scholarly journals Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy

2016 ◽  
Vol 90 (12) ◽  
pp. 5665-5676 ◽  
Author(s):  
Aya Ishizaka ◽  
Hidenori Sato ◽  
Hitomi Nakamura ◽  
Michiko Koga ◽  
Tadashi Kikuchi ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Immune Activation ◽  
Viral Suppression ◽  
Immune Status ◽  
Viral Persistence ◽  
Chronic Immune Activation ◽  
Viral Reservoirs ◽  
Increased Risk ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTHIV-1 patients continue to remain at an abnormal immune status despite prolonged combination antiretroviral therapy (cART), which results in an increased risk of non-AIDS-related diseases. Given the growing recognition of the importance of understanding and controlling the residual virus in patients, additional virological markers to monitor infected cells are required. However, viral replication in circulating cells is much poorer than that in lymph nodes, which results in the absence of markers to distinguish these cells from uninfected cells in the blood. In this study, we identified prematurely terminated short HIV-1 transcripts (STs) in peripheral blood mononuclear cells (PBMCs) as an efficient intracellular biomarker to monitor viral activation and immune status in patients with cART-mediated full viral suppression in plasma. STs were detected in PBMCs obtained from both treated and untreated patients. ST levels in untreated patients generally increased with disease progression and decreased after treatment initiation. However, some patients exhibited sustained high levels of ST and low CD4+cell counts despite full viral suppression by treatment. The levels of STs strongly reflected chronic immune activation defined by coexpression of HLA-DR and CD38 on CD8+T cells, rather than circulating proviral load. These observations represent evidence for a relationship between viral persistence and host immune activation, which in turn results in the suboptimal increase in CD4+cells despite suppressive antiretroviral therapy. This cell-based measurement of viral persistence contributes to an improved understanding of the dynamics of viral persistence in cART patients and will guide therapeutic approaches targeting viral reservoirs.IMPORTANCECombination antiretroviral therapy (cART) suppresses HIV-1 load to below the detectable limit in plasma. However, the virus persists, and patients remain at an abnormal immune status, which results in an increased risk of non-AIDS-related complications. To achieve a functional cure for HIV-1 infection, activities of viral reservoirs must be quantified and monitored. However, latently infected cells are difficult to be monitored. Here, we identified prematurely terminated short HIV-1 transcripts (STs) as an efficient biomarker for monitoring viral activation and immune status in patients with cART-mediated full viral suppression in plasma. This cell-based measurement of viral persistence will contribute to our understanding of the impact of residual virus on chronic immune activation in HIV-1 patients during cART.

scholarly journals Impact of Antiretroviral Therapy Duration on HIV-1 Infection of T Cells within Anatomic Sites

2019 ◽  
Vol 94 (3) ◽  
Author(s):  
Eunok Lee ◽  
Susanne von Stockenstrom ◽  
Vincent Morcilla ◽  
Lina Odevall ◽  
Bonnie Hiener ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Antiretroviral Therapy ◽  
Cellular Proliferation ◽  
Memory T Cells ◽  
Viral Persistence ◽  
Effector Memory ◽  
Infected Cells ◽  
The Impact ◽  
Hiv 1

