Publications by authors named "Sonya Heath"

46 Publications

Characteristics of HIV Seroconverters Identified in an Emergency Department HIV Screening Program.

AIDS Patient Care STDS 2021 Jul;35(7):255-262

Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

The emergency department (ED) may represent a missed opportunity to proactively intervene upon patients at "high risk" for HIV. We sought to describe characteristics of ED HIV seroconverters (individuals who screened positive in the ED for HIV who had either (1) a previous prior negative HIV test in the electronic health record (EHR) or who (2) self-reported a prior negative HIV test) to identify a "high-risk" phenotype for pre-infection engagement. A retrospective chart-review was performed of HIV seroconverters at an academic, urban ED. General demographics, mental health illness comorbidities, and Centers for Disease Control and Prevention (CDC)-identified "high risk" factors, including intravenous drug use (IVDU) and history of sexually transmitted infection (STI) were noted. One hundred thirty total patients were identified, 48 (36.9%) with prior HER-negative test and 82 (63.1%) with self-reported previous negative test. Of total seroconverters: 100 (76.9%) were male and 77 (59.2%) were between the ages of 13-34, comparable to national rates of new HIV diagnoses. Ninety-two patients (70.8%) were Black and 16 (12.3%) had a history of IVDU, significantly increased compared with regional and national new HIV rates ( < 0.05). Fifty-two patients (40%) had an STI within 1 year before HIV-positive screen, 67 (51.5%) had a history of mental health illness, and 77 (59.2%) were uninsured. This review revealed an HIV seroconversion population disproportionately affected by race, IVDU, mental health comorbidities, and additional social factors. The ED may represent a unique opportunity for at-risk, pre-HIV exposure intervention, particularly for vulnerable populations.
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http://dx.doi.org/10.1089/apc.2021.0031DOI Listing
July 2021

A link between IL-23 and anti-CD4 autoantibody production in antiretroviral-treated HIV-infected individuals.

J Virol 2021 Mar 17. Epub 2021 Mar 17.

Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA

Potential mechanisms of poor CD4+ T cell reconstitution after viral suppression with antiretroviral therapy (ART) in HIV disease have been extensively investigated. We recently discovered that anti-CD4 autoantibody plays a role in impaired CD4+ T cell recovery from ART in HIV-infected individuals with viral suppression, which accounts for a mechanism specific for CD4+ T cell depletion. However, the mechanism of pathologic anti-CD4 autoantibody production in treated HIV disease remains unknown. Here we report that seasonal influenza vaccination induced IgG anti-CD4 autoantibodies, predominant IgG3 subclass, in some viral-suppressed ART-treated HIV+ subjects. To explore the mechanism of anti-CD4 antibody production in this population, we performed and analyzed gene profiles in isolated B cells using a gene microarray and plasma 32 cytokines. Notably, both gene expression and multiple cytokine analyses showed pre-vaccination plasma level of IL-23 was the key cytokine linked to IgG anti-CD4 antibody production in response to immunization Exogenous rIL-23 increased autoreactive IgG binding on CD4+ T cells from HIV+ subjects Results from this study may reveal a role of IL-23 in anti-CD4 autoantibody production in treated HIV.In our published studies, we determine that pathological anti-CD4 IgGs from immunologic non-responders on virally-suppressive ART (CD4 cell counts < 350 cells/μL) mediated CD4+ T cell death via antibody-mediated cytotoxicity (ADCC), which play a role in poor CD4+ T cell recovery from ART. Up to 25% of HIV-infected individuals are non-responders and demonstrate increased morbidity and mortality. However, the mechanism of anti-CD4 autoantibody production in treated HIV remains unknown. In this study, we report that IL-23 may be the key cytokine to promote anti-CD4 autoantibody production after immunization in ART-treated HIV-infected individuals.
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http://dx.doi.org/10.1128/JVI.00271-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139695PMC
March 2021

Convalescent plasma-mediated resolution of COVID-19 in a patient with humoral immunodeficiency.

Cell Rep Med 2021 Jan 5;2(1):100164. Epub 2020 Dec 5.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Convalescent plasma (CP) is widely used to treat COVID-19, but without formal evidence of efficacy. Here, we report the beneficial effects of CP in a severely ill COVID-19 patient with prolonged pneumonia and advanced chronic lymphocytic leukemia (CLL), who was unable to generate an antiviral antibody response of her own. On day 33 after becoming symptomatic, the patient received CP containing high-titer (ID > 5,000) neutralizing antibodies (NAbs), defervesced, and improved clinically within 48 h and was discharged on day 37. Hence, when present in sufficient quantities, NAbs to SARS-CoV-2 have clinical benefit even if administered relatively late in the disease course. However, analysis of additional CP units revealed widely varying NAb titers, with many recipients exhibiting endogenous NAb responses far exceeding those of the administered units. To obtain the full therapeutic benefits of CP immunotherapy, it will thus be important to determine the neutralizing activity in both CP units and transfusion candidates.
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http://dx.doi.org/10.1016/j.xcrm.2020.100164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817775PMC
January 2021

Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption.

Sci Transl Med 2021 01;13(576)

Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.

Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4 T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 50% (IC) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4 T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant.
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http://dx.doi.org/10.1126/scitranslmed.abd8179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923595PMC
January 2021

Glycan Positioning Impacts HIV-1 Env Glycan-Shield Density, Function, and Recognition by Antibodies.

iScience 2020 Nov 21;23(11):101711. Epub 2020 Oct 21.

Department of Microbiology, University of Alabama at Birmingham, 845 19th Street S, Birmingham, AL 35294, USA.

HIV-1 envelope (Env) N-glycosylation impact virus-cell entry and immune evasion. How each glycan interacts to shape the Env-protein-sugar complex and affects Env function is not well understood. Here, analysis of two Env variants from the same donor, with differing functional characteristics and N-glycosylation-site composition, revealed that changes to key N-glycosylation sites affected the Env structure at distant locations and had a ripple effect on Env-wide glycan processing, virus infectivity, antibody recognition, and virus neutralization. Specifically, the N262 glycan, although not in the CD4-binding site, modulated Env binding to the CD4 receptor, affected Env recognition by several glycan-dependent neutralizing antibodies, and altered site-specific glycosylation heterogeneity, with, for example, N448 displaying limited glycan processing. Molecular-dynamic simulations visualized differences in glycan density and how specific oligosaccharide positions can move to compensate for a glycan loss. This study demonstrates how changes in individual glycans can alter molecular dynamics, processing, and function of the Env-glycan shield.
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http://dx.doi.org/10.1016/j.isci.2020.101711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649354PMC
November 2020

Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain.

