclass correlation coefficient (ICC). HIV replication was similar between CT and VT for each virus, but HIV-1BaL had 1.5 log10 and 0.9 log10 higher levels of p24 than HIV-1JR-CSF in CT and VT, respectively (p < .001), which correlated with HIV-1 relative RNA copies. Cumulative p24 and RNA copies in both tissues demonstrated low intraperson correlation for both viruses (ICC ≤0.513 HIV-1BaL; ICC ≤0.419 HIV-1JR-CSF). Enrollment into previous clinical studies in which genital biopsies were collected modestly decreased the HIV-1BaL cumulative p24 for CT, but not for VT. To improve the ex vivo challenge assay, viruses should be evaluated for replication in mucosal tissue before study implementation, baseline mucosal tissue is not needed if a placebo/no treatment group is included within the clinical trial, and previous biopsy sites should be avoided.

KEYWORDS:

HIV prevention; efficacy biomarker; ex vivo challenge assay; pharmacodynamics

3.
AIDS Res Hum Retroviruses. 2018 Feb;34(2):148-155. doi: 10.1089/AID.2017.0092. Epub 2017 Nov 8.

Comparison of the Hepatitis C Continua of Care Between Hepatitis C Virus/HIV Coinfected and Hepatitis C Virus Mono-Infected Patients in Two Treatment Eras During 2008-2015.

Author information

1
1 Department of Medicine, The George Washington University School of Medicine and Health Sciences , Washington, District of Columbia.
2
2 Veterans Affairs Medical Center, The George Washington University School of Medicine and Health Sciences , Washington, District of Columbia.

Abstract

Treatment of chronic hepatitis C virus (HCV) infection included use of pegylated interferon-based regimens before 2014 and direct-acting agents (DAA) since 2014 at the VA Medical Center in Washington, DC. We compared the continua of care between our HCV/HIV coinfected and HCV mono-infected patients during 2008-2015. A review of summary data from our local HCV Clinical Case Registry was conducted for the interferon treatment era (2008-2013) and the DAA era (2014-2015). Data were analyzed on a modified HCV Continuum of Care based on these stages: HCV diagnosis, engagement in medical care, HCV treatment, and HCV sustained virologic response (SVR) for differences between HCV/HIV coinfected and HCV mono-infected patients. All patients had 88% engagement in primary care during 2008-2013. HCV mono-infected and HCV/HIV coinfected patients had similar treatment (6% vs. 5%, p = .6622) and HCV SVR (1% vs. 0.5%, p = .1737) rates in the interferon era. However, more HCV/HIV coinfected patients were engaged in care (93% vs. 87%, p = .0044), accessed HCV treatment (36% vs. 23%, p < .0001), and achieved HCV SVR (31% vs. 21% p = .0002) compared to mono-infected patients in the DAA era. Both HCV/HIV coinfected and HCV mono-infected patients achieved higher SVR of ≥86% after DAA treatment. Although improvements were seen for treatment and SVR among HCV mono-infected patients, better rates for care engagement, HCV treatment, and SVR were realized for HCV/HIV coinfected patients in the DAA era.

KEYWORDS:

HCV; HCV mono-infection; HCV/HIV coinfection; direct-acting agents; hepatitis C; pegylated interferon

4.
AIDS Res Hum Retroviruses. 2018 Mar;34(3):282-285. doi: 10.1089/AID.2017.0164. Epub 2017 Nov 17.

Short Communication: The Effect of Rosuvastatin on Vascular Disease Differs by Smoking Status in Treated HIV Infection.

Author information

1
1 Division of Infectious Diseases, Department of Medicine, MetroHealth Medical Center , Cleveland, Ohio.
2
2 Case Western Reserve University , Cleveland, Ohio.
3
3 Departments of Pediatrics and Medicine, University Hospitals Cleveland Medical Center , Cleveland, Ohio.

Abstract

Smoking is an important contributor to cardiovascular disease risk and is highly prevalent in the HIV population. In the Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV trial (SATURN-HIV), a 96-week, randomized placebo-controlled study testing the effect of rosuvastatin on subclinical vascular disease and immune activation in HIV-infected adults, rosuvastatin improved immune activation and arrested common carotid artery intima media thickness (CCA IMT) progression. In this exploratory analysis, ANOVA was used to test for effect modification by smoking. One-hundred forty-seven adults were included (72 in rosuvastatin group; 75 in placebo group). Groups were similar at baseline. Overall, mean ± SD age was 45.4 ± 9.9 years, 115 (78%) were men and 100 (68%) were African American. Ninety-three (63%) were current smokers (mean ± SD 0.6 ± 0.44 packs/day) and another 24 (16%) were smokers in the past. There were statistically significant randomization group by smoking status interactions for 0-24 (p = .01) and 0-48 (p < .01) week changes in proportion of activated CD4+ T cells and for 0-48 (p < .01) and 0-96 (trend only; p = .06) week changes in CCA IMT. No effect modification by smoking was detected for changes in markers of inflammation or monocyte activation. The beneficial effect of rosuvastatin on CCA IMT was not apparent in smokers although T cell activation improved to a greater degree in this subgroup.

