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1.
Eur Radiol ; 2020 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-32052172

RESUMEN

OBJECTIVES: Assess carotid artery strain and motion in people living with HIV as markers of premature aging using ultrasound noninvasive vascular elastography (NIVE). METHODS: Seventy-four HIV-infected and 75 age-matched control subjects were recruited from a prospective, controlled cohort study from October 2015 to October 2017 (mean age 56 years ± 8 years; 128 men). NIVE applied to longitudinal ultrasound images of common and internal carotid arteries quantified the cumulated axial strain, cumulated shear strain, cumulated axial translation, and cumulated lateral translations. The presence of plaque was also assessed. An association between elastography biomarkers and HIV status was evaluated with Mann-Whitney tests and multivariable linear regression models. RESULTS: A higher occurrence of carotid artery plaques was found in HIV-infected individuals (p = 0.011). Lower cumulated lateral translations were found in HIV-infected subjects on both common and internal carotid arteries (p = 0.037 and p = 0.026, respectively). These observations remained significant when considering multivariable models including common cardiovascular risk factors and clinical characteristics (p < 0.05). Lower cumulated axial strains were also observed in internal carotid arteries when considering both multivariable models (p < 0.05). CONCLUSION: Lower translation and strain of the carotid artery wall in HIV-infected individuals indicates increased vessel wall stiffness. These new imaging biomarkers could be used to characterize premature atherosclerosis development. KEY POINTS: • Noninvasive vascular elastography (NIVE) based on ultrasound imaging quantifies translations and strains of carotid arteries. • Lower translation and strain of the carotid artery wall found in HIV-infected individuals indicate premature arterial stiffening, compared with age-matched controls. • Carotid artery plaques were more prevalent in HIV-infected individuals than in control subjects.

2.
Nature ; 578(7793): 160-165, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31969707

RESUMEN

Long-lasting, latently infected resting CD4+ T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir1. Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect2-9. Here we show that activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow-liver-thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4+ T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal-in combination with appropriate tools for systemic clearance of persistent HIV infection-greatly increases opportunities for HIV eradication.

3.
Clin Infect Dis ; 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31905383

RESUMEN

BACKGROUND: The 2-drug regimen (2DR) dolutegravir (DTG) + lamivudine (3TC) is indicated for treatment-naive adults with HIV-1. We present efficacy and safety of switching to DTG/3TC in virologically suppressed individuals. METHODS: TANGO is an open-label, multicenter, phase III study that randomized adults (1:1, stratified by baseline third agent class) with HIV-1 RNA <50 copies/mL to switch to a once-daily DTG/3TC fixed-dose combination or remain on a tenofovir alafenamide (TAF)-based regimen. Primary endpoint was proportion of participants with HIV-1 RNA ≥50 copies/mL at Week 48 (FDA Snapshot algorithm) in the intention-to-treat-exposed population (4% non-inferiority margin). RESULTS: 743 adults were enrolled and 741 received ≥1 dose of study drug (DTG/3TC, N=369; TAF-based regimen, N=372). At Week 48, proportion of participants with HIV-1 RNA ≥50 copies/mL treated with DTG/3TC was 0.3% (1/369) vs 0.5% (2/372) with a TAF-based regimen (adjusted treatment difference [95% CI], -0.3 [-1.2, 0.7]), meeting non-inferiority criteria. No participants receiving DTG/3TC and 1 receiving a TAF-based regimen met confirmed virologic withdrawal criteria, with no emergent resistance at time of failure. Drug-related grade ≥2 adverse events and adverse events leading to study withdrawal were reported in 17 (4.6%) and 13 (3.5%) participants with DTG/3TC and 3 (0.8%) and 2 (0.5%) with a TAF-based regimen, respectively. CONCLUSIONS: The 2DR DTG/3TC was non-inferior in maintaining virologic suppression vs a TAF-based regimen at Week 48, with no virologic failure or emergent resistance reported in the DTG/3TC group, supporting its use as a simplification strategy for virologically suppressed people living with HIV-1.

