Antigen Presenting Cells Contribute to Persistent Immune Activation Despite Antiretroviral Therapy Initiation During Hyperacute HIV-1 Infection

Human immunodeficiency virus (HIV)-induced changes in immune cells during the acute phase of infection can cause irreversible immunological damage and predict the rate of disease progression. Antiretroviral therapy (ART) remains the most effective strategy for successful immune restoration in immunocompromised people living with HIV and the earlier ART is initiated after infection, the better the long-term clinical outcomes. Here we explored the effect of ART on peripheral antigen presenting cell (APC) phenotype and function in women with HIV-1 subtype C infection who initiated ART in the hyperacute phase (before peak viremia) or during chronic infection. Peripheral blood mononuclear cells obtained longitudinally from study participants were used for immunophenotyping and functional analysis of monocytes and dendritic cells (DCs) using multiparametric flow cytometry and matched plasma was used for measurement of inflammatory markers IL-6 and soluble CD14 (sCD14) by enzyme-linked immunosorbent assay. HIV infection was associated with expansion of monocyte and plasmacytoid DC (pDC) frequencies and perturbation of monocyte subsets compared to uninfected persons despite antiretroviral treatment during hyperacute infection. Expression of activation marker CD69 on monocytes and pDCs in early treated HIV was similar to uninfected individuals. However, despite early ART, HIV infection was associated with elevation of plasma IL-6 and sCD14 levels which correlated with monocyte activation. Furthermore, HIV infection with or without early ART was associated with downmodulation of the co-stimulatory molecule CD86. Notably, early ART was associated with preserved toll-like receptor (TLR)-induced IFN-α responses of pDCs. Overall, this data provides evidence of the beneficial impact of ART initiated in hyperacute infection in preservation of APC functional cytokine production activity; but also highlights persistent inflammation facilitated by monocyte activation even after prolonged viral suppression and suggests the need for therapeutic interventions that target residual immune activation.

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Buprenorphine Increases HIV-1 Infection In Vitro but Does Not Reactivate HIV-1 from Latency

Viruses ◽

10.3390/v13081472 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1472

Author(s):

Germán Gustavo Gornalusse ◽

Lucia N. Vojtech ◽

Claire N. Levy ◽

Sean M. Hughes ◽

Yeseul Kim ◽

...

Keyword(s):

Epithelial Cells ◽

Hiv Infection ◽

Cell Lines ◽

Mononuclear Cells ◽

Receptor Expression ◽

People Living With Hiv ◽

Peripheral Blood Mononuclear ◽

In Vitro Susceptibility ◽

Hiv 1

Background: medication-assisted treatment (MAT) with buprenorphine is now widely prescribed to treat addiction to heroin and other illicit opioids. There is some evidence that illicit opioids enhance HIV-1 replication and accelerate AIDS pathogenesis, but the effect of buprenorphine is unknown. Methods: we obtained peripheral blood mononuclear cells (PBMCs) from healthy volunteers and cultured them in the presence of morphine, buprenorphine, or methadone. We infected the cells with a replication-competent CCR5-tropic HIV-1 reporter virus encoding a secreted nanoluciferase gene, and measured infection by luciferase activity in the supernatants over time. We also surveyed opioid receptor expression in PBMC, genital epithelial cells and other leukocytes by qPCR and western blotting. Reactivation from latency was assessed in J-Lat 11.1 and U1 cell lines. Results: we did not detect expression of classical opioid receptors in leukocytes, but did find nociception/orphanin FQ receptor (NOP) expression in blood and vaginal lymphocytes as well as genital epithelial cells. In PBMCs, we found that at physiological doses, morphine, and methadone had a variable or no effect on HIV infection, but buprenorphine treatment significantly increased HIV-1 infectivity (median: 8.797-fold increase with 20 nM buprenorphine, eight experiments, range: 3.570–691.9, p = 0.0078). Using latently infected cell lines, we did not detect reactivation of latent HIV following treatment with any of the opioid drugs. Conclusions: our results suggest that buprenorphine, in contrast to morphine or methadone, increases the in vitro susceptibility of leukocytes to HIV-1 infection but has no effect on in vitro HIV reactivation. These findings contribute to our understanding how opioids, including those used for MAT, affect HIV infection and reactivation, and can help to inform the choice of MAT for people living with HIV or who are at risk of HIV infection.

