A MODEL OF HIV-1 TREATMENT: THE LATENTLY INFECTED CD4+ T CELLS BECOMES UNDETECTABLE

2005 ◽  
pp. 313-331
Author(s):  
Karen O'Hara
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Latently Infected ◽  
Hiv 1

scholarly journals Similar frequency and inducibility of intact HIV-1 proviruses in blood and lymph nodes

2020 ◽  
Author(s):  
Alyssa R Martin ◽  
Alexandra M Bender ◽  
Jada Hackman ◽  
Kyungyoon J Kwon ◽  
Briana A Lynch ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd4 T Cells ◽  
Viral Rna ◽  
Latent Reservoir ◽  
Similar Frequency ◽  
Latently Infected ◽  
Infected Cells ◽  
Secondary Lymphoid Organs ◽  
Hiv 1

Abstract Background The HIV-1 latent reservoir (LR) in resting CD4 + T cells is a barrier to cure. LR measurements are commonly performed on blood samples and therefore may miss latently infected cells residing in tissues, including lymph nodes. Methods We determined the frequency of intact HIV-1 proviruses and proviral inducibility in matched peripheral blood (PB) and lymph node (LN) samples from ten HIV-1-infected patients on ART using the intact proviral DNA assay and a novel quantitative viral induction assay. Prominent viral sequences from induced viral RNA were characterized using a next-generation sequencing assay. Results The frequencies of CD4 + T cells with intact proviruses were not significantly different in PB vs LN (61vs104/10 6CD4 + cells), and were substantially lower than frequencies of CD4 + T cells with defective proviruses. The frequencies of CD4 + T cells induced to produce high levels of viral RNA were not significantly different in PB vs LN (4.3/10 6 vs 7.9/10 6), but were 14-fold lower than the frequencies of cells with intact proviruses. Sequencing of HIV-1 RNA from induced proviruses revealed comparable sequences in paired PB and LN samples. Conclusions These results further support the use of PB as an appropriate proxy for the HIV-1 LR in secondary lymphoid organs

scholarly journals Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells

2019 ◽  
Author(s):  
Birgitta Lindqvist ◽  
Sara Svensson Akusjarvi ◽  
Anders Sonnerborg ◽  
Marios Dimitriou ◽  
J. Peter Svensson
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Ex Vivo ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Active Transcription ◽  
Hiv 1

Human immunodeficiency virus type 1 (HIV-1) infection is a chronic condition, where viral DNA integrates into the genome. Latently infected cells form a persistent, heterogeneous reservoir. The reservoir that reinstates an active replication comprises only cells with intact provirus that can be reactivated. We confirmed that latently infected cells from patients exhibited active transcription throughout the provirus. To find transcriptional determinants, we characterized the establishment and maintenance of viral latency during proviral chromatin maturation in cultures of primary CD4+ T-cells for four months after ex vivo HIV-1 infection. As heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus became less accessible with reduced activation potential. In a subset of infected cells, active marks (i.e., H3K27ac) remained detectable, even after prolonged proviral silencing. After T-cell activation, the proviral activation occurred uniquely in cells with H3K27ac-marked proviruses. Our observations suggested that, after transient proviral activation, cells were actively returned to latency.

scholarly journals Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb and reverses HIV-1 latency

2019 ◽  
Author(s):  
Mateusz Stoszko ◽  
Abdullah M.S. Al-Hatmi ◽  
Anton Skriba ◽  
Michael Roling ◽  
Enrico Ne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mass Spectrometry ◽  
T Cells ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Reversal Agents ◽  
Latently Infected ◽  
Infected Cells ◽  
Therapeutic Compounds ◽  
Hiv 1

AbstractA leading pharmacological strategy towards HIV cure requires “shock” or activation of HIV gene expression in latently infected cells with Latency Reversal Agents (LRAs) followed by their subsequent clearance. In a screen for novel LRAs we used fungal secondary metabolites (extrolites) as a source of bio-active molecules. Using orthogonal mass spectrometry (MS) coupled to latency reversal bioassays, we identified gliotoxin (GTX) as a novel LRA. GTX significantly induced HIV-1 gene expression in latent ex vivo infected primary cells and in CD4+ T cells from all aviremic HIV-1+ participants. RNA sequencing identified 7SK RNA, the scaffold of the P-TEFb inhibitory 7SK snRNP complex to be significantly reduced upon GTX treatment of independent donor CD4+T cells. GTX disrupted 7SK snRNP, releasing active P-TEFb, which then phosphorylated RNA Pol II CTD, inducing HIV transcription. Our data highlight the power of combining a medium throughput bioassay, mycology and orthogonal mass spectrometry to identify novel potentially therapeutic compounds.

scholarly journals High Levels of CD2 Expression Identify HIV-1 Latently Infected Resting Memory CD4+ T Cells in Virally Suppressed Subjects