KEYWORDS:

HIV; antiretroviral therapy; inflammation; smoking; subclinical vascular disease

5.
AIDS Res Hum Retroviruses. 2017 Nov 27. doi: 10.1089/AID.2017.0052. [Epub ahead of print]

High Prevalence of Drug Resistance Mutations Among Patients Failing First-Line Antiretroviral Therapy and Predictors of Virological Response 24 Weeks After Switch to Second-Line Therapy in São Paulo State, Brazil.

Author information

1
1 Ambulatório de referência de moléstias infecciosas, Programa de AIDS de Santo André , Santo André, Brazil .
2
2 Núcleo de doenças de vinculação sanguínea ou sexual, Centro de Virologia, Instituto Adolfo Lutz , São Paulo, Brazil .
3
3 Departamento de Clínica Médica, Faculdade de Ciências Médicas da UNICAMP , Campinas, Brazil .
4
4 Departamento de Clínica Médica, Hospital das Clínicas , Faculdade de Medicina, Ribeirão Preto, Brazil .
5
5 Instituto de Infectologia Emílio Ribas , São Paulo, Brazil .

Abstract

Universal antiretroviral treatment with sustained viral suppression benefits patients and reduces HIV transmission. Effectiveness of therapy may be limited by antiretroviral drug resistance. Information on the resistance profile at treatment failure and its impact on antiretroviral drugs may subsidize subsequent treatment strategies. Partial pol sequences from 319 patients failing first-line therapy were analyzed for resistance associated mutations (RAMs) and HIV subtype. Demographic data, CD4 T cell count, viral load, and antiretroviral regimens and mutational profile at first-line failure were also investigated for associations to the response to second-line regimens. RAMs at the reverse transcriptase gene were frequent. Most sequences (88%) showed at least one mutation. A higher number of reverse transcriptase RAMs were associated to lower CD4 T cell counts and the use of tenofovir/lamivudine in first line. Among 205 with follow-up data, 76.6% were virally suppressed (below 200 copies/ml) after 24 weeks of second-line therapy. Most cases initiated second line with a regimen genotypic susceptibility score ≥2, but it did not predict viral suppression, that was independently associated with higher CD4 T cell counts and with the presence of nucleos(t)ide analog reverse transcriptase inhibitor (NRTI) RAMs. This study documented extensive resistance at first-line failure in this area in Brazil, highlights the risks of low CD4 T cell counts to second-line therapy, and supports the notion that recycled NRTIs may contribute to viral suppression even when genotypic resistance is present.

KEYWORDS:

HIV; antiretroviral therapy; mutations; resistance; treatment failure

6.
AIDS Res Hum Retroviruses. 2018 Mar;34(3):254-260. doi: 10.1089/AID.2017.0156. Epub 2017 Nov 17.

HIV Self-Testing in Lusaka Province, Zambia: Acceptability, Comprehension of Testing Instructions, and Individual Preferences for Self-Test Kit Distribution in a Population-Based Sample of Adolescents and Adults.

Author information

1
1 Centre for Infectious Disease Research in Zambia , Lusaka, Zambia .
2
2 American Institutes for Research , Lusaka, Zambia .
3
3 School of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
4
4 School of Medicine, University of Zambia , Lusaka, Zambia .
5
5 School of Medicine, Johns Hopkins University , Baltimore, Maryland.
6
6 Gillings School of Global Public Health, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina.