Redox Biol 2020 09 13;36:101684. Epub 2020 Aug 13.

Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, USA.

The prevalence of chronic widespread pain (CWP) in people with HIV is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin, within their endoplasmic reticulum (ER). When released into plasma, β-endorphin dampens nociception by binding to opioid receptors on sensory neurons. We hypothesized that the heme-dependent redox signaling induces ER stress, which attenuates leukocyte β-endorphins levels/release, thereby increasing pain sensitivity in people with HIV. Results demonstrated that HIV positive individuals with CWP had increased plasma methemoglobin, erythrocytes membrane oxidation, hemolysis, and low plasma heme scavenging enzyme, hemopexin, compared to people with HIV without CWP and HIV-negative individuals with or without pain. In addition, the leukocytes from people with HIV with CWP had attenuated levels of the heme metabolizing enzyme, heme oxygenase-1, which metabolizes free heme to carbon-monoxide and biliverdin. These individuals also had elevated ER stress, and low β-endorphin in leukocytes. In vitro, heme exposure or heme oxygenase-1 deletion, decreased β-endorphins in murine monocytes/macrophages. Treating cells with a carbon-monoxide donor or an ER stress inhibitor, increased β-endorphins. To mimic hemolytic effects in a preclinical model, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-endorphin levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with hemopexin blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-endorphin is responsible for hypersensitivity in people with HIV.
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http://dx.doi.org/10.1016/j.redox.2020.101684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451624PMC
September 2020

Classical monocyte transcriptomes reveal significant anti-inflammatory statin effect in women with chronic HIV.

Cardiovasc Res 2021 Mar;117(4):1166-1177

Laboratory of Inflammation Biology, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.

Aims: During virally suppressed chronic HIV infection, persistent inflammation contributes to the development of cardiovascular disease (CVD), a major comorbidity in people living with HIV (LWH). Classical blood monocytes (CMs) remain activated during antiretroviral therapy and are a major source of pro-inflammatory and pro-thrombotic factors that contribute to atherosclerotic plaque development and instability.

Methods And Results: Here, we identify transcriptomic changes in circulating CMs in peripheral blood mononuclear cell samples from participants of the Women's Interagency HIV Study, selected by HIV and subclinical CVD (sCVD) status. We flow-sorted CM from participants of the Women's Interagency HIV Study and deep-sequenced their mRNA (n = 92). CMs of HIV+ participants showed elevated interleukin (IL)-6, IL-1β, and IL-12β, overlapping with many transcripts identified in sCVD+ participants. In sCVD+ participants LWH, those reporting statin use showed reduced pro-inflammatory gene expression to a level comparable with healthy (HIV-sCVD-) participants. Statin non-users maintained an elevated inflammatory profile and increased cytokine production.

Conclusion: Statin therapy has been associated with a lower risk of cardiac events, such as myocardial infarction in the general population, but not in those LWH. Our data suggest that women LWH may benefit from statin therapy even in the absence of overt CVD.
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http://dx.doi.org/10.1093/cvr/cvaa188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983000PMC
March 2021

Estimating the First 90 of the UNAIDS 90-90-90 Goal: A Review.

J Int Assoc Provid AIDS Care 2020 Jan-Dec;19:2325958220919290

Center for AIDS Research, University of Alabama at Birmingham, AL, USA.

Estimating the population with undiagnosed HIV (PUHIV) is the most methodologically challenging aspect of evaluating 90-90-90 goals. The objective of this review is to discuss assumptions, strengths, and shortcomings of currently available methods of this estimation. Articles from 2000 to 2018 on methods to estimate PUHIV were reviewed. Back-calculation methods including CD4 depletion and test-retest use diagnosis CD4 count, or previous testing history to determine likely infection time thus, providing an estimate of PUHIV for previous years. Biomarker methods use immunoassays to differentiate recent from older infections. Statistical techniques treat HIV status as missing data and impute data for models of infection. Lastly, population surveys using HIV rapid testing most accurately calculates the current HIV prevalence. Although multiple methods exist to estimate the number of PUHIV, the appropriate method for future applications depends on multiple factors, namely data availability and population of interest.
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http://dx.doi.org/10.1177/2325958220919290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235967PMC
May 2021

Impact of first-line antiretroviral therapy regimens on the restoration of the CD4/CD8 ratio in the CNICS cohort.

J Antimicrob Chemother 2020 06;75(6):1604-1610

University Hospital Ramón y Cajal and Universidad de Alcalá (IRYCIS), Madrid, 28034, Spain.

Background: The CD4/CD8 ratio is an indicator of immunosenescence and a predictor of all-cause mortality in HIV-infected patients. The effects of different ART regimens on CD4/CD8 ratio recovery remain unclear.

Methods: Clinical cohort study of ART-treated patients from the CFAR Network of Integrated Clinical Systems (CNICS). We included ART-naive adults with HIV infection who achieved undetectable HIV RNA during the first 48 weeks of treatment and had additional follow-up 48 weeks after virological suppression (VS). Primary endpoints included increase in CD4/CD8 ratio at both timepoints and secondary endpoints were CD4/CD8 ratio recovery at cut-offs of ≥0.5 or ≥1.0.

Results: Of 3971 subjects who met the study criteria, 1876 started ART with an NNRTI, 1804 with a PI and 291 with an integrase strand transfer inhibitor (INSTI). After adjusting for age, sex, race, year of entry, risk group, HCV serostatus, baseline viral load and baseline CD4/CD8 ratio, subjects on an NNRTI showed a significantly greater CD4/CD8 ratio gain compared with those on a PI, either 48 weeks after ART initiation or after 48 weeks of HIV RNA VS. The greater CD4/CD8 ratio improvement in the NNRTI arm was driven by a higher decline in CD8 counts. The INSTI group showed increased rates of CD4/CD8 ratio normalization at the ≥1.0 cut-off compared with the PI group.