4.
Clin Infect Dis ; 70(2): 232-241, 2020 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-30877304

RESUMEN

BACKGROUND: Microbial translocation from the gut to systemic circulation contributes to immune activation during human immunodeficiency virus (HIV) infection and is usually assessed by measuring plasma levels of bacterial lipopolysaccharide (LPS). Fungal colonization in the gut increases during HIV-infection and people living with HIV (PLWH) have increased plasma levels of fungal polysaccharide (1→3)-ß-D-Glucan (ßDG). We assessed the contribution of circulating DG to systemic immune activation in PLWH. METHODS: Cross-sectional and longitudinal assessments of plasma ßDG levels were conducted along with markers of HIV disease progression, epithelial gut damage, bacterial translocation, proinflammatory cytokines, and ßDG-specific receptor expression on monocytes and natural killer (NK) cells. RESULTS: Plasma ßDG levels were elevated during early and chronic HIV infection and persisted despite long-term antiretroviral therapy (ART). ßDG increased over 24 months without ART but remained unchanged after 24 months of treatment. ßDG correlated negatively with CD4 T-cell count and positively with time to ART initiation, viral load, intestinal fatty acid-binding protein, LPS, and soluble LPS receptor soluble CD14 (sCD14). Elevated ßDG correlated positively with indoleamine-2,3-dioxygenase-1 enzyme activity, regulatory T-cell frequency, activated CD38+Human Leukocyte Antigen - DR isotype (HLA-DR)+ CD4 and CD8 T cells and negatively with Dectin-1 and NKp30 expression on monocytes and NK cells, respectively. CONCLUSIONS: PLWH have elevated plasma ßDG in correlation with markers of disease progression, gut damage, bacterial translocation, and inflammation. Early ART initiation prevents further ßDG increase. This fungal antigen contributes to immune activation and represents a potential therapeutic target to prevent non-acquired immunodeficiency syndrome events.

5.
AIDS ; 34(2): 237-244, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31651429

RESUMEN

OBJECTIVE: HIV-infected patients are at increased risk of nonalcoholic steatohepatitis (NASH). Vitamin E is recommended for treatment of NASH in the general population. However, its safety and efficacy among HIV-infected patients remain unknown. DESIGN: Single-centre, phase IV, open-label, single arm clinical trial. METHODS: HIV mono-infected patients without significant alcohol intake or viral hepatitis coinfection were included. The diagnosis of NASH was based on the co-existence of fatty liver, diagnosed by controlled attenuation parameter (CAP) at least 248 dB/m and significant hepatocyte apoptosis, defined by the serum biomarker cytokeratin 18 (CK-18) greater than 130.5 U/L. Participants were treated with 800 IU daily of oral vitamin E (alpha-tocopherol) for 24 weeks, and followed for an additional 24 weeks postdiscontinuation. Generalized linear mixed effects models were used to evaluate changes in alanine aminotransferase (ALT), CAP and CK-18 at the completion of treatment and end of follow-up, controlling for pretreatment trends. RESULTS: A total of 27 patients were included. Four (15%) had a pretreatment liver biopsy, which confirmed the diagnosis of NASH in all cases. Compared with baseline, 24 weeks of vitamin E treatment improved ALT [-27 units/l; 95% confidence interval (CI) -37 to -17], CAP scores (-22 dB/m; 95% CI -42 to -1) and CK-18 (-123 units/l; 95% CI -201 to -46). Conversely, there was no change in BMI. No serious adverse event was reported and no patient was lost to follow-up. CONCLUSION: In this first clinical trial, we showed that vitamin E is an effective and well tolerated treatment for NASH in HIV-infected patients.