Abstract

We assessed attitudes and preferences toward HIV self-testing (HIVST) among Zambian adolescents and adults. We conducted a population-based survey of individuals aged 16-49 years old in Lusaka Province, Zambia. HIVST was shown to participants through a short video on oral fluid-based self-testing. In addition to demographics, HIV risk perceptions, and HIV testing history, we assessed participants' acceptability and concerns regarding HIVST. Using a discrete choice experiment, we investigated preferences for the location of self-test pickup, availability of counseling, and cost. After reviewing an instructional sheet or an additional video, we assessed participants' understanding of self-test performance. Among 1617 participants, 647 (40.0%) were male, 269 (16.6%) were adolescents and 754 (46.6%) were nontesters (i.e., no HIV test in the past 12 months). After viewing the video, 1392 (86.0%) reported that HIVST would make them more likely to test and while 35.0% reported some concerns with HIVST, only 2% had serious concerns. Participants strongly preferred HIVST over finger prick testing as well as having counseling and reported willingness to pay out-of-pocket (US$3.5 for testers and US$5.5 for nontesters). Viewing an HIVST demonstration video did not improve participant understanding of self-test usage procedures compared to an instructional sheet alone, but it increased confidence in the ability to self-test. In conclusion, HIVST was highly acceptable and desirable, especially among those not accessing existing HIV testing services. Participants expressed a strong preference for counseling and a willingness to pay for test kits. These data can guide piloting and scaling-up of HIVST in Zambia and elsewhere in Africa.

KEYWORDS:

Africa; HIV prevention; HIV self-testing; HIV/AIDS; discrete choice experiment; population-based survey

7.
AIDS Res Hum Retroviruses. 2017 Nov 27. doi: 10.1089/AID.2017.0121. [Epub ahead of print]

Intradermal HIV-1 DNA Immunization Using Needle-Free Zetajet Injection Followed by HIV-Modified Vaccinia Virus Ankara Vaccination Is Safe and Immunogenic in Mozambican Young Adults: A Phase I Randomized Controlled Trial.

Author information

1
1 Instituto Nacional de Saúde , Maputo, Mozambique .
2
2 Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet , Huddinge, Sweden .
3
3 Eduardo Mondlane University , Maputo, Mozambique .
4
4 Public Health Agency of Sweden , Stockholm, Sweden .
5
5 Bioject, Inc. , Tualatin, Oregon.
6
6 IRCCS San Raffaele Scientific Institute , Milan, Italy .
7
7 Department of Surgery and Molecular Genetics and Microbiology, Duke University Medical Center , Durham, North Carolina.
8
8 Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAD)/National Institutes of Health (NIH) , Bethesda, Maryland.
9
9 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm, Sweden .
10
10 Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University , Örebro, Sweden .
11
11 The Military HIV Research Program, Walter Reed Army Institute of Research and The Henry M. Jackson Foundation for the Advancement of Military Medicine , Bethesda, Maryland.
12
12 Department of Education and Clinical Research, Karolinska Institutet , Stockholm, Sweden .

Abstract

We assessed the safety and immunogenicity of HIV-DNA priming using Zetajet™, a needle-free device intradermally followed by intramuscular HIV-MVA boosts, in 24 healthy Mozambicans. Volunteers were randomized to receive three immunizations of 600 μg (n = 10; 2 × 0.1 ml) or 1,200 μg (n = 10; 2 × 0.2 ml) of HIV-DNA (3 mg/ml), followed by two boosts of 108 pfu HIV-MVA. Four subjects received placebo saline injections. Vaccines and injections were safe and well tolerated with no difference between the two priming groups. After three HIV-DNA immunizations, IFN-γ ELISpot responses to Gag were detected in 9/17 (53%) vaccinees, while none responded to Envelope (Env). After the first HIV-MVA, the overall response rate to Gag and/or Env increased to 14/15 (93%); 14/15 (93%) to Gag and 13/15 (87%) to Env. There were no significant differences between the immunization groups in frequency of response to Gag and Env or magnitude of Gag responses. Env responses were significantly higher in the higher dose group (median 420 vs. 157.5 SFC/million peripheral blood mononuclear cell, p = .014). HIV-specific antibodies to subtype C gp140 and subtype B gp160 were elicited in all vaccinees after the second HIV-MVA, without differences in titers between the groups. Neutralizing antibody responses were not detected. Two (13%) of 16 vaccinees, one in each of the priming groups, exhibited antibodies mediating antibody-dependent cellular cytotoxicity to CRF01_AE. In conclusion, HIV-DNA vaccine delivered intradermally in volumes of 0.1-0.2 ml using Zetajet was safe and well tolerated. Priming with the 1,200 μg dose of HIV-DNA generated higher magnitudes of ELISpot responses to Env.

KEYWORDS:

HIV; HIV-DNA; HIV-MVA; Mozambique; vaccine

8.
AIDS Res Hum Retroviruses. 2017 Oct 2. doi: 10.1089/AID.2017.0106. [Epub ahead of print]

Is it possible to control HIV infection in a middle-income country through a multidisciplinary approach?