Conclusions: NNRTI therapy was associated with a greater increase in the CD4/CD8 ratio compared with PIs. NNRTI- and INSTI-based first-line ART were associated with higher rates of CD4/CD8 ratio normalization at a cut-off of 1.0 than a PI-based regimen, which might have clinical implications.
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http://dx.doi.org/10.1093/jac/dkaa024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225872PMC
June 2020

Systemic translocation of Staphylococcus drives autoantibody production in HIV disease.

Microbiome 2019 02 14;7(1):25. Epub 2019 Feb 14.

Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave. BSB208D, Charleston, SC, 29425, USA.

Background: Increased autoreactive antibodies have been reported in HIV disease; however, the mechanism accounting for autoantibody induction in HIV remains unknown.

Results: Herein, we show that seasonal influenza vaccination induces autoantibody production (e.g., IgG anti-nuclear antibody (ANA) and anti-double-stranded DNA antibody (anti-dsDNA)) in some viral-suppressed antiretroviral therapy (ART)-treated HIV+ subjects, but not in healthy controls. These autoantibodies were not derived from antigen-specific B cells but from activated "bystander" B cells analyzed by single-cell assay and by study of purified polyclonal ANAs from plasma. To explore the mechanism of autoantibody generation in HIV+ subjects, plasma level of microbial products, gene expression profile of B cells, and B cell receptor (BCR) repertoires were analyzed. We found that autoantibody production was associated with increased plasma level of microbial translocation; the patients with high autoantibodies had skewed B cell repertoires and upregulation of genes related to innate immune activation in response to microbial translocation. By analyzing circulating microbial 16S rDNA in plasma, the relative abundance of Staphylococcus was found to be associated with autoantibody production in HIV+ subjects. Finally, we found that injection of heat-killed Staphylococcus aureus promoted germinal center B cell responses and autoantibody production in mice, consistent with the notion that autoantibody production in HIV+ patients is triggered by microbial products.

Conclusions: Our results showed that translocation of Staphylococcus can promote B cell activation through enhancing germinal center response and induces autoantibody production. It uncovers a potential mechanism linking microbial translocation and autoimmunity in HIV+ disease and provides a strong rationale for targeting Staphylococcus to prevent autoantibody production.
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http://dx.doi.org/10.1186/s40168-019-0646-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376754PMC
February 2019

Loss of CXCR4 on non-classical monocytes in participants of the Women's Interagency HIV Study (WIHS) with subclinical atherosclerosis.

Cardiovasc Res 2019 05;115(6):1029-1040

La Jolla Institute of Immunology, Athena Circle Drive La Jolla, CA, USA.

Aims: To test whether human immunodeficiency virus (HIV) infection and subclinical cardiovascular disease (sCVD) are associated with expression of CXCR4 and other surface markers on classical, intermediate, and non-classical monocytes in women.

Methods And Results: sCVD was defined as presence of atherosclerotic lesions in the carotid artery in 92 participants of the Women's Interagency HIV Study (WIHS). Participants were stratified into four sets (n = 23 each) by HIV and sCVD status (HIV-/sCVD-, HIV-/sCVD+, HIV+/sCVD-, and HIV+/sCVD+) matched by age, race/ethnicity, and smoking status. Three subsets of monocytes were determined from archived peripheral blood mononuclear cells. Flow cytometry was used to count and phenotype surface markers. We tested for differences by HIV and sCVD status accounting for multiple comparisons. We found no differences in monocyte subset size among the four groups. Expression of seven surface markers differed significantly across the three monocyte subsets. CXCR4 expression [median fluorescence intensity (MFI)] in non-classical monocytes was highest among HIV-/CVD- [628, interquartile range (IQR) (295-1389)], followed by HIV+/CVD- [486, IQR (248-699)], HIV-/CVD+ (398, IQR (89-901)), and lowest in HIV+/CVD+ women [226, IQR (73-519)), P = 0.006 in ANOVA. After accounting for multiple comparison (Tukey) the difference between HIV-/CVD- vs. HIV+/CVD+ remained significant with P = 0.005 (HIV-/CVD- vs. HIV+/CVD- P = 0.04, HIV-/CVD- vs. HIV-/CVD+ P = 0.06, HIV+/CVD+ vs. HIV+/CVD- P = 0.88, HIV+/CVD+ vs. HIV-/CVD+ P = 0.81, HIV+/CVD- vs. HIV-/CVD+, P = 0.99). All pairwise comparisons with HIV-/CVD- were individually significant (P = 0.050 vs. HIV-/CVD+, P = 0.028 vs. HIV+/CVD-, P = 0.009 vs. HIV+/CVD+). CXCR4 expression on non-classical monocytes was significantly higher in CVD- (501.5, IQR (249.5-887.3)) vs. CVD+ (297, IQR (81.75-626.8) individuals (P = 0.028, n = 46 per group). CXCR4 expression on non-classical monocytes significantly correlated with cardiovascular and HIV-related risk factors including systolic blood pressure, platelet and T cell counts along with duration of antiretroviral therapy (P < 0.05). In regression analyses, adjusted for education level, study site, and injection drug use, presence of HIV infection and sCVD remained significantly associated with lower CXCR4 expression on non-classical monocytes (P = 0.003), but did not differ in classical or intermediate monocytes.

Conclusion: CXCR4 expression in non-classical monocytes was significantly lower among women with both HIV infection and sCVD, suggesting a potential atheroprotective role of CXCR4 in non-classical monocytes.
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http://dx.doi.org/10.1093/cvr/cvy292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735712PMC
May 2019

Enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain.

J Neurovirol 2019 02 9;25(1):57-71. Epub 2018 Nov 9.

Department of Psychology, University of Alabama at Birmingham, 1300 University Boulevard, Campbell Hall, Room 237, Birmingham, AL, 35294, USA.

Chronic pain in persons living with HIV (PLWH) may be related to alterations in endogenous pain modulatory processes (e.g., high facilitation and low inhibition of nociception) that promote exaggerated pain responses, known as hyperalgesia, and central nervous system (CNS) sensitization. This observational study examined differences in endogenous pain modulatory processes between 59 PLWH with chronic pain, 51 PLWH without chronic pain, and 50 controls without HIV or chronic pain. Quantitative sensory testing for temporal summation (TS) of mechanical and heat pain as well as conditioned pain modulation (CPM) were used to assess endogenous pain facilitatory and inhibitory processes, respectively. Associations among TS, CPM, and self-reported clinical pain severity were also examined in PLWH with chronic pain. Findings demonstrated significantly greater TS of mechanical and heat pain for PLWH with chronic pain compared to PLWH without chronic pain and controls. CPM effects were present in controls, but not in either PLWH with or without chronic pain. Among PLWH with chronic pain, greater TS of mechanical pain was significantly associated with greater average clinical pain severity. Results of this study suggest that enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain.
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http://dx.doi.org/10.1007/s13365-018-0686-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446934PMC
February 2019

Increased influenza-specific antibody avidity in HIV-infected women compared with HIV-infected men on antiretroviral therapy.

