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

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.

scholarly journals Th1/17 Polarization of CD4 T Cells Supports HIV-1 Persistence during Antiretroviral Therapy

2015 ◽  
Vol 89 (22) ◽  
pp. 11284-11293 ◽  
Author(s):  
Hong Sun ◽  
Dhohyung Kim ◽  
Xiaodong Li ◽  
Maja Kiselinova ◽  
Zhengyu Ouyang ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Memory Cell ◽  
Viral Reservoir ◽  
Target Cells ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTThe ability to persist long term in latently infected CD4 T cells represents a characteristic feature of HIV-1 infection and the predominant barrier to efforts aiming at viral eradication and cure. Yet, increasing evidence suggests that only small subsets of CD4 T cells with specific developmental and maturational profiles are able to effectively support HIV-1 long-term persistence. Here, we analyzed how the functional polarization of CD4 T cells shapes and structures the reservoirs of HIV-1-infected cells. We found that CD4 T cells enriched for a Th1/17 polarization had elevated susceptibilities to HIV-1 infection inex vivoassays, harbored high levels of HIV-1 DNA in persons treated with antiretroviral therapy, and made a disproportionately increased contribution to the viral reservoir relative to their contribution to the CD4 T memory cell pool. Moreover, HIV-1 DNA levels in Th1/17 cells remained stable over many years of antiretroviral therapy, resulting in a progressively increasing contribution of these cells to the viral reservoir, and phylogenetic studies suggested preferential long-term persistence of identical viral sequences during prolonged antiretroviral treatment in this cell compartment. Together, these data suggest that Th1/17 CD4 T cells represent a preferred site for HIV-1 DNA long-term persistence in patients receiving antiretroviral therapy.IMPORTANCECurrent antiretroviral therapy is very effective in suppressing active HIV-1 replication but does not fully eliminate virally infected cells. The ability of HIV-1 to persist long term despite suppressive antiretroviral combination therapy represents a perplexing aspect of HIV-1 disease pathogenesis, since most HIV-1 target cells are activated, short-lived CD4 T cells. This study suggests that CD4 T helper cells with Th1/17 polarization have a preferential role as a long-term reservoir for HIV-1 infection during antiretroviral therapy, possibly because these cells may imitate some of the functional properties traditionally attributed to stem cells, such as the ability to persist for extremely long periods of time and to repopulate their own pool size through homeostatic self-renewal. These observations support the hypothesis that HIV-1 persistence is driven by small subsets of long-lasting stem cell-like CD4 T cells that may represent particularly promising targets for clinical strategies aiming at HIV-1 eradication and cure.

scholarly journals Intragenic proviral elements support transcription of defective HIV-1 proviruses

2021 ◽  
Author(s):  
Jeffrey Kuniholm ◽  
Elise Armstrong ◽  
Brandy Bernabe ◽  
Carolyn Coote ◽  
Anna Berenson ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Treatment Interruption ◽  
Regulatory Elements ◽  
Host Cells ◽  
People Living With Hiv ◽  
Latently Infected ◽  
Infected Cells ◽  
Living With Hiv ◽  
Hiv 1

ABSTRACTHIV-establishes a persistent proviral reservoir by integrating into the genome of infected host cells. Current antiretroviral treatments do not target this persistent population of proviruses which include latently infected cells that upon treatment interruption can be reactivated to contribute to HIV-1 rebound. Deep sequencing of persistent HIV proviruses has revealed that greater than 90% of integrated HIV genomes are defective and unable to produce infectious virions. We hypothesized that intragenic elements in the HIV genome support transcription of aberrant HIV-1 RNAs from defective proviruses that lack long terminal repeats (LTRs). Using an intact provirus detection assay, we observed that resting CD4+ T cells and monocyte-derived macrophages (MDMs) are biased towards generating defective HIV-1 proviruses. Multiplex reverse transcription digital drop PCR identified Env and Nef transcripts which lacked 5’ untranslated regions (UTR) in acutely infected CD4+ T cells and MDMs indicating transcripts are generated that do not utilize the promoter within the LTR. 5’UTR-deficient Env transcripts were also identified in a cohort of people living with HIV (PLWH) on ART, suggesting that these aberrant RNAs are produced in vivo. Using 5’ rapid amplification of cDNA ends (RACE), we mapped the start site of these transcripts within the Env gene. This region bound several cellular transcription factors and functioned as a transcriptional regulatory element that could support transcription and translation of downstream HIV-1 RNAs. These studies provide mechanistic insights into how defective HIV-1 proviruses are persistently expressed to potentially drive inflammation in PLWH.Author SummaryPeople living with HIV establish a persistent reservoir which includes latently infected cells that fuel viral rebound upon treatment interruption. However, the majority of HIV-1 genomes in these persistently infected cells are defective. Whether these defective HIV genomes are expressed and whether they contribute to HIV associated diseases including accelerated aging, neurodegenerative symptoms, and cardiovascular diseases are still outstanding questions. In this paper, we demonstrate that acute infection of macrophages and resting T cells is biased towards generating defective viruses which are expressed by DNA regulatory elements in the HIV genome. These studies describe an alternative mechanism for chronic expression of HIV genomes.