Author information

1
Universidade de Sao Paulo Faculdade de Medicina, 37884, Dermatology , av. dr. eneas 500 , Sao Paulo, Brazil , 01246-903 ; jcasseb10@gmail.com.
2
Sao Paulo, Brazil ; luizaugusto.marcondes@gmail.com.
3
FMUSP, Dermatology, Sao Paulo, Sao Paulo, Brazil ; adjsduar@usp.br.

Abstract

Despite the difficulties to follow and retain patients for a long time in the public health service, special programs may bring about increased chances of survival and better quality of life, as well as higher rates of retention in care; this is also true for middle-income developing countries such as Brazil. Our relatively small outpatient service (~500 HIV-infected patients) may not mirror the reality encountered in other settings, including São Paulo city, but retention and high quality of care may improve rates of virologic success, even in poorer settings. Furthermore, prevention of depression or anxiety, with discussion in groups of patients with the presence of a therapist, regular HIV RNA viral and CD4 cells counts, genotyping tests pre-HAART, and vigilance for drug failure, may explain this successful experience. We should also take into consideration that our cohort consists mostly of asymptomatic at-entry patients referred by the Blood Bank of São Paulo, located at the same Hospital, implying that they had a better immunological status at start than the more usual HIV population. Besides that, the degree of adherence to treatment in our service, in general, is quite high and the patients have a higher mean educational level; over 90% of the patients a high school or college education . Such features make this cohort a very specific and differentiated sample. In order to extend our findings, we intend to conduct similar studies in other HIV treatment centers, enabling comparisons of populations with different profiles.

9.
AIDS Res Hum Retroviruses. 2018 Feb;34(2):132-139. doi: 10.1089/AID.2017.0158. Epub 2017 Nov 1.

Improving Laboratory Efficiency in the Caribbean to Attain the World Health Organization HIV Treat All Recommendations.

Author information

1
1 Division of Global HIV and Tuberculosis, Centers for Disease Control and Prevention (CDC) , Atlanta, Georgia .
2
2 State Department Office of the Global AIDS Coordinator and Health Diplomacy (S/GAC) , Washington, District of Columbia.
3
3 Caribbean Regional Office, Division of Global HIV/AIDS, Centers for Disease Control and Prevention (CDC) , US Embassy, Bridgetown, Barbados .
4
4 Ladymeade Reference Unit Laboratory, Ministry of Health , Bridgetown, Barbados .

Abstract

Scientific evidence showing the benefits of early initiation of antiretroviral therapy (ART) prompted World Health organization (WHO) to recommend that all persons diagnosed as HIV positive should commence ART irrespective of CD4 count and disease progression. Based on this recommendation, countries should adopt and implement the HIV "Treat All" policy to achieve the UNAIDS 90-90-90 targets and ultimately reach epidemic control. Attaining this goal along the HIV treatment cascade depends on the laboratory to monitor progress and measure impact. The laboratory plays an important role in HIV diagnosis to attain the first 90 and in viral load (VL) and HIV drug resistance testing to reinforce adherence, improve viral suppression, and measure the third 90. Countries in the Caribbean region have endorsed the WHO HIV "Treat all" recommendation; however, they are faced with diminishing financial resources to support laboratory testing, seen as a rate-limiting factor to achieving this goal. To improve laboratory coverage with fewer resources in the Caribbean there is the need to optimize laboratory operations to ensure the implementation of high quality, less expensive evidence-based approaches that will result in more efficient and effective service delivery. Suggested practical and innovative approaches to achieve this include: (1) targeted testing within HIV hotspots; (2) strengthening sample referral systems for VL; (3) better laboratory data collection systems; and (4) use of treatment cascade data for programmatic decision-making. Furthermore, strengthening quality improvement and procurement systems will minimize diagnostic errors and guarantee a continuum of uninterrupted testing which is critical for routine monitoring of patients to meet the stated goal.

KEYWORDS:

efficiency; laboratory; viral load

10.
JAMA. 2017 Oct 3;318(13):1233-1240. doi: 10.1001/jama.2017.10913.

Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial.

Author information

1
Institute for Global Health, Vanderbilt University Medical Center, Nashville, Tennessee.
2
Department of Internal Medicine, School of Medicine, University of Zambia, Lusaka.
3
Division of Allergy, Pulmonary, and Critical Care Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.
4
Barts and the London School of Medicine, Queen Mary University of London, London, England.
5
Zambia Ministry of Health, Lusaka.

Abstract

Importance:

The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown.

Objective:

To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care.

Design, Setting, and Participants:

Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013.

Interventions:

Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management.

Main Outcomes and Measures:

The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors.

Results:

Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001).