AIDS 2019 01;33(1):33-44

Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.

Background: It is recommended that HIV-infected individuals receive annual influenza vaccination due to their high susceptibility to influenza infection, especially among women. However, there have been few studies investigating sex-related responses to influenza vaccine in antiretroviral therapy (ART)-treated HIV-infected individuals.

Method: In this study, 26 aviremic ART-treated HIV-infected individuals and 16 healthy controls were enrolled in the current study. Blood was collected prior to vaccination (D0), on days 7-10 (D7) and on days 14-21 (D14) following administration of the 2013-2014 seasonal influenza vaccine. A series of analyses evaluated the serological and cellular responses following influenza vaccination.

Results: Female HIV-infected individuals had increased influenza-specific antibody avidity relative to male HIV-infected individuals, but similar plasma levels of influenza-specific binding antibodies and neutralizing antibodies. Increased cycling B cells and follicular helper CD4 T (Tfh) cells were observed in female HIV-infected individuals pre and postvaccination compared with male HIV-infected individuals, and cycling Tfh cells were directly correlated with influenza-specific antibody avidity. Moreover, plasma testosterone levels were inversely correlated with antibody avidity index. The magnitude of microbial translocation [plasma lipopolysaccharide (LPS)] level was directly correlated with influenza-specific antibody avidity. Circulating 16S rDNA microbiome showed that enrichment of specific species within Proteobacteria was associated with influenza-specific antibody avidity. These results, including differences based on sex and correlations, were only observed in HIV-infected individuals but not in the healthy controls.

Conclusion: This study demonstrated sex differences in influenza-specific antibody avidity in ART-treated HIV disease, and provides valuable information on vaccination strategy in the ART-treated HIV-infected population.
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http://dx.doi.org/10.1097/QAD.0000000000002022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279558PMC
January 2019

Distinct systemic microbiome and microbial translocation are associated with plasma level of anti-CD4 autoantibody in HIV infection.

Sci Rep 2018 08 27;8(1):12863. Epub 2018 Aug 27.

Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA.

Microbial signals have been linked to autoantibody induction. Recently, we found that purified anti-CD4 autoantibodies from the plasma of chronic HIV-1-infected patients under viral-suppressed antiretroviral therapy (ART) play a pathologic role in poor CD4+ T cell recovery. The purpose of the study was to investigate the association of systemic microbiome and anti-CD4 autoantibody production in HIV. Plasma microbiome from 12 healthy controls and 22 HIV-infected subjects under viral-suppressed ART were analyzed by MiSeq sequencing. Plasma level of autoantibodies and microbial translocation (LPS, total bacterial 16S rDNA, soluble CD14, and LPS binding protein) were analyzed by ELISA, limulus amebocyte assay, and qPCR. We found that plasma level of anti-CD4 IgGs but not anti-CD8 IgGs was increased in HIV+ subjects compared to healthy controls. HIV+ subjects with plasma anti-CD4 IgG > 50 ng/mL (high) had reduced microbial diversity compared to HIV+ subjects with anti-CD4 IgG ≤ 50 ng/mL (low). Moreover, plasma anti-CD4 IgG level was associated with elevated microbial translocation and reduced microbial diversity in HIV+ subjects. The Alphaproteobacteria class was significantly enriched in HIV+ subjects with low anti-CD4 IgG compared to patients with high anti-CD4 IgG even after controlling for false discovery rate (FDR). The microbial components were different from the phylum to genus level in HIV+ subjects with high anti-CD4 IgGs compared to the other two groups, but these differences were not significant after controlling for FDR. These results suggest that systemic microbial translocation and microbiome may associate with anti-CD4 autoantibody production in ART-treated HIV disease.
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http://dx.doi.org/10.1038/s41598-018-31116-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110826PMC
August 2018

Antisense-Derived HIV-1 Cryptic Epitopes Are Not Major Drivers of Viral Evolution during the Acute Phase of Infection.

J Virol 2018 10 12;92(19). Epub 2018 Sep 12.

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

While prior studies have demonstrated that CD8 T cell responses to cryptic epitopes (CE) are readily detectable during HIV-1 infection, their ability to drive escape mutations following acute infection is unknown. We predicted 66 CE in a Zambian acute infection cohort based on escape mutations occurring within or near the putatively predicted HLA-I-restricted epitopes. The CE were evaluated for CD8 T cell responses for patients with chronic and acute HIV infections. Of the 66 predicted CE, 10 were recognized in 8/32 and 4/11 patients with chronic and acute infections, respectively. The immunogenic CE were all derived from a single antisense reading frame within However, when these CE were tested using longitudinal study samples, CE-specific T cell responses were detected but did not consistently select for viral escape mutations. Thus, while we demonstrated that CE are immunogenic in acute infection, the immune responses to CE are not major drivers of viral escape in the initial stages of HIV infection. The latter finding may be due to either the subdominant nature of CE-specific responses, the low antigen sensitivity, or the magnitude of CE responses during acute infections. Although prior studies demonstrated that cryptic epitopes of HIV-1 induce CD8 T cell responses, evidence that targeting these epitopes drives HIV escape mutations has been substantially limited, and no studies have addressed this question following acute infection. In this comprehensive study, we utilized longitudinal viral sequencing data obtained from three separate acute infection cohorts to predict potential cryptic epitopes based on HLA-I-associated viral escape. Our data show that cryptic epitopes are immunogenic during acute infection and that many of the responses they elicit are toward translation products of HIV-1 antisense reading frames. However, despite cryptic epitope targeting, our study did not find any evidence of early CD8-mediated immune escape. Nevertheless, improving cryptic epitope-specific CD8 T cell responses may still be beneficial in both preventative and therapeutic HIV-1 vaccines.
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http://dx.doi.org/10.1128/JVI.00711-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146806PMC
October 2018

Drug Use is Associated with Anti-CD4 IgG-mediated CD4+ T Cell Death and Poor CD4+ T Cell Recovery in Viral-suppressive HIV-infected Individuals Under Antiretroviral Therapy.