6.
J Infect Dis ; 221(1): 110-121, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31504638

RESUMEN

BACKGROUND: Regenerating islet-derived protein 3α (REG3α) is an antimicrobial peptide secreted by intestinal Paneth cells. Circulating REG3α has been identified as a gut damage marker in inflammatory bowel diseases. People living with human immunodeficiency virus (PWH) on antiretroviral therapy (ART) present with an abnormal intestinal landscape leading to microbial translocation, persistent inflammation, and development of non-AIDS comorbidities. Herein, we assessed REG3α as a marker of gut damage in PWH. METHODS: Plasma from 169 adult PWH, including 30 elite controllers (ECs), and 30 human immunodeficiency virus (HIV)-uninfected controls were assessed. REG3α plasma levels were compared with HIV disease progression, epithelial gut damage, microbial translocation, and immune activation markers. RESULTS: Cross-sectionally, REG3α levels were elevated in untreated and ART-treated PWH compared with controls. ECs also had elevated REG3α levels compared to controls. Longitudinally, REG3α levels increased in PWH without ART and decreased in those who initiated ART. REG3α levels were inversely associated with CD4 T-cell count and CD4:CD8 ratio, while positively correlated with HIV viral load in untreated participants, and with fungal product translocation and inflammatory markers in all PWH. CONCLUSIONS: Plasma REG3α levels were elevated in PWH, including ECs. The gut inflammatory marker REG3α may be used to evaluate therapeutic interventions and predict non-AIDS comorbidity risks in PWH.

8.
mBio ; 10(6)2019 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-31848282

RESUMEN

Measuring Envelope (Env)-specific antibody (Ab)-dependent cellular cytotoxicity (ADCC)-competent Abs in HIV+ plasma is challenging because Env displays distinctive epitopes when present in a native closed trimeric conformation on infected cells or in a CD4-bound conformation on uninfected bystander cells. We developed an ADCC model which distinguishes Env-specific ADCC-competent Abs based on their capacity to eliminate infected, bystander, or Env rgp120-coated cells as a surrogate for shed gp120 on bystander cells. A panel of monoclonal Abs (MAbs), used to opsonize these target cells, showed that infected cells were preferentially recognized/eliminated by MAbs to CD4 binding site, V3 loop, and viral spike epitopes whereas bystander/coated cells were preferentially recognized/eliminated by Abs to CD4-induced (CD4i) epitopes. In HIV-positive (HIV+) plasma, Env-specific Abs recognized and supported ADCC of infected cells, though a majority were directed toward CD4i epitopes on bystander cells. For ADCC activity to be effective in HIV control, ADCC-competent Abs need to target genuinely infected cells.IMPORTANCE HIV Env-specific nonneutralizing Abs (NnAbs) able to mediate ADCC have been implicated in protection from HIV infection. However, Env-specific NnAbs have the capacity to support ADCC of both HIV-infected and HIV-uninfected bystander cells, potentially leading to misinterpretations when the assay used to measure ADCC does not distinguish between the two target cell types present in HIV cultures. Using a novel ADCC assay, which simultaneously quantifies the killing activity of Env-specific Abs on both infected and uninfected bystander cells, we observed that only a minority of Env-specific Abs in HIV+ plasma mediated ADCC of genuinely HIV-infected cells displaying Env in its native closed conformation. This assay can be used for the development of vaccine strategies aimed at eliciting Env-specific Ab responses capable of controlling HIV infection.

9.
Cell Rep ; 29(9): 2783-2795.e5, 2019 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-31775045

RESUMEN

Latent proviruses persist in central (TCM), transitional (TTM), and effector (TEM) memory cells. We measured the levels of cellular factors involved in HIV gene expression in these subsets. The highest levels of acetylated H4, active nuclear factor κB (NF-κB), and active positive transcription elongation factor b (P-TEFb) were measured in TEM, TCM, and TTM cells, respectively. Vorinostat and romidepsin display opposite abilities to induce H4 acetylation across subsets. Protein kinase C (PKC) agonists are more efficient at inducing NF-κB phosphorylation in TCM cells but more potent at activating PTEF-b in the TEM subset. We selected the most efficient latency-reversing agents (LRAs) and measured their ability to reverse latency in each subset. While ingenol alone has modest activities in the three subsets, its combination with a histone deacetylase inhibitor (HDACi) dramatically increases latency reversal in TCM cells. Altogether, these results indicate that cellular HIV reservoirs are differentially responsive to common LRAs and suggest that combination of compounds will be required to achieve latency reversal in all subsets.