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HIV Infection and Related Mental Disorders

Brain Sciences ◽

10.3390/brainsci11020248 ◽

2021 ◽

Vol 11 (2) ◽

pp. 248

Author(s):

Marina Nosik ◽

Vyacheslav Lavrov ◽

Oxana Svitich

Keyword(s):

Human Immunodeficiency Virus ◽

Antiretroviral Therapy ◽

Mental Disorders ◽

Hiv Infection ◽

Current Knowledge ◽

People Living With Hiv ◽

Immunodeficiency Virus ◽

Living With Hiv ◽

The Impact ◽

Hiv 1

Over the more than thirty-year period of the human immunodeficiency virus type 1 (HIV-1) epidemic, many data have been accumulated indicating that HIV infection predisposes one to the development of mental pathologies. It has been proven that cognitive disorders in HIV-positive individuals are the result of the direct exposure of the virus to central nervous system (CNS) cells. The use of antiretroviral therapy has significantly reduced the number of cases of mental disorders among people infected with HIV. However, the incidence of moderate to mild cognitive impairment at all stages of HIV infection is still quite high. This review describes the most common forms of mental pathology that occur in people living with HIV and presents the current concepts on the possible pathogenetic mechanisms of the influence of human immunodeficiency virus (HIV-1) and its viral proteins on the cells of the CNS and the CNS’s functions. This review also provides the current state of knowledge on the impact of the antiretroviral therapy on the development of mental pathologies in people living with HIV, as well as current knowledge on the interactions between antiretroviral and psychotropic drugs that occur under their simultaneous administration.

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Antiretroviral Therapy Administration in Healthy Rhesus Macaques Is Associated with Transient Shifts in Intestinal Bacterial Diversity and Modest Immunological Perturbations

Journal of Virology ◽

10.1128/jvi.00472-19 ◽

2019 ◽

Vol 93 (18) ◽

Cited By ~ 1

Author(s):

Alexandra M. Ortiz ◽

Jacob K. Flynn ◽

Sarah R. DiNapoli ◽

Ornella Sortino ◽

Ivan Vujkovic-Cvijin ◽

...

Keyword(s):

T Cell ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Bacterial Diversity ◽

Rhesus Macaques ◽

Therapeutic Interventions ◽

People Living With Hiv ◽

Fecal Microbiome ◽

Immunodeficiency Virus ◽

Proinflammatory Responses

ABSTRACT Gastrointestinal (GI) immune system competency is dependent upon interactions with commensal microbiota, which can be influenced by wide-ranging pharmacologic interventions. In simian immunodeficiency virus (SIV)-infected Asian macaque models of human immunodeficiency virus (HIV) infection, we previously noted that initiation of antiretroviral therapy (ART) is associated with a specific imbalance (dysbiosis) of the composition of the intestinal bacteriome. To determine if ART itself might contribute to dysbiosis or immune dysfunction, we treated healthy rhesus macaques with protease, integrase, or reverse transcriptase inhibitors for 1 to 2 or for 5 to 6 weeks and evaluated intestinal immune function and the composition of the fecal bacterial microbiome. We observed that individual antiretrovirals (ARVs) modestly altered intestinal T-cell proinflammatory responses without disturbing total or activated T-cell frequencies. Moreover, we observed transient disruptions in bacterial diversity coupled with perturbations in the relative frequencies of bacterial communities. Shifts in specific bacterial frequencies were not persistent posttreatment, however, with individual taxa showing only isolated associations with T-cell proinflammatory responses. Our findings suggest that intestinal bacterial instability and modest immunological alterations can result from ART itself. These data could lead to therapeutic interventions which stabilize the microbiome in individuals prescribed ART. IMPORTANCE Dysbiosis of the fecal microbiome is a common feature observed in ARV-treated people living with HIV. The degree to which HIV infection itself causes this dysbiosis remains unclear. Here, we demonstrate that medications used to treat HIV infection can influence the composition of the GI tract immune responses and its microbiome in the nonhuman primate SIV model.

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Antiretroviral Therapy Dampens Mucosal CD4+ T Lamina Propria Lymphocytes Immune Activation in Long-Term Treated People Living with HIV-1

Microorganisms ◽

10.3390/microorganisms9081624 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1624

Author(s):

Alessandro Lazzaro ◽

Giuseppe Pietro Innocenti ◽

Letizia Santinelli ◽

Claudia Pinacchio ◽

Gabriella De Girolamo ◽

...