Curr HIV Res 2018 ;16(2):143-150

Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, 29425, United States.

Background: The role and mechanism of drug use or abuse in Antiretroviral Therapy (ART)-treated HIV disease are not completely known.

Methods: To investigate the impact of drug use on HIV pathogenesis without confounding by HIV replication and ART adherence, we first analyzed the data from our clinical database in 103 HIV+ subjects with viral-suppressed ART treatment by a multiple regression test.

Results: We found that HIV+ drug users had lower CD4+ T cell counts but higher CD8+ T cell counts compared to HIV+ non-drug users, and both drug use and nadir CD4+ T cell counts was independently associated with CD4+ T cell recovery after controlling for sex and age. Next, we enrolled individuals from four study groups, HIV-negative and HIV+ subjects without any substance use, HIV-negative and HIV+ subjects with current illicit drug use (either non-injection cocaine or cannabis). All HIV+ subjects were viral-suppressed with ART treatment (≥ 2 years). Notably, HIV+ drug users had increased plasma anti-CD4 IgG levels compared to the other three study groups which were inversely correlated with decreased CD4+ T cell counts only in HIV+ drug users. There was a significant increase in CD4+ T cell recovery following ART in HIV+ non-drug users but not in HIV+ drug users. Anti-CD4 IgGs purified from plasma of HIV+ drug users induced CD4+ T cell death in vitro through Antibody-Dependent Cytotoxicity (ADCC).

Conclusion: These results suggest that drug use prevents immune reconstitution in HIV-infected individuals despite long-term ART treatment and viral suppression.
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http://dx.doi.org/10.2174/1570162X16666180703151208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115301PMC
April 2019

Intersectional health-related stigma in persons living with HIV and chronic pain: implications for depressive symptoms.

AIDS Care 2018 06 30;30(sup2):66-73. Epub 2018 May 30.

e Divisions of General Internal Medicine and Infectious Diseases , University of Pittsburgh , Pittsburgh , PA , USA.

"Intersectional health-related stigma" (IHRS) refers to stigma that arises at the convergence of multiple health conditions. People living with HIV (PLWH) and chronic pain have two highly stigmatized health conditions, and thus may be at especially high risk for internalizing these stigmas and consequently experiencing depression. This study examined the intersectionality of internalized HIV and chronic pain stigma in relation to depressive symptoms in a sample of PLWH and chronic pain. Sixty participants were recruited from an HIV clinic in the Southeastern United States. Chronic pain was defined as pain that has been present for at least three consecutive months, and that has been an ongoing problem for at least half the days in the past six months. All participants completed the HIV Stigma Mechanisms Scale, Internalized Stigma in Chronic Pain Scale, the Short-Form Brief Pain Inventory, and the Center for Epidemiological Studies - Depression Scale. Clinical data was collected from medical records. An intersectional HIV and chronic pain composite variable was created and participants were categorized as either high (28%), moderate (32%), or low (40%). Results revealed that intersectional HIV and chronic pain stigma was significantly associated with severity of depressive symptoms (p = .023). Pairwise contrasts revealed that participants with high (p = .009) and moderate (p = .033) intersectional stigma reported significantly greater mean depressive symptom severity than those with low intersectional stigma. Participants who reported the highest levels of internalized HIV and chronic pain stigma also reported the greatest severity of depressive symptoms. This suggests that the experience of both HIV and chronic pain stigma (i.e., IHRS) among PLWH and chronic pain may synergistically perpetuate negative mood in a more profound manner than experiencing either one stigma alone.
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http://dx.doi.org/10.1080/09540121.2018.1468012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080251PMC
June 2018

Regulatory CD4 T cells inhibit HIV-1 expression of other CD4 T cell subsets via interactions with cell surface regulatory proteins.

Virology 2018 03 8;516:21-29. Epub 2018 Jan 8.

Division of Rheumatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

During chronic HIV-1 infection, regulatory CD4 T cells (Tregs) frequently represent the largest subpopulation of CD4 T cell subsets, implying relative resistant to HIV-1. When HIV-1 infection of CD4 T cells was explored in vitro and ex vivo from patient samples, Tregs possessed lower levels of HIV-1 DNA and RNA in comparison with conventional effector and memory CD4 T cells. Moreover, Tregs suppressed HIV-1 expression in other CD4 T cells in an in vitro co-culture system. This suppression was mediated in part via multiple inhibitory surface proteins expressed on Tregs. Antibody blockade of CTLA-4, PD-1, and GARP on Tregs resulted in increased HIV-1 DNA integration and mRNA expression in neighboring CD4 T cells. Moreover, antibody blockade of Tregs inhibitory proteins resulted in increased HIV-1 LTR transcription in co-cultured CD4 T cells. Thus, Tregs inhibit HIV-1 infection of other CD4 T cell subsets via interactions with inhibitory cell surface proteins.
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http://dx.doi.org/10.1016/j.virol.2017.12.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357825PMC
March 2018

The effect of plasma auto-IgGs on CD4 T cell apoptosis and recovery in HIV-infected patients under antiretroviral therapy.

J Leukoc Biol 2017 12 13;102(6):1481-1486. Epub 2017 Oct 13.

Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA;

Although effective antiretroviral therapy (ART) suppresses HIV viral replication, prevents AIDS-related complications, and prolongs life, a proportion of patients fails to restore the patients' CD4 T cell number to the level of healthy individuals. Increased mortality and morbidity have been observed in these patients. In the current study, we have investigated the role of auto-IgGs in CD4 T cell apoptosis and recovery in a cross-sectional study. All HIV subjects were on viral-suppressive ART treatment with a different degree of CD4 T cell reconstitution. Total auto-IgG binding on CD4 T cell surfaces and its associated apoptosis and CD4 T cell recovery were analyzed by flow cytometry ex vivo. Total IgGs from plasma were tested for their binding capacities to CD4 T cell surfaces and their mediation to CD4 T cell death through NK cell cytotoxicity in vitro. HIV subjects had increased surface binding of auto-IgGs on CD4 T cells compared with healthy controls, and IgG binding was associated with elevated CD4 T cell apoptosis in HIV subjects but not in healthy controls. Plasma IgGs from HIV subjects bound to CD4 T cells and induced cell apoptosis through NK cytotoxicity in vitro. Soluble CD4 (sCD4) preincubation prevented NK cell-mediated CD4 T cell death. Our results suggest that plasma autoantibodies may play a role in some HIV patients with poor CD4 T cell recovery under viral-suppressive ART.
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http://dx.doi.org/10.1189/jlb.5A0617-219RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608058PMC
December 2017

Pathological Role of Anti-CD4 Antibodies in HIV-Infected Immunologic Nonresponders Receiving Virus-Suppressive Antiretroviral Therapy.