Conclusions and Relevance:

Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations.

Trial Registration:

clinicaltrials.gov Identifier: NCT01663701.

PMID:
28973227
PMCID:
PMC5710318
DOI:
10.1001/jama.2017.10913
[Indexed for MEDLINE]
Free PMC Article
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11.
J Infect Dis. 2017 Dec 1;216(suppl_9):S798-S800. doi: 10.1093/infdis/jix137.

Global HIV Antiretroviral Drug Resistance: A Perspective and Report of a National Institute of Allergy and Infectious Diseases Consultation.

Author information

1
National Institute of Allergy and Infectious Diseases, National Institutes of Health.
2
University College London, United Kingdom.
3
Johns Hopkins University.
4
Brigham and Women's Hospital.
5
McGill University, Canada.
6
Centers for Disease Control and Prevention.

KEYWORDS:

HIV; HIV drug resistance; antiretroviral; drug resistance; genotyping; human immunodeficiency virus; low/middle-income countries; virological failure

PMID:
28973412
PMCID:
PMC5853929
[Available on 2018-12-01]
DOI:
10.1093/infdis/jix137
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12.
J Infect Dis. 2017 Oct 17;216(7):813-818. doi: 10.1093/infdis/jix418.

Tissue Pharmacologic and Virologic Determinants of Duodenal and Rectal Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution in HIV-Infected Patients Initiating Antiretroviral Therapy.

Author information

1
University of California, Davis Medical Center, Sacramento.
2
Eshelman School of Pharmacy, University of North Carolina, Chapel Hill.
3
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
4
California National Primate Research Center, Davis.
5
University Hospital La Paz and IdiPAZ.
6
University Hospital Ramón y Cajal and IRYCIS, Madrid, Spain.
7
University of Texas Medical Branch, Galveston.
8
Rush University Medical Center, Chicago, Illinois.

Abstract

Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery.

KEYWORDS:

ART tissue penetration; HIV persistence; antiretroviral concentration; gastrointestinal-associated lymphoid tissue; immune reconstitution

PMID:
28968888
DOI:
10.1093/infdis/jix418
[Indexed for MEDLINE]
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13.
J Infect Dis. 2018 Feb 14;217(5):703-709. doi: 10.1093/infdis/jix454.

Differences in the Immune Microenvironment of Anal Cancer Precursors by HIV Status and Association With Ablation Outcomes.

Author information

1
Department of Pathology, Icahn School of Medicine at Mount Sinai.
2
Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai.
3
Department of Pathology, University of Massachusetts Medical School, Worcester.
4
Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai.
5
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Abstract

Background:

Anal high-grade squamous intraepithelial lesions (HSILs) are the precursors to anal cancer and frequently persist or recur following electrocautery ablation (EA). Impaired mucosal immunity may facilitate anal carcinogenesis. We characterized the immune microenvironment of anal HSILs in correlation with human immunodeficiency virus (HIV) serostatus and ablation outcomes.

Methods:

Using immunohistochemistry, mucosa-infiltrating CD4+ and CD8+ lymphocytes were quantified in HSILs and benign mucosa from 70 HIV+ and 45 HIV- patients. Clinicopathological parameters were compared.

Results:

Anal HSILs harbored more T lymphocytes than benign mucosa regardless of HIV status (P ≤ .03). Total T lymphocyte count and CD8+ subset were significantly higher in HIV+ HSILs versus HIV- HSILs (median cell count, 71 vs 47; 47 vs 22/high power field [HPF]; P < .001), whereas the CD4+ subset was comparable between groups (median, 24 vs. 25; P = .40). Post EA, HSILs persisted in 41% of HIV+ and 19% of HIV- patients (P = .04). Unadjusted analysis showed trends toward EA failures associated with HIV seropositivity (incidence rate ratio [IRR], 2.0; 95% CI, .8-4.9) and increased CD8+ cells (IRR, 2.3; 95% CI, .9-5.3).

Conclusions:

Human immunodeficiency virus is associated with alterations of the immune microenvironment of anal HSILs manifested by increased local lymphocytic infiltrates, predominately CD8+. Human immunodeficiency virus seropositivity and excess mucosa-infiltrating CD8+ cells may be associated with ablation resistance.

KEYWORDS:

anal cancer precursors; human immunodeficiency virus (HIV); immune microenviroment; mucosa-infiltrating lymphocytes

PMID:
28968881
PMCID:
PMC5853940
[Available on 2019-02-14]
DOI:
10.1093/infdis/jix454
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14.
J Infect Dis. 2017 Dec 1;216(suppl_9):S829-S833. doi: 10.1093/infdis/jix397.