10.
J Acquir Immune Defic Syndr ; 82(5): 503-513, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31714430

RESUMEN

BACKGROUND: Human IL-32 is a polyfunctional cytokine that was initially reported to inhibit HIV-1 infection. However, recent data suggest that IL-32 may enhance HIV-1 replication by activating the HIV-1 primary targets, CD4 T-cells. Indeed, IL-32 is expressed in multiple isoforms, some of which are proinflammatory, whereas others are anti-inflammatory. SETTING AND METHODS: Here, we aimed to determine the relative expression of IL-32 isoforms and to test their inflammatory nature and potential to induce HIV-1 production in latently infected cells from virologically suppressed HIV-infected individuals. IL-32 and other cytokines were quantified from plasma and supernatant of CD4 T-cells by ELISA. Transcripts of IL-32 isoforms were quantified by qRT-PCR in peripheral blood mononuclear cells. The impact of recombinant human IL-32 isoforms on HIV-1 transcription was assessed in CD4 T-cells from HIV-1cART individuals by qRT-PCR. RESULTS: All IL-32 isoforms were significantly upregulated in HIV-1cART compared to HIV individuals with IL-32ß representing the dominantly expressed isoform, mainly in T-cells and NK-cells. At the functional level, although IL-32γ induced typical proinflammatory cytokines (IL-6 and IFN-γ) in TCR-activated CD4 T-cells, IL-32α showed an anti-inflammatory profile by inducing IL-10 but not IL-6 or IFN-γ. However, IL-32ß showed a dual phenotype by inducing both pro- and anti-inflammatory cytokines. Interestingly, consistent with its highly pro-inflammatory nature, IL-32γ, but not IL-32α or IL-32ß, induced HIV-1 production in latently infected CD4 T-cells isolated from combined antiretroviral therapy-treated individuals. CONCLUSIONS: Our data report on the differential expression of IL-32 isoforms and highlight the potential role of IL-32, particularly the γ isoform, in fueling persistent inflammation and transcription of viral reservoir in HIV-1 infection.

11.
PLoS Pathog ; 15(10): e1008060, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31658294

RESUMEN

The loss of Memory CD4 T-cells (Mem) is a major hallmark of HIV-1 immuno-pathogenesis and occurs early during the first months of primary infection. A lot of effort has been put into understanding the molecular mechanisms behind this loss, yet they still have not been fully identified. In this study, we unveil the unreported role of USP18 in the deleterious effects of sustained type I IFN signaling on Mem, including HIV-1-specific CD4 T-cells. We find that interfering with IFN-I signaling pathway in infected patients, notably by targeting the interferon-stimulated gene USP18, resulted in reduced PTEN expression similar to those observed in uninfected control donors. We show that AKT activation in response to cytokine treatment, T-cell receptor (TcR) triggering, as well as HIV-1 Gag stimulation was significantly improved in infected patients when PTEN or USP18 were inhibited. Finally, our data demonstrate that higher USP18 in Mem from infected patients prevent proper cell survival and long-lasting maintenance in an AKT-dependent manner. Altogether, we establish a direct role for type I IFN/USP18 signaling in the maintenance of total and virus-specific Mem and provide a new mechanism for the reduced survival of these populations during primary HIV-1 infection.