J Infect Dis 2017 07;216(1):82-91

Department of Microbiology and Immunology.

Increased mortality and morbidity occur among human immunodeficiency virus (HIV)-infected patients in whom CD4+ T-cell counts do not increase despite viral suppression with antiretroviral therapy (ART). Here we identified an underlying mechanism. Significantly elevated plasma levels of anti-CD4 immunoglobulin G (IgG) were found in HIV-positive immunologic nonresponders (ie, HIV-positive individuals with CD4+ T-cell counts of ≤350 cells/μL), compared with levels in HIV-positive immunologic responders (ie, HIV-positive individuals with CD4+ T-cell counts of ≥500 cells/μL) and healthy controls. Higher plasma level of anti-CD4 IgG correlated with blunted CD4+ T-cell recovery. Furthermore, purified anti-CD4 IgG from HIV-positive immunologic nonresponders induced natural killer (NK) cell-dependent CD4+ T-cell cytolysis and apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. We also found that anti-CD4 IgG-mediated ADCC exerts greater apoptosis of naive CD4+ T cells relative to memory CD4+ T cells. Consistently, increased frequencies of CD107a+ NK cells and profound decreases of naive CD4+ T cells were observed in immunologic nonresponders as compared to responders and healthy controls ex vivo. These data indicate that autoreactive anti-CD4 IgG may play an important role in blunted CD4+ T-cell reconstitution despite effective ART.
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http://dx.doi.org/10.1093/infdis/jix223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853506PMC
July 2017

Detectable Viral Load May Be Associated with Increased Pain Sensitivity in Persons Living with HIV: Preliminary Findings.

Pain Med 2017 Dec;18(12):2289-2295

Division of Infectious Diseases.

Objective: Animal models have previously shown that HIV is associated with hyperalgesia, or heightened sensitivity to painful stimuli. Efforts to determine whether this finding translates to humans are presently lacking. Among persons living with HIV (PLWH), those with detectable viral loads may be at greatest risk for heightened pain sensitivity. It was hypothesized that PLWH with detectable viral loads would be more sensitive to painful stimuli compared with PLWH without detectable viral loads and healthy controls without HIV.

Design: A total of 47 PLWH and 50 community-dwelling, healthy adults without HIV (controls) were recruited. Participants completed a quantitative sensory testing protocol to assess threshold, tolerance, and temporal summation in response to painful mechanical and heat stimuli. Most recent viral load was collected from medical records, and viral load was considered detectable if the count was greater than 50 copies/mL of blood. Of the 47 PLWH, 11 (23.4%) had detectable viral loads, the median viral load count was 10,200 copies/mL.

Results: PLWH with detectable viral loads demonstrated significantly lower pain thresholds for mechanical stimuli (F2,89 = 3.15, P = 0.049), significantly lower heat pain tolerances (F2,89 = 3.38, P = 0.039), and significantly greater temporal summation of heat pain at 48 °C (F2,89 = 10.66, P < 0.001) and 50 °C (F2,89 = 3.82, P = 0.026), compared with PLWH without detectable viral loads and healthy controls.

Conclusions: These preliminary results tentatively suggest that the detectable presence of the virus may sensitize PLWH to painful mechanical and heat stimuli.
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http://dx.doi.org/10.1093/pm/pnx057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914379PMC
December 2017

Monocyte bioenergetic function is associated with body composition in virologically suppressed HIV-infected women.

Redox Biol 2017 08 4;12:648-656. Epub 2017 Apr 4.

Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address:

Women living with HIV may present with high levels of body fat that are associated with altered bioenergetic function. Excess body fat may therefore exacerbate the bioenergetic dysfunction observed with HIV infection. To determine if body fat is associated with bioenergetic function in HIV, we conducted a cross-sectional study of 42 women with HIV who were virologically suppressed on antiretroviral therapy. Body composition was determined via dual-energy x-ray absorptiometry. Oxygen consumption rate (OCR) of monocytes was sorted from peripheral blood mononuclear cells obtained from participants in the fasting state. Differences in bioenergetic function, as measured by OCR, was assessed using Kruskal-Wallis tests and Spearman correlations adjusted for age, race, and smoking status. Participants were 86% Black, 45.5 years old, 48% current smokers, and 57% were obese (body mass index ≥30). Nearly all women (93%) had >30% total fat mass, while 12% had >50% total fat mass. Elevated levels of total fat mass, trunk fat, and leg fat were inversely correlated with measures of bioenergetic health as evidenced by lower maximal and reserve capacity OCR, and Bioenergetic Health Index. Measures of extracellular acidification (ECAR) in the absence (basal) or maximal (with oligomycin) were positively correlated with measures of bioenergetics, except proton leak, and were negatively correlated with fat mass. Despite virological suppression, women with HIV present with extremely high levels of adiposity that correlate with impaired bioenergetic health. Without effective interventions, this syndemic of HIV infection and obesity will likely have devastating consequences for our patients, potentially mediated through altered mitochondrial and glycolytic function.
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http://dx.doi.org/10.1016/j.redox.2017.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388916PMC
August 2017

Brief Report: IL-1β Levels Are Associated With Chronic Multisite Pain in People Living With HIV.

J Acquir Immune Defic Syndr 2017 08;75(4):e99-e103

*Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL; †Division of Gerontology, Geriatrics, and Palliative Care, University of Alabama at Birmingham, Birmingham, AL; ‡Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL; §Department of Psychology, University of Alabama at Birmingham, Birmingham, AL; ‖Division of Pain Medicine, University of Alabama at Birmingham, Birmingham, AL; and ¶Department of Psychology, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis, IN.

