scholarly journals Serum Immune Activation Markers Are Persistently Increased in Patients with HIV Infection after 6 Years of Antiretroviral Therapy despite Suppression of Viral Replication and Reconstitution of CD4+T Cells

2009 ◽  
Vol 200 (8) ◽  
pp. 1212-1215 ◽  
Author(s):  
Martyn A. French ◽  
Martin S. King ◽  
Jean M. Tschampa ◽  
Barbara A. da Silva ◽  
Alan L. Landay
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Viral Replication ◽  
Immune Activation ◽  
Cd4 T Cells ◽  
Activation Markers

scholarly journals Impact of Biological Sex on Immune Activation and Frequency of the Latent HIV Reservoir During Suppressive Antiretroviral Therapy

2020 ◽  
Vol 222 (11) ◽  
pp. 1843-1852 ◽  
Author(s):  
Shane D Falcinelli ◽  
Bonnie E Shook-Sa ◽  
Morgan G Dewey ◽  
Sumati Sridhar ◽  
Jenna Read ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Immune Activation ◽  
Cd4 T Cells ◽  
Acute Infection ◽  
Interferon Response ◽  
Suppressive Therapy ◽  
Hiv Reservoir ◽  
Latent Hiv

Abstract Background Persistent HIV infection of long-lived resting CD4 T cells, despite antiretroviral therapy (ART), remains a barrier to HIV cure. Women have a more robust type 1 interferon response during HIV infection relative to men, contributing to lower initial plasma viremia. As lower viremia during acute infection is associated with reduced frequency of latent HIV infection, we hypothesized that women on ART would have a lower frequency of latent HIV compared to men. Methods ART-suppressed, HIV seropositive women (n = 22) were matched 1:1 to 22 of 39 ART-suppressed men. We also compared the 22 women to all 39 men, adjusting for age and race as covariates. We measured the frequency of latent HIV using the quantitative viral outgrowth assay, the intact proviral DNA assay, and total HIV gag DNA. We also performed activation/exhaustion immunophenotyping on peripheral blood mononuclear cells and quantified interferon-stimulated gene (ISG) expression in CD4 T cells. Results We did not observe evident sex differences in the frequency of persistent HIV in resting CD4 T cells. Immunophenotyping and CD4 T-cell ISG expression analysis revealed marginal differences across the sexes. Conclusions Differences in HIV reservoir frequency and immune activation appear to be small across sexes during long-term suppressive therapy.

scholarly journals Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model

2020 ◽  
Vol 69 (1) ◽  
pp. 28-40 ◽  
Author(s):  
Ross Cromarty ◽  
Alexander Sigal ◽  
Lenine Julie Liebenberg ◽  
Lyle Robert Mckinnon ◽  
Salim Safurdeen Abdool Karim ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Immune Activation ◽  
Cd4 T Cells ◽  
Drug Targets ◽  
Complex Nature ◽  
Peripheral Blood Mononuclear ◽  
Established Risk Factor ◽  
Anti Inflammatory

Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.

scholarly journals Immune Activation and Viral Replication after Vaccination with an Influenza A H1N1 2009 Vaccine in HIV-Infected Children Receiving Antiretroviral Therapy

2013 ◽  
Vol 35 ◽  
pp. 221-227 ◽  
Author(s):  
Nattawat Onlamoon ◽  
Petai Unpol ◽  
Michittra Boonchan ◽  
Kasama Sukapirom ◽  
Orasri Wittawatmongkol ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Viral Replication ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Influenza A ◽  
Haemagglutination Inhibition ◽  
Hla Dr ◽  
Influenza A H1n1 ◽  
The Impact

Immunization with a pandemic influenza A H1N1 2009 was recommended for HIV-infected patients. However, there is limited information concerning the impact of immunization with this vaccine on immune activation and HIV viral replication. In this study, 45 HIV-infected children and adolescents receiving antiretroviral therapy were immunized with a 2-dose series of nonadjuvated monovalent influenza A H1N1 2009 vaccine upon enrollment and approximately 1 month later. Immunogenicity was determined by haemagglutination inhibition assay. The level of immune activation was determined by identification of CD38 and HLA-DR on CD8+ T cells. Patients were divided into 2 groups which include patients who had an undetectable HIV viral load (HIV detectable group) and patients who show virological failure (HIV nondetectable group). The results showed seroconversion rate of 55.2% in HIV nondetectable group, whereas 31.3% was found in HIV detectable group. Both groups of patients showed no major increase in immune activation after immunization. Interestingly, a decrease in the frequency of CD8+ T cells that coexpressed CD38 and HLA-DR was observed after immunization in both groups of patients. We suggested that immunization with influenza A H1N1 2009 vaccine can induce immune response to the pandemic virus without major impact on HIV viral replication and immune activation.

scholarly journals A Comparison of Different Immune Activation Strategies to Reverse HIV-1 Latency