scholarly journals Human Immunodeficiency Virus (HIV)–Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy

2019 ◽  
Vol 221 (5) ◽  
pp. 744-755 ◽  
Author(s):  
Jenny L Anderson ◽  
Gabriela Khoury ◽  
Rémi Fromentin ◽  
Ajantha Solomon ◽  
Nicolas Chomont ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
People Living With Hiv ◽  
Hiv Persistence ◽  
Hiv Dna ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Living With Hiv

Abstract Background Identifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy. Methods Cell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry. Results Integrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines. Conclusions HIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues.

scholarly journals EVALUATION ON THE NUMBER OF CD4 T CELLS AND ANTIRETROVIRAL SIDE EFFECTS IN PATIENTS WITH AIDS

2016 ◽  
Vol 3 (2) ◽  
pp. 96
Author(s):  
Siti Qamariyah Khairunisa ◽  
Irine Normalina ◽  
Nasronudin Nasronudin
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Side Effects ◽  
Cd4 T Cells ◽  
Secondary Data ◽  
Antiretroviral Drugs ◽  
People Living With Hiv ◽  
Before And After ◽  
Record Card ◽  
Living With Hiv

Antiretroviral drug discovery has encouraged a revolution in the care of people living with HIV, although it has not been able to cure diseases and to increase the challenge in terms of drug side effects. Side effects of antiretroviral drugs are fairly common occurrences in HIV patients and generally occur within the first three months after initiation of antiretroviral therapy, although long-term side effects are also often found afterwards. This study aims to evaluate the number of CD4 T-cells in patients with AIDS before and after getting on ARV therapy and side effects arising during the taking of ARVs. Samples were collected from 10 patients infected by HIV/AIDS in a clinic in Surabaya. This study is an analytical survey. Data collection was conducted using secondary data obtained from the medical record card status on HIV paients in a clinic in Surabaya. Data results showed that the side effects that often occur in people with AIDS are appetite loss (90%), headache (80%), insomnia (80%) and nausea (70%). While many combinations of antiretroviral drugs have side effects such as a combination of AZT +3 TC + EFV, d4T +3 TC + followed by EFV and AZT +3 TC + NVP. The present study shows that combination antiretroviral therapy gives good results to the increased number of CD4 T-cellsin patients living with HIV, as shown by the tendency of an increase in the number of CD4 T-cells in 8 out of 10 AIDS patients who received a antiretroviral therapy.

scholarly journals EVALUATION ON THE EFFECT OF ANTIRETROVIRAL DRUGS ON CD4 T-CELL AND THE INCREMENT OF BODY WEIGHT AMONG HIV-AIDS PATIENTS IN SURABAYA

2016 ◽  
Vol 3 (2) ◽  
pp. 92
Author(s):  
Edith Frederika ◽  
Irine Normalina ◽  
Nasronudin Nasronudin ◽  
Rury Mega
Keyword(s):  
T Cells ◽  
Body Weight ◽  
Antiretroviral Therapy ◽  
Side Effects ◽  
Cd4 T Cells ◽  
Antiretroviral Drugs ◽  
People Living With Hiv ◽  
Antiretroviral Drug ◽  
Before And After ◽  
Living With Hiv