Background: The pathophysiology of chronic pain experienced by people living with HIV (PLWH) in the current antiretroviral treatment era is poorly understood. We sought to investigate the relationship between inflammation and chronic pain in PLWH. We hypothesized that, among PLWH who have undetectable HIV viral loads, those with chronic multisite pain (CMP) would have higher levels of circulating pain-related inflammatory markers than those without chronic pain.

Setting: This study was conducted at the University of Alabama at Birmingham's Center for AIDS Research Network of Integrated Clinical System site.

Methods: We compared inflammatory markers in 70 PLWH with CMP and 70 PLWH without chronic pain. Custom multiplex human inflammatory assays were completed on banked plasma specimens to measure cytokines commonly associated with chronic inflammatory pain: interleukin 1β (IL-1β), eotaxin, IL-15, IL-6, tumor necrosis factor α, and leptin. Logistic regression models were built using group status (CMP vs no pain) as the outcome variable, with each cytokine as independent variables and age, sex, substance use, and prescribed opioid medications as covariates.

Results: Participants were mostly men (71%); 53% were 50 years or older. The most common sites of pain were low back (86%), hands/feet (81%), and knee (66%). Median CD4 T-cell count was 676 cells per milliliter. IL-1β was significantly higher in the CMP group than in the individuals without chronic pain (odds ratio: 1.35, 95% confidence interval: 1.01 to 1.82, P < 0.05). Eotaxin, IL-15, IL-6, tumor necrosis factor α, and leptin were not significantly different between groups.

Conclusions: We found that PLWH who also have CMP have significantly higher levels of IL-1β than PLWH who do not have any pain. Future work on the role of IL-1β on chronic pain pathogenesis in this population may inform novel approaches to chronic pain management.
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http://dx.doi.org/10.1097/QAI.0000000000001377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484722PMC
August 2017

Association of Macrophage Inflammation Biomarkers With Progression of Subclinical Carotid Artery Atherosclerosis in HIV-Infected Women and Men.

J Infect Dis 2017 05;215(9):1352-1361

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.

Background: Monocytes and monocyte-derived macrophages promote atherosclerosis through increased inflammation and vascular remodeling. This may be especially true in chronic human immunodeficiency virus (HIV) infection.

Methods: We examined 778 women (74% HIV+) in the Women's Interagency HIV Study and 503 men (65% HIV+) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004-2013. We assessed baseline associations of the serum macrophage inflammation markers soluble (s)CD163, sCD14, galectin-3 (Gal-3), and Gal-3 binding protein (Gal-3BP) with carotid plaque formation (focal intima-media thickness >1.5 mm) over 7 years.

Results: Marker levels were higher in HIV+ persons versus HIV- persons. Presence of focal plaque increased over time: from 8% to 15% in women, and 24% to 34% in men. After adjustment for demographic, behavioral, and cardiometabolic factors, and CRP and interleukin-6, each standard deviation increase in sCD14 was associated with increased plaque formation (risk ratio [RR] 1.24, 95% confidence interval [CI] 1.07-1.43). This pattern was consistentby sex. sCD163 was associated with plaque formation in virally suppressed HIV+ men (RR 1.52, 95% CI 1.04-2.22); Gal-3BP and Gal-3 were not associated with increased plaque.

Conclusions: sCD14 and sCD163 may play important roles in atherogenesis among HIV+ persons.
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http://dx.doi.org/10.1093/infdis/jix082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722037PMC
May 2017

Dysregulation of Systemic and Mucosal Humoral Responses to Microbial and Food Antigens as a Factor Contributing to Microbial Translocation and Chronic Inflammation in HIV-1 Infection.

PLoS Pathog 2017 01 26;13(1):e1006087. Epub 2017 Jan 26.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

HIV-1 infection is associated with an early and profound depletion of mucosal memory CD4+ T cells, a population that plays an indispensable role in the regulation of isotype switching and transepithelial transport of antibodies. In this study, we addressed whether the depletion of CD4+ T cell in HIV-1-infected individuals results in altered humoral responses specific to antigens encountered at mucosal surfaces. Comprehensive protein microarray of systemic humoral responses to intestinal microbiota demonstrated reduced IgG responses to antigens derived from Proteobacteria and Firmicutes but not Bacteroidetes. Importantly, intestinal secretions of antiretroviral therapy-treated HIV-1-infected individuals exhibited a significant elevation of IgM levels and decreased IgA/IgM and IgG/IgM ratios of antibodies specific to a variety of microbial and food antigens. The presented findings indicate reduced competence of mucosal B cells for class switch recombination from IgM to other isotypes limiting their capacity to react to changing antigenic variety in the gut lumen. Decreased availability of microbiota-specific IgA and IgG may be an important factor contributing to the translocation of microbial antigens across the intestinal mucosal barrier and their systemic dissemination that drives chronic inflammation in HIV-1-infected individuals.
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http://dx.doi.org/10.1371/journal.ppat.1006087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5268400PMC
January 2017

Increased Natural Killer Cell Activation in HIV-Infected Immunologic Non-Responders Correlates with CD4+ T Cell Recovery after Antiretroviral Therapy and Viral Suppression.

PLoS One 2017 11;12(1):e0167640. Epub 2017 Jan 11.

Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, United States of America.

The role of natural killer (NK) cell function in HIV disease especially in the setting of long-term antiretroviral therapy (ART) and viral suppression is not fully understood. In the current study, we have investigated NK cell activation in healthy controls and aviremic ART-treated HIV+ subjects with different degrees of immune restoration. We performed a cross sectional study in 12 healthy controls and 24 aviremic ART-treated HIV-infected subjects including 13 HIV+ subjects with CD4+ T cells above 500 cells/μL defined as "immunologic responders" and 11 HIV+ subjects with CD4+ T cells below 350 cells/μL defined as "immunologic non-responders". We analyzed NK cell number, subset, and activation by expression of CD107a and NKG2D and co-expression of CD38 and HLA-DR. NK cell-mediated cytotoxicity against uninfected CD4+ T cells was tested in vitro. We found that NK cell absolute number, percentage of NK cells, and percentage of NK cell subsets were similar in the three study groups. The increased NK cell activation was found predominantly in CD56dimCD16+ subset of immunologic non-responders but not immunologic responders compared to healthy controls. The activation of NK cells was inversely correlated with the peripheral CD4+ T cell count in HIV+ subjects, even after controlling for chronic T cell activation, sex, and age, potential contributors for CD4+ T cell counts in HIV disease. Interestingly, NK cells from immunologic non-responders mediated cytotoxicity against uninfected CD4+ T cells ex vivo. NK cells may play a role in blunted CD4+ T cell recovery in ART-treated HIV disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167640PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226712PMC
August 2017

Increased glucose transporter-1 expression on intermediate monocytes from HIV-infected women with subclinical cardiovascular disease.