2020 ◽  
Vol 7 (4) ◽  
Author(s):  
Caroline C Garliss ◽  
Abena K Kwaa ◽  
Joel N Blankson
Keyword(s):  
T Cells ◽  
Immune Activation ◽  
Cd4 T Cells ◽  
Low Frequency ◽  
Calcium Ionophore ◽  
Latent Reservoir ◽  
People Living With Hiv ◽  
Activation Markers ◽  
Proviral Dna ◽  
Latently Infected

Abstract Resting CD4+ T cells are the best characterized component of the latent reservoir. Activation of these CD4+ T cells is needed to optimize transcription and viral replication, and this strategy has been used to measure the inducible reservoir. There are several methods that can be used to activate CD4+ T cells, and in this study, we compared 3 different strategies: the combination of the lectin phytohaemagglutinin (PHA) and irradiated allogeneic feeders, a combination of PHA and a superagonistic anti-CD28 antibody, and the combination of the protein kinase C agonist phorbol 12-myristate 13-acetate and the calcium ionophore ionomycin. We show that each strategy induces a different pattern of expression of activation markers on CD4+ T cells. However, the different activation strategies induced similar frequencies of latently infected CD4+ T cells from people living with HIV on suppressive antiretroviral therapy regimens to produce replication-competent virus. Furthermore, the frequency of infectious units per million induced by each regimen was positively correlated with the copies of intact proviral DNA per million CD4+ T cells. Our results suggest that no single pattern of activation marker expression is most associated with latency reversal and demonstrate that different immune activation strategies reverse latency in a low frequency of CD4+ T cells that harbor intact proviral DNA.

scholarly journals Differential Expression of Activation Markers by Mycobacterium tuberculosis-specific CD4+ T Cell Distinguishes Extrapulmonary From Pulmonary Tuberculosis and Latent Infection

2019 ◽  
Vol 71 (8) ◽  
pp. 1905-1911 ◽  
Author(s):  
Paulo S Silveira-Mattos ◽  
Beatriz Barreto-Duarte ◽  
Beatriz Vasconcelos ◽  
Kiyoshi F Fukutani ◽  
Caian L Vinhaes ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Activation Markers ◽  
Timely Initiation ◽  
Latent Tb

Abstract Background Diagnosis of active tuberculosis (ATB) currently relies on detection of Mycobacterium tuberculosis (Mtb). Identifying patients with extrapulmonary TB (EPTB) remains challenging because microbiological confirmation is often not possible. Highly accurate blood-based tests could improve diagnosis of both EPTB and pulmonary TB (PTB) and timely initiation of anti-TB therapy. Methods A case-control study was performed using discriminant analyses to validate an approach using Mtb-specific CD4+T-cell activation markers in blood to discriminate PTB and EPTB from latent TB infection (LTBI) as well as EPTB from PTB in 270 Brazilian individuals. We further tested the effect of human immunodeficiency virus (HIV) coinfection on diagnostic performance. Frequencies of interferon-γ +CD4+T cells expressing CD38, HLADR, and/or Ki67 were assessed by flow cytometry. Results EPTB and PTB were associated with higher frequencies of CD4+T cells expressing CD38, HLADR, or Ki67 compared with LTBI (all P values &lt; .001). Moreover, frequencies of HLADR+ (P = .03) or Ki67+ (P &lt; .001) cells accurately distinguished EPTB from PTB. HIV infection did not affect the capacity of these markers to distinguish ATB from LTBI or EPTB from PTB. Conclusions Cell activation markers in Mtb-specific CD4+T cells distinguished ATB from LTBI and EPTB from PTB, regardless of HIV infection status. These parameters provide an attractive approach for developing blood-based diagnostic tests for both active and latent TB.

scholarly journals Intensifying Antiretroviral Therapy With Raltegravir and Maraviroc During Early Human Immunodeficiency Virus (HIV) Infection Does Not Accelerate HIV Reservoir Reduction

2015 ◽  
Vol 2 (4) ◽  
Author(s):  
Mario Ostrowski ◽  
Erika Benko ◽  
Feng Yun Yue ◽  
Connie J. Kim ◽  
Sanja Huibner ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Replication Competent Virus ◽  
Proviral Dna ◽  
Significant Difference ◽  
Immunodeficiency Virus ◽  
Dna 2

Abstract Background.  Persistent human immunodeficiency virus (HIV) within the CD4+ T-cell reservoir is an obstacle to eradication. We hypothesized that adding raltegravir and maraviroc to standard combination antiretroviral therapy (cART) during early HIV infection could substantially reduce viral reservoirs as a step towards eradication. Methods.  A prospective, randomized, double-blinded, placebo-controlled pilot trial enrolled 32 participants with documented early (&lt;6 months) HIV infection to either standard cART (emtricitabine/tenofovir/lopinavir/ritonavir) or intensive cART (standard regimen + raltegravir/maraviroc). Human immunodeficiency virus reservoirs were assessed at baseline and at 48 weeks by (1) proviral DNA, (2) cell-associated RNA, and (3) replication-competent virus, all from purified blood CD4+ T cells, and (4) gut proviral DNA. A multiassay algorithm (MAA) on baseline sera estimated timing of infection. Results.  Thirty individuals completed the study to the 48-week endpoint. The reduction in blood proviral burden was −1.03 log DNA copies/106 CD4+ T cells versus −.84 log in the standard and intensive groups, respectively (P = .056). Overall, there was no significant difference in the rate of decline of HIV-associated RNA, replication-competent virus in blood CD4+ T cells, nor proviral gut HIV DNA to 48 weeks. Individuals who presented with more recent HIV infection had significantly lower virus reservoirs, and cART tended to reduce their reservoirs to a greater extent. Conclusions.  Intensive cART led to no additional reduction in the blood virus reservoir at 48 weeks compared with standard cART. Human immunodeficiency virus reservoir size is smaller earlier in HIV infection. Other novel treatment strategies in combination with early cART will be needed to eliminate the HIV latent reservoir.