Keyword(s):

T Cells ◽

Antiretroviral Therapy ◽

Lamina Propria ◽

Immune Activation ◽

Cd4 T Cells ◽

People Living With Hiv ◽

Living With Hiv ◽

Lamina Propria Lymphocytes ◽

Hiv 1

HIV infection is characterized by a severe deterioration of an immune cell-mediated response due to a progressive loss of CD4+ T cells from gastrointestinal tract, with a preferential loss of IL-17 producing Th cells (Th17), a specific CD4+ T cells subset specialized in maintaining mucosal integrity and antimicrobial inflammatory responses. To address the effectiveness of antiretroviral therapy (ART) in reducing chronic immunological dysfunction and immune activation of intestinal mucosa, we conducted a cross-sectional observational study comparing total IFN-γ-expressing (Th1) and IL-17-expressing (Th17) frequencies of CD4+ T lamina propria lymphocytes (LPLs) and their immune activation status between 11 male ART-naïve and 11 male long-term ART-treated people living with HIV-1 (PLWH) who underwent colonoscopy and retrograde ileoscopy for biopsies collection. Flow cytometry for surface and intracellular staining was performed. Long-term ART-treated PLWH showed lower levels of CD38+ and/or HLA-DR+ LPLs compared to ART-naïve PLWH. Frequencies of Th1 and Th17 LPLs did not differ between the two groups. Despite ART failing to restore the Th1 and Th17 levels within the gut mucosa, it is effective in increasing overall CD4+ T LPLs frequencies and reducing mucosal immune activation.

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STING and cGAS gene expressions were downregulated among HIV-1-infected persons after antiretroviral therapy

Virology Journal ◽

10.1186/s12985-021-01548-6 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Lorena Leticia Peixoto de Lima ◽

Allysson Quintino Tenório de Oliveira ◽

Tuane Carolina Ferreira Moura ◽

Ednelza da Silva Graça Amoras ◽

Sandra Souza Lima ◽

...

Keyword(s):

Gene Expression ◽

Viral Load ◽

T Cell ◽

Antiretroviral Therapy ◽

Cell Count ◽

Enzyme Linked Immunosorbent Assay ◽

Type I ◽

Α Level ◽

The Impact ◽

Hiv 1

Abstract Background The HIV-1 epidemic is still considered a global public health problem, but great advances have been made in fighting it by antiretroviral therapy (ART). ART has a considerable impact on viral replication and host immunity. The production of type I interferon (IFN) is key to the innate immune response to viral infections. The STING and cGAS proteins have proven roles in the antiviral cascade. The present study aimed to evaluate the impact of ART on innate immunity, which was represented by STING and cGAS gene expression and plasma IFN-α level. Methods This cohort study evaluated a group of 33 individuals who were initially naïve to therapy and who were treated at a reference center and reassessed 12 months after starting ART. Gene expression levels and viral load were evaluated by real-time PCR, CD4+ and CD8+ T lymphocyte counts by flow cytometry, and IFN-α level by enzyme-linked immunosorbent assay. Results From before to after ART, the CD4+ T cell count and the CD4+/CD8+ ratio significantly increased (p < 0.0001), the CD8+ T cell count slightly decreased, and viral load decreased to undetectable levels in most of the group (84.85%). The expression of STING and cGAS significantly decreased (p = 0.0034 and p = 0.0001, respectively) after the use of ART, but IFN-α did not (p = 0.1558). Among the markers evaluated, the only markers that showed a correlation with each other were STING and CD4+ T at the time of the first collection. Conclusions ART provided immune recovery and viral suppression to the studied group and indirectly downregulated the STING and cGAS genes. In contrast, ART did not influence IFN-α. The expression of STING and cGAS was not correlated with the plasma level of IFN-α, which suggests that there is another pathway regulating this cytokine in addition to the STING–cGAS pathway.

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Integrated analysis of lncRNA, miRNA and mRNA profiles reveals potential lncRNA functions during early HIV infection

Journal of Translational Medicine ◽

10.1186/s12967-021-02802-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lianwei Ma ◽

Hui Zhang ◽

Yue Zhang ◽

Hailong Li ◽

Minghui An ◽

...

Keyword(s):