Next-Generation Human Immunodeficiency Virus Sequencing for Patient Management and Drug Resistance Surveillance.

Author information

1
IrsiCaixa AIDS Research Institute.
2
Universitat Autònoma de Barcelona.
3
Universitat de Vic-Universitat Central de Catalunya, Spain.
4
United States Agency for International Development.
5
British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia.
6
National HIV and Retrovirology Laboratory, JC Wilt Infectious Diseases Research Centre, Public Health Agency of Canada, Canada.
7
Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
8
Infectious Diseases Unit, Hospital Universitari Germans Trias i Pujol, Spain.

Abstract

High-quality, simplified, and low-cost human immunodeficiency virus (HIV) drug resistance tests that are able to provide timely actionable HIV resistance data at individual, population, and programmatic levels are needed to confront the emerging drug-resistant HIV epidemic. Next-generation sequencing technologies embedded in automated cloud-computing analysis environments are ideally suited for such endeavor. Whereas NGS can reduce costs over Sanger sequencing, automated analysis pipelines make NGS accessible to molecular laboratories regardless of the available bioinformatic skills. They can also produce highly structured, high-quality data that could be examined by healthcare officials and program managers on a real-time basis to allow timely public health action. Here we discuss the opportunities and challenges of such an approach.

KEYWORDS:

HIV resistance; NGS; bioinformatics; public health; surveillance

PMID:
28968834
PMCID:
PMC5853595
[Available on 2018-12-01]
DOI:
10.1093/infdis/jix397
[Indexed for MEDLINE]
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15.
J Infect Dis. 2017 Nov 27;216(9):1070-1079. doi: 10.1093/infdis/jix444.

Homeostatic Expansion of CD4+ T Cells Promotes Cortical and Trabecular Bone Loss, Whereas CD8+ T Cells Induce Trabecular Bone Loss Only.

Author information

1
Atlanta Department of Veterans Affairs Medical Center, Decatur.
2
Division of Endocrinology and Metabolism and Lipids.
3
The Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine.
4
Grady Healthcare System, Atlanta, Georgia.

Abstract

Background:

Bone loss occurs in human immunodeficiency virus (HIV) infection but paradoxically is intensified by HIV-associated antiretroviral therapy (ART), resulting in an increased fracture incidence that is largely independent of ART regimen. Inflammation in the bone microenvironment associated with T-cell repopulation following ART initiation may explain ART-induced bone loss. Indeed, we have reported that reconstitution of CD3+ T cells in immunodeficient mice mimics ART-induced bone loss observed in humans. In this study, we quantified the relative effects of CD4+ and CD8+ T-cell subsets on bone.

Methods:

T-cell subsets in T-cell receptor β knockout mice were reconstituted by adoptive transfer with CD4+ or CD8+ T-cells subsets were reconstituted in T-cell receptor β knockout mice by adoptive transfer, and bone turnover, bone mineral density, and indices of bone structure and turnover were quantified.

Results:

Repopulating CD4+ but not CD8+ T cells significantly diminished bone mineral density. However, micro-computed tomography revealed robust deterioration of trabecular bone volume by both subsets, while CD4+ T cells additionally induced cortical bone loss.

Conclusions:

CD4+ T-cell reconstitution, a key function of ART, causes significant cortical and trabecular bone loss. CD8+ T cells may further contribute to trabecular bone loss in some patients with advanced AIDS, in whom CD8+ T cells may also be depleted. Our data suggest that bone densitometry used for assessment of the condition of bone in humans may significantly underestimate trabecular bone damage sustained by ART.

KEYWORDS:

AIDS; ART; HIV; T cells; antiretroviral therapy; bone loss; inflammation; osteoclasts; osteoporosis

PMID:
28968828
PMCID:
PMC5853557
[Available on 2018-11-27]
DOI:
10.1093/infdis/jix444
[Indexed for MEDLINE]
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16.
J Infect Dis. 2017 Dec 1;216(suppl_9):S816-S819. doi: 10.1093/infdis/jix408.

Regional Challenges in the Prevention of Human Immunodeficiency Virus Drug Resistance.

Author information

1
Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH).
2
Ivanovsky Institute of Virology, Russia.
3
Erasmus Medical Center, Department of Viroscience, The Netherlands.
4
Pan American Health Organization/World Health Organization.
5
China Office, Office of Global Research, NIAID, NIH.
6
Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University.
7
Division of Treatment and Care, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
8
Division of Infectious Diseases, Department of Medicine, Brown University Alpert Medical School.