AIDS 2017 01;31(2):199-205

aDepartment of Microbiology, University of the West Indies, Mona, Kingston, Jamaica bDepartment of Epidemiology and Population Health cDepartment of Medicine, Albert Einstein College of Medicine, Bronx, New York dDepartment of Pathology, SUNY Downstate Medical Center, New York City, New York eDivision of Infectious Diseases, Georgetown University, Washington, D.C fDepartment of Medicine, University of Southern California, Los Angeles gDepartment of Medicine, University of California, San Francisco, California hDepartment of Epidemiology, Johns Hopkins University, Baltimore, Maryland iDivision of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina jDepartment of Medicine, Emory University, Atlanta, Georgia kDivision of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida lDivision of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama mDepartment of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, USA nCentre for Biomedical Research, Burnet Institute oDepartment of Infectious Diseases, Monash University pDepartment of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia.

Objective: People living with HIV (PLWH) have chronic immune activation and increased cardiovascular disease (CVD) risk. Activation of monocytes and T lymphocytes causes upregulation of glucose transporter-1 (GLUT1) for efficient function. PLWH have an increased percentage of GLUT1-expressing monocytes and T lymphocytes, but it is unclear if these cells are associated with CVD. We evaluated the expression of GLUT1 and CD38 on monocyte and T lymphocyte populations from HIV-infected women with subclinical CVD.

Methods: Participants with more than 75th percentile (n = 15) and less than 25th percentile (n = 15) age-adjusted intima-media thickness (IMT) at the right common carotid artery and bifurcation were identified from the Women's Interagency HIV Study. Groups were matched by age, race/ethnicity, smoking status, and CD4 cell count. All women were receiving suppressive antiretroviral therapy except for one high and one low IMT participant. Monocyte and T lymphocyte populations were evaluated for GLUT1 and CD38 expression using flow cytometry.

Results: Intermediate monocytes from high IMT women had significantly increased expression of GLUT1 (310 MFI vs. 210 MFI, P = 0.024) (66.4% vs. 48.5%, P = 0.031) and CD38 (339 MFI vs. 211 MFI, P = 0.002) (10.5% vs. 3.8%, P = 0.0002) compared with women with low IMT. High and low IMT participants showed no differences in GLUT1 or CD38 expression on classical monocytes, nonclassical monocytes, CD4 and CD8 T lymphocytes.

Conclusion: GLUT1-expressing intermediate monocytes are elevated in HIV-infected women with subclinical CVD. These cells may contribute to development of CVD in PLWH and could be a novel target to limit inflammation.
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http://dx.doi.org/10.1097/QAD.0000000000001320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393043PMC
January 2017

Use of Dried Blood Spots to Elucidate Full-Length Transmitted/Founder HIV-1 Genomes.

Pathog Immun 2016 ;1(1):129-153

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Identification of HIV-1 genomes responsible for establishing clinical infection in newly infected individuals is fundamental to prevention and pathogenesis research. Processing, storage, and transportation of the clinical samples required to perform these virologic assays in resource-limited settings requires challenging venipuncture and cold chain logistics. Here, we validate the use of dried-blood spots (DBS) as a simple and convenient alternative to collecting and storing frozen plasma.

Methods: We performed parallel nucleic acid extraction, single genome amplification (SGA), next generation sequencing (NGS), and phylogenetic analyses on plasma and DBS.

Results: We demonstrated the capacity to extract viral RNA from DBS and perform SGA to infer the complete nucleotide sequence of the transmitted/founder (TF) HIV-1 envelope gene and full-length genome in two acutely infected individuals. Using both SGA and NGS methodologies, we showed that sequences generated from DBS and plasma display comparable phylogenetic patterns in both acute and chronic infection. SGA was successful on samples with a range of plasma viremia, including samples as low as 1,700 copies/ml and an estimated ∼50 viral copies per blood spot. Further, we demonstrated reproducible efficiency in gp160 sequencing in DBS stored at ambient temperature for up to three weeks or at -20°C for up to five months.

Conclusions: These findings support the use of DBS as a practical and cost-effective alternative to frozen plasma for clinical trials and translational research conducted in resource-limited settings.
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http://dx.doi.org/10.20411/pai.v1i1.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096837PMC
January 2016

DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus.

PLoS One 2016 6;11(10):e0163164. Epub 2016 Oct 6.

GeoVax, Inc., Atlanta, Georgia, United States of America.

GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine.

Trial Registration: clinicaltrials.gov NCT01378156.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163164PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053438PMC
June 2017

HIV-1-Specific CD8 T Cells Exhibit Limited Cross-Reactivity during Acute Infection.

J Immunol 2016 Apr 16;196(8):3276-86. Epub 2016 Mar 16.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;

Prior work has demonstrated that HIV-1-specific CD8 T cells can cross-recognize variant epitopes. However, most of these studies were performed in the context of chronic infection, where the presence of viral quasispecies makes it difficult to ascertain the true nature of the original antigenic stimulus. To overcome this limitation, we evaluated the extent of CD8 T cell cross-reactivity in patients with acute HIV-1 clade B infection. In each case, we determined the transmitted founder virus sequence to identify the autologous epitopes restricted by individual HLA class I molecules. Our data show that cross-reactive CD8 T cells are infrequent during the acute phase of HIV-1 infection. Moreover, in the uncommon instances where cross-reactive responses were detected, the variant epitopes were poorly recognized in cytotoxicity assays. Molecular analysis revealed that similar antigenic structures could be cross-recognized by identical CD8 T cell clonotypes mobilized in vivo, yet even subtle differences in a single TCR-accessible peptide residue were sufficient to disrupt variant-specific reactivity. These findings demonstrate that CD8 T cells are highly specific for autologous epitopes during acute HIV-1 infection. Polyvalent vaccines may therefore be required to provide optimal immune cover against this genetically labile pathogen.
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http://dx.doi.org/10.4049/jimmunol.1502411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821763PMC
April 2016