Nonproliferating Bystander CD4+T Cells Lacking Activation Markers Support HIV Replication During Immune Activation

2001 ◽  
Vol 166 (10) ◽  
pp. 6437-6443 ◽  
Author(s):  
David Scales ◽  
Houping Ni ◽  
Farida Shaheen ◽  
John Capodici ◽  
Georgetta Cannon ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Activation ◽  
Cd4 T Cells ◽  
Hiv Replication ◽  
Activation Markers

scholarly journals Effects of HCV co-infection on apoptosis of CD4+ T-cells in HIV-positive patients

2009 ◽  
Vol 116 (12) ◽  
pp. 861-870 ◽  
Author(s):  
Christian Körner ◽  
Benjamin Krämer ◽  
Daniela Schulte ◽  
Martin Coenen ◽  
Stefan Mauss ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Cell Apoptosis ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Hiv Positive ◽  
T Cell Apoptosis

Apoptosis importantly contributes to loss of CD4+ T-cells in HIV infection, and modification of their apoptosis may explain why HIV/HCV (hepatitis C virus)-co-infected patients are more likely to die from liver-related causes, although the effects of HCV on HIV infection remain unclear. In the present study, we studied in a cross-sectional and serial analysis spontaneous ex vivo CD4+ T-cell apoptosis in HIV/HCV-co-infected and HIV-mono-infected patients before and after HAART (highly active antiretroviral therapy). Apoptosis of peripheral blood CD4+ T-cells was measured by both a PARP [poly(ADP-ribose) polymerase] and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay to detect cells with irreversible apoptosis. Although hepatitis C alone did not increase CD4+ T-cell apoptosis, HCV co-infection disproportionately increased elevated rates of apoptosis in CD4+ T-cells from untreated HIV-positive patients. Increased CD4+ T-cell apoptosis was closely correlated with HIV, but not HCV, viral loads. Under HAART, increased rates of CD4+ T-cell apoptosis rapidly decreased both in HIV-mono-infected and HIV/HCV-co-infected patients, without any significant difference in apoptosis rates between the two patient groups after 4 weeks of therapy. Nevertheless residual CD4+ T-cell apoptosis did not reach the normal levels seen in healthy controls and remained higher in HIV patients receiving protease inhibitors than in patients with other antiretroviral regimens. The results of the present study suggest that HCV co-infection sensitizes CD4+ T-cells towards apoptosis in untreated HIV-positive patients. However, this effect is rapidly lost under effective antiretroviral therapy.

scholarly journals Intestinal CD4 Depletion in HIV / SIV Infection

2019 ◽  
Vol 15 (1) ◽  
pp. 76-91
Author(s):  
Ronald S. Veazey
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Hiv Infection ◽  
Viral Replication ◽  
Cd4 T Cells ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Target Cells ◽  
Mucosal Integrity

Among the most significant findings in the pathogenesis of HIV infection was the discovery that almost total depletion of intestinal CD4+ T cells occurs rapidly after SIV or HIV infection, regardless of the route of exposure, and long before CD4+ T cell losses occur in blood or lymph nodes. Since these seminal discoveries, we have learned much about mucosal and systemic CD4+ T cells, and found several key differences between the circulating and intestinal CD4+ T cell subsets, both in phenotype, relative proportions, and functional capabilities. Further, specific subsets of CD4+ T cells are selectively targeted and eliminated first, especially cells critically important for initiating primary immune responses, and for maintenance of mucosal integrity (Th1, Th17, and Th22 cells). This simultaneously results in loss of innate immune responses, and loss of mucosal integrity, resulting in mucosal, and systemic immune activation that drives proliferation and activation of new target cells throughout the course of infection. The propensity for the SIV/HIV to infect and efficiently replicate in specific cells also permits viral persistence, as the mucosal and systemic activation that ensues continues to damage mucosal barriers, resulting in continued influx of target cells to maintain viral replication. Finally, infection and elimination of recently activated and proliferating CD4+ T cells, and infection and dysregulation of Tfh and other key CD4+ T cell results in hyperactive, yet non-protective immune responses that support active viral replication and evolution, and thus persistence in host tissue reservoirs, all of which continue to challenge our efforts to design effective vaccine or cure strategies.

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