Abstract

In diverse global regions with significant human immunodeficiency virus (HIV) burden, programmatic, cultural, and provider-, patient-, and virus-related factors may result in HIV drug resistance, with global implications. This article reviews such common and unique challenges in Russia, Latin America and the Caribbean, China, and India, to suggest potential solutions.

KEYWORDS:

China; HIV drug resistance; India; Latin America; Russia

PMID:
28968824
PMCID:
PMC5853282
[Available on 2018-12-01]
DOI:
10.1093/infdis/jix408
[Indexed for MEDLINE]
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17.
J Infect Dis. 2017 Oct 17;216(7):867-876. doi: 10.1093/infdis/jix274.

Naturally Occurring Single Amino Acid Substitution in the L1 Major Capsid Protein of Human Papillomavirus Type 16: Alteration of Susceptibility to Antibody-Mediated Neutralization.

Author information

1
Graduate School of Peking Union Medical College.
2
Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China.
3
Program in Genetic, Molecular, and Cellular Biology, Keck School of Medicine.
4
Molecular and Computational Biology Section, Department of Biological Sciences.
5
Department of Chemistry, University of Southern California, Los Angeles.

Abstract

Background:

Each vaccine for human papillomavirus type 16 (HPV16) has been developed on the basis of a single variant, and whether these vaccines can prevent infection due to naturally occurring variants was not clear.

Methods:

To examine this question, constructs of 39 naturally occurring single amino acid substitutions in L1 were generated for pseudovirion production, based on the analysis of 1204 HPV16 L1 protein sequences from the National Center for Biotechnology Information and Papilloma Virus Episteme.

Results:

Thirty-one of 39 HPV16 L1 mutants produced infectious pseudovirions that exhibited similar particle-to-infectivity ratios, compared with reference pseudovirions. Twenty-one of 31 pseudovirion-producing mutants showed different susceptibilities to monoclonal antibodies, with 6 resulting in complete loss of reactivity to some of the tested monoclonal antibodies. The vaccinated sera neutralized all 31 variants. Mean neutralization titers of most variants changed by approximately 4-fold, compared with the reference pseudovirions, with the C428W and K430Q mutations displaying 9-fold and 11-fold lower susceptibilities, respectively, to neutralization by the sera than the reference pseudovirions.

Conclusions:

These results suggest that the current HPV vaccines may not offer equal protection against all of the naturally occurring HPV16 variants discovered so far.

KEYWORDS:

Human papillomavirus; amino acid substitution; major capsid protein; neutralization; pseudovirus; susceptibility

PMID:
28968823
DOI:
10.1093/infdis/jix274
[Indexed for MEDLINE]
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18.
J Infect Dis. 2017 Dec 12;216(11):1415-1424. doi: 10.1093/infdis/jix483.

Control of HIV-1 by an HLA-B*52:01-C*12:02 Protective Haplotype.

Author information

1
Center for AIDS Research, Kumamoto University, Tokyo, Japan.
2
AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.

Abstract

HLA-B*52:01-C*12:02, which is found in approximately 20% of all Japanese persons, is well known to be associated with ulcerative colitis and Takayasu arteritis. This haplotype is also known to be protective in individuals infected with human immunodeficiency virus (HIV) type 1. Recent studies showed that HLA-B*52:01-restricted HIV-1-specific T cells suppress HIV-1 and that HLA-C*12:02 together with KIR2DL2 play an important role in natural killer cell-mediated control of HIV-1. However, the role of HLA-C*12:02-restricted cytotoxic T lymphocytes (CTLs) in suppressing HIV-1 replication remains unknown. In the present study, we demonstrated that HLA-C*12:02-restricted CTLs specific for 2 immunodominant epitopes, Pol IY11 and Nef MY9, contributed to the suppression of HIV-1 replication in HIV-1-infected individuals. Further analysis demonstrated that these 2 HLA-C*12:02-restricted CTLs together with 4 HLA-B*52:01-restricted ones effectively suppressed HIV-1 in individuals with the HLA-B*52:01-C*12:02 haplotype. Thus, both HLA-C*12:02 and HLA-B*52:01 alleles contribute to HIV-1 suppression via both HIV-1-specific CTLs and natural killer cells in individuals with this haplotype.

KEYWORDS:

CTL; HIV-1; HLA-B*52:01; HLA-C*12:02; haplotype

PMID:
28968792
DOI:
10.1093/infdis/jix483
[Indexed for MEDLINE]
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19.
J Infect Dis. 2017 Nov 15;216(8):969-976. doi: 10.1093/infdis/jix425.