Hiv Infection ◽

Immune Activation ◽

Expression Profiles ◽

Critical Role ◽

Differentially Expressed ◽

Integrated Analysis ◽

Target Mrnas ◽

Immunodeficiency Virus ◽

Mirna Sequencing ◽

Hiv 1

Abstract Background Long noncoding RNAs (lncRNAs) can regulate gene expression in a cis-regulatory fashion or as “microRNA sponges”. However, the expression and functions of lncRNAs during early human immunodeficiency virus (HIV) infection (EHI) remain unclear. Methods 3 HAART-naive EHI patients and 3 healthy controls (HCs) were recruited in this study to perform RNA sequencing and microRNA (miRNA) sequencing. The expression profiles of lncRNAs, mRNAs and miRNAs were obtained, and the potential roles of lncRNAs were analysed based on discovering lncRNA cis-regulatory target mRNAs and constructing lncRNA–miRNA–mRNA competing endogenous RNA (ceRNA) networks. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on 175 lncRNA-associated differentially expressed (DE) mRNAs to investigate the potential functions of DE lncRNAs in ceRNA networks. Results A total of 242 lncRNAs, 1240 mRNAs and 21 mature known miRNAs were determined as differentially expressed genes in HAART-naive EHI patients compared to HCs. Among DE lncRNAs, 44 lncRNAs were predicted to overlap with 41 target mRNAs, and 107 lncRNAs might regulate their nearby DE mRNAs. Two DE lncRNAs might regulate their cis-regulatory target mRNAs BTLA and ZAP70, respectively, which were associated with immune activation. In addition, the ceRNA networks comprised 160 DE lncRNAs, 21 DE miRNAs and 175 DE mRNAs. Seventeen DE lncRNAs were predicted to regulate HIF1A and TCF7L2, which are involved in the process of HIV-1 replication. Twenty DE lncRNAs might share miRNA response elements (MREs) with FOS, FOSB and JUN, which are associated with both immune activation and HIV-1 replication. Conclusions This study revealed that lncRNAs might play a critical role in HIV-1 replication and immune activation during EHI. These novel findings are helpful for understanding of the pathogenesis of HIV infection and provide new insights into antiviral therapy.

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Early Antiretroviral Therapy in South African Children Reduces HIV-1-Infected Cells and Cell-Associated HIV-1 RNA in Blood Mononuclear Cells

The Journal of Infectious Diseases ◽

10.1093/infdis/jiu827 ◽

2014 ◽

Vol 212 (1) ◽

pp. 39-43 ◽

Cited By ~ 30

Author(s):

G. U. van Zyl ◽

M. A. Bedison ◽

A. J. van Rensburg ◽

B. Laughton ◽

M. F. Cotton ◽

...

Keyword(s):

Antiretroviral Therapy ◽

South African ◽

Mononuclear Cells ◽

African Children ◽

Blood Mononuclear Cells ◽

Infected Cells ◽

Hiv 1 ◽

South African Children

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Identification of Immune Activation Profiles That May Predict Morbidity During Antiretroviral Therapy Treated HIV Infection

EBioMedicine ◽

10.1016/j.ebiom.2016.05.012 ◽

2016 ◽

Vol 8 ◽

pp. 16-17 ◽

Cited By ~ 1

Author(s):

Nicholas T. Funderburg

Keyword(s):

Antiretroviral Therapy ◽

Hiv Infection ◽

Immune Activation

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Streptavidin-conjugated gold nanoclusters as ultrasensitive fluorescent sensors for early diagnosis of HIV infection

Science Advances ◽

10.1126/sciadv.aar6280 ◽

2018 ◽

Vol 4 (11) ◽

pp. eaar6280 ◽

Cited By ~ 15

Author(s):

Aditya Dileep Kurdekar ◽

L. A. Avinash Chunduri ◽

C. Sai Manohar ◽

Mohan Kumar Haleyurgirisetty ◽

Indira K. Hewlett ◽

...

Keyword(s):

Hiv Infection ◽

Limit Of Detection ◽

Gold Nanoclusters ◽

Enzyme Linked Immunosorbent Assay ◽

Dependent Manner ◽

Metal Nanoclusters ◽

Detection Range ◽

In Silico Studies ◽

P24 Antigen ◽

Hiv 1

We have engineered streptavidin-labeled fluorescent gold nanoclusters to develop a gold nanocluster immunoassay (GNCIA) for the early and sensitive detection of HIV infection. We performed computational simulations on the mechanism of interaction between the nanoclusters and the streptavidin protein via in silico studies and showed that gold nanoclusters enhance the binding to the protein, by enhancing interaction between the Au atoms and the specific active site residues, compared to other metal nanoclusters. We also evaluated the role of glutathione conjugation in binding to gold nanoclusters with streptavidin. As proof of concept, GNCIA achieved a sensitivity limit of detection of HIV-1 p24 antigen in clinical specimens of 5 pg/ml, with a detection range up to1000 pg/ml in a linear dose-dependent manner. GNCIA demonstrated a threefold higher sensitivity and specificity compared to enzyme-linked immunosorbent assay for the detection of HIV p24 antigen. The specificity of the immunoassay was 100% when tested with plasma samples negative for HIV-1 p24 antigen and positive for viruses such as hepatitis B virus, hepatitis C virus, and dengue. GNCIA could be developed into a universal labeling technology using the relevant capture and detector antibodies for the specific detection of antigens of various pathogens in the future.

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