ABSTRACT Understanding the impact of antiretroviral therapy (ART) duration on HIV-infected cells is critical for developing successful curative strategies. To address this issue, we conducted a cross-sectional/inter-participant genetic characterization of HIV-1 RNA from pre- and on-therapy plasmas and HIV-1 DNA from CD4+ T cell subsets derived from peripheral blood (PB), lymph node (LN), and gut tissues of 26 participants after 3 to 17.8 years of ART. Our studies revealed in four acute/early participants who had paired PB and LN samples a substantial reduction in the proportion of HIV-infected cells per year on therapy within the LN. Extrapolation to all 12 acute/early participants estimated a much smaller reduction in the proportion of HIV-1-infected cells within LNs per year on therapy that was similar to that in the participants treated during chronic infection. LN-derived effector memory T (TEM) cells contained HIV-1 DNA that was genetically identical to viral sequences derived from pre- and on-therapy plasma samples. The proportion of identical HIV-1 DNA sequences increased within PB-derived TEM cells. However, the infection frequency of TEM cells in PB was stable, indicating that cellular proliferation that compensates for T cell loss over time contributes to HIV-1 persistence. This study suggests that ART reduces HIV-infected T cells and that clonal expansion of HIV-infected cells maintains viral persistence. Importantly, LN-derived TEM cells are a probable source of HIV-1 genomes capable of producing infectious HIV-1 and should be targeted by future curative strategies. IMPORTANCE HIV-1 persists as an integrated genome in CD4+ memory T cells during effective therapy, and cessation of current treatments results in resumption of viral replication. To date, the impact of antiretroviral therapy duration on HIV-infected CD4+ T cells and the mechanisms of viral persistence in different anatomic sites is not clearly elucidated. In the current study, we found that treatment duration was associated with a reduction in HIV-infected T cells. Our genetic analyses revealed that CD4+ effector memory T (TEM) cells derived from the lymph node appeared to contain provirus that was genetically identical to plasma-derived virions. Moreover, we found that cellular proliferation counterbalanced the decay of HIV-infected cells throughout therapy. The contribution of cellular proliferation to viral persistence is particularly significant in TEM cells. Our study emphasizes the importance of HIV-1 intervention and provides new insights into the location of memory T cells infected with HIV-1 DNA, which is capable of contributing to viremia.

scholarly journals HIV-1 Persistence in Children during Suppressive ART

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1134
Author(s):  
Mary Grace Katusiime ◽  
Gert U. Van Zyl ◽  
Mark F. Cotton ◽  
Mary F. Kearney
Keyword(s):  
Antiretroviral Therapy ◽  
Early Life ◽  
Clonal Expansion ◽  
Hiv Cure ◽  
Major Barrier ◽  
Hiv Persistence ◽  
Increased Risk ◽  
Infected Cells ◽  
Hiv 1

There is a growing number of perinatally HIV-1-infected children worldwide who must maintain life-long ART. In early life, HIV-1 infection is established in an immunologically inexperienced environment in which maternal ART and immune dynamics during pregnancy play a role in reservoir establishment. Children that initiated early antiretroviral therapy (ART) and maintained long-term suppression of viremia have smaller and less diverse HIV reservoirs than adults, although their proviral landscape during ART is reported to be similar to that of adults. The ability of these early infected cells to persist long-term through clonal expansion poses a major barrier to finding a cure. Furthermore, the effects of life-long HIV persistence and ART are yet to be understood, but growing evidence suggests that these individuals are at an increased risk for developing non-AIDS-related comorbidities, which underscores the need for an HIV cure.

scholarly journals HIV-1 Nef-induced secretion of the proinflammatory protease TACE into extracellularvesicles is mediated by Raf-1, and can be suppressed by clinical protein kinase inhibitors

2021 ◽  
Author(s):  
Zhe Zhao ◽  
Riku Fagerlund ◽  
Andreas S. Baur ◽  
Kalle Saksela
Keyword(s):  
Antiretroviral Therapy ◽  
Extracellular Vesicles ◽  
Protein Secretion ◽  
Immune Activation ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Protein Kinase Inhibitors ◽  
Chronic Immune Activation ◽  
Cd4 Lymphocyte ◽  
Hiv 1

Chronic immune activation is an important driver of HIV-1 pathogenesis, and has been associated with the presence of tumor necrosis factor-α converting enzyme (TACE) in extracellular vesicles (EV) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase Hck by HIV-1 Nef can trigger the packaging of TACE into EVs via an unconventional protein secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and SIV Nef alleles we now show that the capacity to promote TACE secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of unconventional protein secretion, and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation. IMPORTANCE Chronic immune activation contributes to the immunopathogenesis of HIV-1 infection, and is associated with poor recovery of the immune system despite potent antiretroviral therapy, which is observed in 10-40% drug-treated patients depending on the definition of immune reconstitution. We have previously shown that the HIV pathogenicity factor Nef can promote loading of the proinflammatory protease TACE into extracellular vesicles (EV), and the levels of such TACE-containing EVs circulating in the blood correlate with low CD4 lymphocyte counts in HIV patients receiving antiretroviral therapy. Here we show that Nef promotes uploading of TACE into EVs by triggering unconventional secretion via activation of the Hck/Raf/MAPK kinase cascade. We find that several pharmaceutical inhibitors of these kinases that are currently in clinical use for other diseases can potently suppress this pathogenic deregulation, and could thus provide a novel strategy for treating HIV-associated immune activation.