Mucosal-Associated Invariant T Cells Are More Activated in Chronic Hepatitis B, but Not Depleted in Blood: Reversal by Antiviral Therapy.

Author information

1
Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.

Abstract

Background:

Mucosal-associated invariant T (MAIT) cells might play a role in control of viral replication during chronic hepatitis B (cHBV) infection, but little is known of their number, phenotype, or function in cHBV patients.

Methods:

We performed flow cytometry on CD3+Vɑ7.2+CD161+ MAIT cells in blood of 55 cHBV patients. Nine patients were sampled before and on entecavir treatment. Six patients on therapy underwent a liver biopsy for flow cytometric analysis. Measurements included MAIT cell frequency, phenotype, and cytokine-producing capacity.

Results:

The MAIT cells were not deleted in blood or liver of cHBV patients compared with healthy controls, but they had higher percentages of CD38+ MAIT cells in blood, which declined on entecavir treatment. Peripheral MAIT cells of patients in the HBeAg-negative phase were least activated. Cytokine-producing MAIT cells were as frequent, but granzyme B-producing MAIT cells were more frequent upon stimulation with Escherichia coli compared with healthy controls.

Conclusions:

We demonstrate that, in sharp contrast to hepatitis C virus and human immunodeficiency virus patients, MAIT cells isolated from HBV patients are not deleted but are more activated, which can be normalized by nucleoside analog therapy. These observations may aid in deciphering the role of MAIT cells in immune responses to HBV.

KEYWORDS:

MAIT cells; entecavir; hepatitis B; nucleoside analogs

PMID:
28968772
DOI:
10.1093/infdis/jix425
[Indexed for MEDLINE]
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20.
J Infect Dis. 2017 Nov 27;216(9):1080-1090. doi: 10.1093/infdis/jix456.

Safety and Immunogenicity of PENNVAX-G DNA Prime Administered by Biojector 2000 or CELLECTRA Electroporation Device With Modified Vaccinia Ankara-CMDR Boost.

Author information

1
US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring.
2
Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda.
3
Armed Forces Research Institute of Medical Sciences, Department of Retrovirology, Bangkok, Thailand.
4
Makerere University/Walter Reed Project, Kampala, Uganda.
5
KEMRI/Walter Reed Project, Kericho, Kenya.
6
National Institute of Medical Research, Mbeya Medical Research Centre, Mbeya, United Republic of Tanzania.
7
Wistar Institute, Philadelphia.
8
Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich, Germany.
9
Laboratory of Viral Diseases.
10
Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda.
11
Military Infectious Diseases Research Program, Ft. Detrick, Maryland.
12
Inovio Pharmaceuticals, Inc, Plymouth Meeting, Pennsylvania.

Abstract

Background:

We report the first-in-human safety and immunogenicity evaluation of PENNVAX-G DNA/modified vaccinia Ankara-Chiang Mai double recombinant (MVA-CMDR) prime-boost human immuonodeficiency virus (HIV) vaccine, with intramuscular DNA delivery by either Biojector 2000 needle-free injection system (Biojector) or CELLECTRA electroporation device.

Methods:

Healthy, HIV-uninfected adults were randomized to receive 4 mg of PENNVAX-G DNA delivered intramuscularly by Biojector or electroporation at baseline and week 4 followed by intramuscular injection of 108 plaque forming units of MVA-CMDR at weeks 12 and 24. The open-label part A was conducted in the United States, followed by a double-blind, placebo-controlled part B in East Africa. Solicited and unsolicited adverse events were recorded, and immune responses were measured.

Results:

Eighty-eight of 100 enrolled participants completed all study injections, which were generally safe and well tolerated, with more immediate, but transient, pain in the electroporation group. Cellular responses were observed in 57% of vaccine recipients tested and were CD4 predominant. High rates of binding antibody responses to CRF01_AE antigens, including gp70 V1V2 scaffold, were observed. Neutralizing antibodies were detected in a peripheral blood mononuclear cell assay, and moderate antibody-dependent, cell-mediated cytotoxicity activity was demonstrated.

Discussion:

The PVG/MVA-CMDR HIV-1 vaccine regimen is safe and immunogenic. Substantial differences in safety or immunogenicity between modes of DNA delivery were not observed.

Clinical Trials Registration:

NCT01260727.

KEYWORDS:

HIV vaccine; electroporation; modified vaccinia Ankara; needle-free injection

PMID:
28968759
PMCID:
PMC5853809
[Available on 2018-11-27]
DOI:
10.1093/infdis/jix456
[Indexed for MEDLINE]
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