12.
Clin Infect Dis ; 2019 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-31608409

RESUMEN

BACKGROUND: Cytomegalovirus (CMV) seropositivity and anti-CMV IgG levels are associated with adverse health outcomes in elderly populations. Among people living with HIV (PLWH) CMV seropositivity has been associated with persistent CD8 T-cell elevation and increased risk of developing non-AIDS comorbidities despite long-term antiretroviral therapy (ART). Herein, we investigated whether CMV seropositivity and elevation of anti-CMV IgG levels were associated with increased epithelial gut damage, microbial translocation, and systemic inflammation. METHODS: A total of 150 PLWH (79 ART-naïve and 71 ART-treated) were compared to 26 HIV-uninfected controls (UC). Plasma markers of HIV disease progression, epithelial gut damage, microbial translocation, non-specific B cell activation, anti-CMV and anti-EBV IgG levels, and pro-inflammatory cytokines were measured. RESULTS: CMV seropositivity and elevated anti-CMV IgG levels were associated with markers of epithelial gut damage, microbial translocation, and inflammation in PLWH and HIV-uninfected participants. In contrast, total non-specific IgG, IgM, IgA, and anti-EBV IgG levels were not associated with these markers. CMV seropositivity was associated with markers of epithelial gut damage, microbial translocation, and inflammation independently of sociodemographic and behavioural characteristics of the study population. CONCLUSION: CMV-seropositive people with and without HIV had increased epithelial gut damage, microbial translocation, and inflammation. Furthermore, anti-CMV IgG levels were independently associated with increased epithelial gut damage and microbial translocation. CMV co-infection may partially explain persistent gut damage, microbial translocation, and inflammation in ART-treated PLWH.

13.
Medicine (Baltimore) ; 98(39): e16997, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31574798

RESUMEN

This study aimed to determine the association between different lymphocyte subsets and cytomegalovirus (CMV) infection status in patients with systemic lupus erythematosus (SLE). We performed a retrospective study among SLE patients with CMV infection and collected patient socio-demographic and clinical characteristics, as well as their recorded circulating lymphocyte subsets. Univariate and multivariable logistic regression analyses examined the relationship between CMV infection status and lymphocyte subset counts. We included 125 hospitalized patients with SLE, consisting of 88 with documented CMV infection and 37 without any evidence of CMV or other infections. Among the 88 CMV-infected patients, 65 (73.8%) patients developed CMV disease and 23 (26.2%) presented as CMV viremia. Compared to uninfected patients (1520 ±â€Š101 cells/µL), lymphocytes remained stable among those with CMV viremia (1305 ±â€Š272 cells/µL, P = .995). However, compared to their uninfected counterparts, there was a marked decrease in lymphocytes among patients with CMV disease (680 ±â€Š513 cells/µL, P < .001). Analysis of lymphocyte subsets via flow cytometry showed that CD4+ T cell, CD8+ T cell, and natural killer cell counts were lower among those with CMV disease compared to those with CMV viremia and those without infection. Further, multivariable analysis showed that total lymphocyte (odds ratio [OR] 0.999, 95% confidence interval [CI] 0.998-1.000, P = .007) and CD4+ T cell counts (OR 0.99, 95% CI 0.992-0.998, P = .003) were negatively associated with CMV disease. Our findings support a potential inverse relationship between lymphopenia, specifically CD4+ T-cell lymphopenia, and CMV disease among hospitalized SLE patients.


Asunto(s)
Infecciones por Citomegalovirus/diagnóstico , Lupus Eritematoso Sistémico/inmunología , Subgrupos Linfocitarios , Viremia/diagnóstico , Adulto , Sedimentación Sanguínea , Estudios de Casos y Controles , Femenino , Humanos , Recuento de Linfocitos , Linfopenia/complicaciones , Masculino , Proyectos Piloto , Estudios Retrospectivos
14.
J Virol ; 94(1)2019 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-31597764