scholarly journals High Levels of Chronic Immune Activation in the T-Cell Compartments of Patients Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus Type 1 and on Highly Active Antiretroviral Therapy Are Reverted by Alpha Interferon and Ribavirin Treatment

2009 ◽  
Vol 83 (21) ◽  
pp. 11407-11411 ◽  
Author(s):  
Veronica D. Gonzalez ◽  
Karolin Falconer ◽  
Kim G. Blom ◽  
Olle Reichard ◽  
Birgitte Mørn ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiretroviral Therapy ◽  
Immune Activation ◽  
Chronic Immune Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic immune activation may contribute to the high rates of viral disease progression observed in HCV/HIV-1-coinfected patients.

scholarly journals Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1798
Author(s):  
Grant R. Campbell ◽  
Stephen A. Spector
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Functional Cure ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity—the “kick and kill” approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a “functional cure” where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission—a “block and lock” approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.

Persistent chronic immune activation in HIV/HBV coinfected patients after antiretroviral therapy

2021 ◽  
Author(s):  
Yaozu He ◽  
Weiping Cai ◽  
Jingliang Chen ◽  
Fengyu Hu ◽  
Feng Li ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Immune Activation ◽  
Chronic Immune Activation

scholarly journals Human Endogenous Retrovirus Expression Is Inversely Associated with Chronic Immune Activation in HIV-1 Infection

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e41021 ◽  
Author(s):  
Christopher E. Ormsby ◽  
Devi SenGupta ◽  
Ravi Tandon ◽  
Steven G. Deeks ◽  
Jeffrey N. Martin ◽  
...  
Keyword(s):  
Immune Activation ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Chronic Immune Activation ◽  
Hiv 1

scholarly journals Human retroviral antisense mRNAs are retained in the nuclei of infected cells for viral persistence

2021 ◽  
Vol 118 (17) ◽  
pp. e2014783118
Author(s):  
Guangyong Ma ◽  
Jun-ichirou Yasunaga ◽  
Kazuya Shimura ◽  
Keiko Takemoto ◽  
Miho Watanabe ◽  
...  
Keyword(s):  
Viral Persistence ◽  
Protein Translation ◽  
Regulatory Function ◽  
Antisense Gene ◽  
Cell Leukemia Virus Type ◽  
Antisense Mrna ◽  
Human T Cell ◽  
Infected Cells ◽  
Hiv 1

Human retroviruses, including human T cell leukemia virus type 1 (HTLV-1) and HIV type 1 (HIV-1), encode an antisense gene in the negative strand of the provirus. Besides coding for proteins, the messenger RNAs (mRNAs) of retroviral antisense genes have also been found to regulate transcription directly. Thus, it has been proposed that retroviruses likely localize their antisense mRNAs to the nucleus in order to regulate nuclear events; however, this opposes the coding function of retroviral antisense mRNAs that requires a cytoplasmic localization for protein translation. Here, we provide direct evidence that retroviral antisense mRNAs are localized predominantly in the nuclei of infected cells. The retroviral 3′ LTR induces inefficient polyadenylation and nuclear retention of antisense mRNA. We further reveal that retroviral antisense RNAs retained in the nucleus associate with chromatin and have transcriptional regulatory function. While HTLV-1 antisense mRNA is recruited to the promoter of C-C chemokine receptor type 4 (CCR4) and enhances transcription from it to support the proliferation of HTLV-1–infected cells, HIV-1 antisense mRNA is recruited to the viral LTR and inhibits sense mRNA expression to maintain the latency of HIV-1 infection. In summary, retroviral antisense mRNAs are retained in nucleus, act like long noncoding RNAs instead of mRNAs, and contribute to viral persistence.

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