Antiretroviral drug discovery has encouraged a revolution in the care of people living with HIV, although it has not been able to cure diseases and to increase the challenge in terms of drug side effects. Side effects of antiretroviral drugs are fairly common occurrences in HIV patients and generally occurr within the first three months after initiation of antiretroviral therapy, although long-term side effects are also often found afterwards. This study aims to evaluate the number of CD4 T-cells in patients with AIDS before and after getting on ARV therapy, the side effects arising during the taking of ARVs are related to the increment of body weight among the HIVAIDS patients. Subjects were then narrowed down from 25 to 12 due to the incomplete data. The results showed that the top three most side effects which often occur in people with AIDS are appetite loss (20.0%), nausea (17.8%), and diarrhoea (15.6%). Meanwhile, about 58% of the subjects experienced increment of their body weight, and 42% were losing weight due to the side effects of the ARV therapy. Among those who lost their body weight, 50% were in the productive ages between 21–30 years old. The present study shows that combination antiretroviral therapy gives good results to the increased number of CD4 T-cells in patients living with HIV, as shown by the tendency of an increment in the number of CD4 T-cells in patients who received antiretroviral therapy. However, around 42% of those patients were losing weight because of the side effects of the therapy. Therefore, the importance of giving specific nutrient to overcome with the weight loss is needed to be given to the patients HIV instead of only giving the ARV treatment.

scholarly journals People with HIV-1 demonstrate type 1 interferon refractoriness associated with upregulated USP18

2021 ◽  
Author(s):  
Sho Sugawara ◽  
Ramy El-Diwany ◽  
Laura K. Cohen ◽  
Kimberly E. Rousseau ◽  
Christopher Y. K. Williams ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Innate Immune ◽  
People Living With Hiv ◽  
Virologic Suppression ◽  
Treatment Type ◽  
Living With Hiv ◽  
Hiv 1 ◽  
Type 1 Interferons

HIV-1 infection persists in humans despite expression of antiviral type 1 interferons (IFN). Even exogenous administration of IFNα only marginally reduces HIV-1 abundance, raising the hypothesis that people living with HIV-1 (PLWH) are refractory to type 1 IFN. We demonstrated type 1 IFN refractoriness in CD4+ and CD8+ T cells isolated from HIV-1 infected persons by detecting diminished STAT1 phosphorylation (pSTAT1) and interferon-stimulated gene (ISG) induction upon type 1 IFN stimulation compared to healthy controls. Importantly, HIV-1 infected people who were virologically suppressed with antiretrovirals also showed type 1 IFN refractoriness. We found that USP18 levels were elevated in people with refractory pSTAT1 and ISG induction and confirmed this finding ex vivo in CD4+ T cells from another cohort of HIV-HCV coinfected persons who received exogenous pegylated interferon-α2b in a clinical trial. We used a cell culture model to recapitulate type 1 IFN refractoriness in uninfected CD4+ T cells that were conditioned with media from HIV-1 inoculated PBMCs, inhibiting de novo infection with antiretroviral agents. In this model, RNA interference against USP18 partly restored type 1 IFN responses in CD4+ T cells. We found evidence of type 1 IFN refractoriness in PLWH irrespective of virologic suppression that was associated with upregulated USP18, a process that might be therapeutically targeted to improve endogenous control of infection. Importance People living with HIV-1 (PLWH) have elevated constitutive expression of type 1 interferons (IFN). However, it is unclear whether this impacts downstream innate immune responses. We identified refractory responses to type 1 IFN stimulation in T cells from PLWH, independent of antiretroviral treatment. Type 1 IFN refractoriness was linked to elevated USP18 levels in the same cells. Moreover, we found that USP18 levels predicted the anti-HIV-1 effect of type 1 IFN-based therapy on PLWH. In vitro, we demonstrated that refractory type 1 IFN responses were transferrable to HIV-1 uninfected target CD4+ T cells, and this phenomenon was mediated by type 1 IFN from HIV-1 infected cells. Type 1 IFN responses were partially restored by USP18 knockdown. Our findings illuminate a new mechanism by which HIV-1 contributes to innate immune dysfunction in PLWH, through the continuous production of type 1 IFN that induces a refractory state of responsiveness.

scholarly journals Peculiar Phenotypic and Cytotoxic Features of Pulmonary Mucosal CD8 T Cells in People Living with HIV Receiving Long-Term Antiretroviral Therapy

2020 ◽  
pp. ji2000916
Author(s):  
Oussama Meziane ◽  
Yulia Alexandrova ◽  
Ronald Olivenstein ◽  
Franck P. Dupuy ◽  
Syim Salahuddin ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Cd8 T Cells ◽  
People Living With Hiv ◽  
Living With Hiv

scholarly journals CD73+ CD127high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection

2021 ◽  
Vol 22 (2) ◽  
pp. 912
Author(s):  
Nabila Seddiki ◽  
John Zaunders ◽  
Chan Phetsouphanh ◽  
Vedran Brezar ◽  
Yin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Significant Proportion ◽  
Long Term Memory ◽  
Ki 67 ◽  
Memory Cd4 T Cells ◽  
Hiv 1

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.

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