RESUMEN

Whereas human immunodeficiency virus (HIV) persists in tissue macrophages during antiretroviral therapy (ART), the role of circulating monocytes as HIV reservoirs remains controversial. Three magnetic bead selection methods and flow cytometry cell sorting were compared for their capacity to yield pure CD14+ monocyte populations. Cell sorting by flow cytometry provided the purest population of monocytes (median CD4+ T-cell contamination, 0.06%), and the levels of CD4+ T-cell contamination were positively correlated with the levels of integrated HIV DNA in the monocyte populations. Using cell sorting by flow cytometry, we assessed longitudinally the infection of monocytes and other cell subsets in a cohort of 29 Thai HIV-infected individuals. Low levels of HIV DNA were detected in a minority of monocyte fractions obtained before and after 1 year of ART (27% and 33%, respectively), whereas HIV DNA was readily detected in CD4+ T cells from all samples. Additional samples (2 to 5 years of ART) were obtained from 5 individuals in whom monocyte infection was previously detected. Whereas CD4+ T cells were infected at high levels at all time points, monocyte infection was inconsistent and absent in at least one longitudinal sample from 4/5 individuals. Our results indicate that infection of monocytes is infrequent and highlight the importance of using flow cytometry cell sorting to minimize contamination by CD4+ T cells.IMPORTANCE The role of circulating monocytes as persistent HIV reservoirs during ART is still controversial. Several studies have reported persistent infection of monocytes in virally suppressed individuals; however, others failed to detect HIV in this subset. These discrepancies are likely explained by the diversity of the methods used to isolate monocytes and to detect HIV infection. In this study, we show that only flow cytometry cell sorting yields a highly pure population of monocytes largely devoid of CD4 contaminants. Using this approach in a longitudinal cohort of HIV-infected individuals before and during ART, we demonstrate that HIV is rarely found in monocytes from untreated and treated HIV-infected individuals. This study highlights the importance of using methods that yield highly pure populations of cells as flow cytometry cell sorting to minimize and control for CD4+ T-cell contamination.

15.
Cannabis Cannabinoid Res ; 4(3): 204-213, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31579835

RESUMEN

Introduction: Rates of cannabis consumption range from 40% to 74% among people living with HIV (PLWH). Little is known about the reasons for cannabis use, related modes of administration, effectiveness for symptom relief, or undesirable effects in the modern antiretroviral therapy (ART) era. Our aim was to conduct an exploratory study to identify potential areas for further evaluation and intervention. Materials and Methods: From January to June 2018, health care providers at the Chronic Viral Illness Service in Montreal, Canada, asked their patients about cannabis use during routine visits. Patients reporting cannabis use were invited to complete a 20-min coordinator-administered questionnaire. Questions related to patterns of use, modes of administration, reasons for use, secondary effects, and HIV health-related factors (e.g., adherence to ART). Results: One hundred and four PLWH reporting cannabis use participated. Median age was 54 years (interquartile range [IQR] 46-59), 13% were female, and 42% were HIV-Hepatitis C co-infected. Median CD4 count was 590 cells/mm3 (IQR 390-821), 95% of participants were on ART, and 88% had suppressed viral loads. Reported cannabis use was more than once daily (32%); daily (25%); weekly (22%); monthly (17%); and rarely (twice to thrice per year; 6%). The majority of participants (97%) smoked dry plant cannabis. Other modes included vaping (12%), capsules (2%), edibles (21%), and oils (12%). Common reasons for cannabis use were for pleasure (68%) and to reduce anxiety (57%), stress (55%), and pain (57%). Many participants found cannabis "quite effective" or "extremely effective" (45%) for symptom relief. Secondary effects included feeling high (74%), increased cough (45%), paranoia (22%), palpitations (20%), and increased anxiety (21%). Over two-thirds of participants indicated that secondary effects were not bothersome at all. Most participants (68%) rarely missed doses of their ART, while 27% missed occasionally (once to twice per month). The most commonly accessed sources of information about cannabis were friends (77%) and the internet (55%). Conclusion: The most common reasons for cannabis use in our population were for pleasure, followed by reduction of stress/anxiety and symptoms associated with a medical condition. Most smoke cannabis and rate cannabis as quite effective for symptom relief. While many participants experience secondary effects, most are not bothered by these symptoms. Amid widespread changes in the regulatory landscape of recreational cannabis, health care providers should be prepared to answer questions about cannabis.

16.
Nat Immunol ; 20(8): 1059-1070, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31308541

RESUMEN

Dysfunction of virus-specific CD4+ T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4+ T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (TFH cell)-like profile characterized HIV-specific CD4+ T cells in viremic infection. HIV-specific CD4+ T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the TH1, TH17 and TH22 subsets of helper T cells. Viral suppression by ART resulted in a distinct transcriptional landscape, with a reduction in the expression of genes associated with TFH cells, but persistently low expression of genes associated with TH1, TH17 and TH22 cells compared to the elite controller profile. Thus, altered differentiation is central to the impairment of HIV-specific CD4+ T cells and involves both gain of function and loss of function.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Expresión Génica/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Células TH1/patología , Células Th17/patología , Perfilación de la Expresión Génica , Infecciones por VIH/virología , Humanos , Receptores CXCR5/metabolismo , Células TH1/citología , Células TH1/inmunología , Células Th17/citología , Células Th17/inmunología , Carga Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacos
17.
AIDS ; 33(11): 1693-1703, 2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31149943

RESUMEN

BACKGROUND: IL-37 is a member of the IL-1 family with potent anti-inflammatory effects. Little is known about regulation of the cytokine and of its signaling co-receptor SIGIRR in HIV infection. OBJECTIVES: Our main objective was to investigate how production of the cytokine and expression of SIGIRR on immune cells is regulated in HIV infection. METHODS: The study was conducted using biological samples from a cross section of HIV-infected individuals. Concentrations of IL-37, TNF-α and soluble form of SIGIRR in serum samples were determined by ELISA. The expression of SIGIRR on immune cells was determined by flow cytometry. IL-37 isoform-specific transcripts were determined in PBMC by RT-PCR using isoform-specific primers. The effects of exogenous IL-37 on HIV replication in human phytohaemagglutinin (PHA) blasts were determined in in-vitro assays. RESULTS: The cytokine concentrations tended to decrease in treatment-naive HIV-infected individuals. They were higher in treated HIV-infected individuals compared with those from treatment-naive ones. Higher concentrations of the cytokine were observed in sera from LTNP. The expression of SIGIRR on immune cells was decreased in HIV-infected individuals. On the other hand, its soluble form increased in the sera in these individuals. The trend was reversed in the patients undergoing antiretroviral treatment. Soluble SIGIRR attenuated anti-inflammatory effects of the cytokine. Serum IL-37 and soluble SIGIRR concentrations correlated with certain clinical parameters of the patients. Furthermore, recombinant human IL-37 inhibited HIV replication in human PHA blasts. CONCLUSION: The IL-37/SIGIRR axis is functionally compromised in HIV-infected individuals. Targeting the axis may alleviate inflammation and decrease HIV replication in this viral infection.

18.
J Virol ; 93(17)2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31189714

RESUMEN

HIV's ability to persist during suppressive antiretroviral therapy is the main barrier to cure. Immune-privileged tissues, such as the testes, may constitute distinctive sites of HIV persistence, but this has been challenging to study in humans. We analyzed the proviral burden and genetics in the blood and testes of 10 individuals on suppressive therapy who underwent elective gender-affirming surgery. HIV DNA levels in matched blood and testes were quantified by quantitative PCR, and subgenomic proviral sequences (nef region) were characterized from single templates. HIV diversity, compartmentalization, and immune escape burden were assessed using genetic and phylogenetic approaches. Diverse proviruses were recovered from the blood (396 sequences; 354 nef-intact sequences) and testes (326 sequences; 309 nef-intact sequences) of all participants. Notably, the frequency of identical HIV sequences varied markedly between and within individuals. Nevertheless, proviral loads, within-host unique HIV sequence diversity, and the immune escape burden correlated positively between blood and testes. When all intact nef sequences were evaluated, 60% of participants exhibited significant blood-testis genetic compartmentalization, but none did so when the evaluation was restricted to unique sequences per site, suggesting that compartmentalization, when present, is attributable to the clonal expansion of HIV-infected cells. Our observations confirm the testes as a site of HIV persistence and suggest that individuals with larger and more diverse blood reservoirs will have larger and more diverse testis reservoirs. Furthermore, while the testis microenvironment may not be sufficiently unique to facilitate the seeding of unique viral populations therein, differential clonal expansion dynamics may be at play, which may complicate HIV eradication.IMPORTANCE Two key questions in HIV reservoir biology are whether immune-privileged tissues, such as the testes, harbor distinctive proviral populations during suppressive therapy and, if so, by what mechanism. While our results indicated that blood-testis HIV genetic compartmentalization was reasonably common (60%), it was always attributable to differential frequencies of identical HIV sequences between sites. No blood-tissue data set retained evidence of compartmentalization when only unique HIV sequences per site were considered; moreover, HIV immune escape mutation burdens were highly concordant between sites. We conclude that the principal mechanism by which blood and testis reservoirs differ is not via seeding of divergent HIV sequences therein but, rather, via differential clonal expansion of latently infected cells. Thus, while viral diversity and escape-related barriers to HIV eradication are of a broadly similar magnitude across the blood and testes, clonal expansion represents a challenge. The results support individualized analysis of within-host reservoir diversity to inform curative approaches.

19.
Medicine (Baltimore) ; 98(25): e16112, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31232958

RESUMEN

Lipo-accumulation of the dorsocervical fat pad ("buffalo hump") is a complication observed in people living with human immunodeficiency virus (HIV). We described the clinical outcome of people living with HIV with "buffalo hump" treated by excisional lipectomy.From April 2013 to March 2018, medical records of people living with HIV, who received care in our hospital have been evaluated. Among them, patients with dorsocervical fat accumulation treated by excisional lipectomy have been retrospectively assessed.Nine patients with "buffalo hump" among 2886 people living with HIV (3.1‰, 9/2886) were included. Eight were women with a mean age of 47.9 ±â€Š8.0 years old (range, 36-60). Most of them have been infected by blood transfusion (77%, 7/9) and the mean duration of HIV infection was 14.1 ±â€Š5.5 years (range, 6-22). The mean duration for antiretroviral therapy was 8.8 ±â€Š2.1 years (range, 6-11). The mean pre-ART CD4+ T cell count was 91.3 ±â€Š76.5 cells/µL (range, 4-233) and 477.4 ±â€Š271.8 cells/µL (range, 114-926) at the time of surgery. All 9 patients underwent excisional lipectomy of their hypertrophied dorsocervical fat pad. The mean size of the excised specimens was 14 × 11 × 6 cm. The median follow-up time was 24 months (range, 2-60), all 9 patients reported satisfaction with their results, with no recurrence has been observed.Corrective surgery used to treat localized fat accumulations in people living with HIV with "buffalo hump" showed a favorable effect and can therefore be considered when necessary. Whereas drugs such as integrase inhibitors may avoid lipo-accumulation related syndrome and should be given to people living with HIV in China.


Asunto(s)
Tejido Adiposo/cirugía , Infecciones por VIH/cirugía , Lipectomía/normas , Resultado del Tratamiento , Tejido Adiposo/anomalías , Tejido Adiposo/patología , Adulto , China , Estudios de Cohortes , Femenino , Humanos , Lipectomía/métodos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
20.
Viruses ; 11(6)2019 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-31141927

RESUMEN

Quantifying HIV Envelope (Env)-specific antibodies in HIV+ plasma is useful for interpreting antibody dependent cellular cytotoxicity assay results. HIV Env, the only viral protein expressed on the surface of infected cells, has a native trimeric closed conformation on cells infected with wild-type HIV. However, CD4+ uninfected bystander cells in HIV+ cell cultures bind gp120 shed from HIV+ cells exposing CD4-induced epitopes normally hidden in native Env. We used flow-cytometry based assays to quantify antibodies in HIV+ plasma specific for native trimeric Env or gp120/CD4 conjugates using CEM.NKr.CCR5 (CEM) cells infected with HIV (iCEM) or coated with recombinant gp120 (cCEM), as a surrogate for gp120+ HIV- bystander cells. Results from both assays were compared to those of a plate-based ELISA to monomeric gp120. The levels of Env-specific antibodies to cCEM and iCEM, measured by flow cytometry, and to gp120 by ELISA were positively correlated. More antibodies in HIV+ plasma recognized the gp120 conformation exposed on cCEM than on iCEM. Comparisons of plasma from untreated progressors, treated progressors, and elite controllers revealed that antibodies to Env epitopes were the lowest in treated progressors. Plasma from elite controllers and untreated progressors had similarly high levels of Env-specific antibodies, despite elite controllers having undetectable HIV viral loads, while untreated progressors maintained high viral loads.

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