2013 ◽  
Vol 87 (16) ◽  
pp. 9148-9158 ◽  
Author(s):  
M. Iglesias-Ussel ◽  
C. Vandergeeten ◽  
L. Marchionni ◽  
N. Chomont ◽  
F. Romerio
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Latently Infected ◽  
Memory Cd4 T Cells ◽  
Hiv 1

Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy

10.1038/9498 ◽  
1999 ◽  
Vol 5 (6) ◽  
pp. 651-655 ◽  
Author(s):  
Tae-Wook Chun ◽  
Delphine Engel ◽  
Stephanie B. Mizell ◽  
Claire W. Hallahan ◽  
Maria Fischette ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Highly Active ◽  
Latently Infected ◽  
Hiv 1

scholarly journals Antigen-responsive CD4+ T cell clones contribute to the HIV-1 latent reservoir

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Pilar Mendoza ◽  
Julia R. Jackson ◽  
Thiago Y. Oliveira ◽  
Christian Gaebler ◽  
Victor Ramos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Half Life ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Latent Reservoir ◽  
T Cell Clones ◽  
Cell Clones ◽  
Latently Infected ◽  
Hiv 1

Antiretroviral therapy suppresses but does not cure HIV-1 infection due to the existence of a long-lived reservoir of latently infected cells. The reservoir has an estimated half-life of 44 mo and is largely composed of clones of infected CD4+ T cells. The long half-life appears to result in part from expansion and contraction of infected CD4+ T cell clones. However, the mechanisms that govern this process are poorly understood. To determine whether the clones might result from and be maintained by exposure to antigen, we measured responses of reservoir cells to a small subset of antigens from viruses that produce chronic or recurrent infections. Despite the limited panel of test antigens, clones of antigen-responsive CD4+ T cells containing defective or intact latent proviruses were found in seven of eight individuals studied. Thus, chronic or repeated exposure to antigen may contribute to the longevity of the HIV-1 reservoir by stimulating the clonal expansion of latently infected CD4+ T cells.

scholarly journals Apobec3A maintains HIV-1 latency through recruitment of epigenetic silencing machinery to the long terminal repeat

2019 ◽  
Vol 116 (6) ◽  
pp. 2282-2289 ◽  
Author(s):  
Manabu Taura ◽  
Eric Song ◽  
Ya-Chi Ho ◽  
Akiko Iwasaki
Keyword(s):  
T Cells ◽  
Long Terminal Repeat ◽  
Cd4 T Cells ◽  
Terminal Repeat ◽  
Target Cells ◽  
Mrna Editing ◽  
Latently Infected ◽  
Infected Cells ◽  
Editing Enzyme ◽  
Hiv 1

HIV-1 integrates into the genome of target cells and establishes latency indefinitely. Understanding the molecular mechanism of HIV-1 latency maintenance is needed for therapeutic strategies to combat existing infection. In this study, we found an unexpected role for Apobec3A (apolipoprotein B MRNA editing enzyme catalytic subunit 3A, abbreviated “A3A”) in maintaining the latency state within HIV-1–infected cells. Overexpression of A3A in latently infected cell lines led to lower reactivation, while knockdown or knockout of A3A led to increased spontaneous and inducible HIV-1 reactivation. A3A maintains HIV-1 latency by associating with proviral DNA at the 5′ long terminal repeat region, recruiting KAP1 and HP1, and imposing repressive histone marks. We show that knockdown of A3A in latently infected human primary CD4 T cells enhanced HIV-1 reactivation. Collectively, we provide evidence and a mechanism by which A3A reinforces HIV-1 latency in infected CD4 T cells.

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 CD32+and PD-1+Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Alessandra Noto ◽  
Francesco A. Procopio ◽  
Riddhima Banga ◽  
Madeleine Suffiotti ◽  
Jean-Marc Corpataux ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Population ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Populations ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTA recent study conducted in blood has proposed CD32 as the marker identifying the “elusive” HIV reservoir. We have investigated the distribution of CD32+CD4 T cells in blood and lymph nodes (LNs) of HIV-1-uninfected subjects and viremic untreated and long-term-treated HIV-1-infected individuals and their relationship with PD-1+CD4 T cells. The frequency of CD32+CD4 T cells was increased in viremic compared to treated individuals in LNs, and a large proportion (up to 50%) of CD32+cells coexpressed PD-1 and were enriched within T follicular helper (Tfh) cells. We next investigated the role of LN CD32+CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32+and PD-1+CD4 T cells compared to CD32−and PD-1−cells in both viremic and treated individuals, but there was no difference between CD32+and PD-1+cells. There was no enrichment of latently infected cells with inducible HIV-1 in CD32+versus PD-1+cells in antiretroviral therapy (ART)-treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32+PD-1+CD4 T cells were significantly enriched in cell-associated HIV RNA compared to CD32−PD-1−(averages of 5.2-fold in treated individuals and 86.6-fold in viremics), CD32+PD-1−(2.2-fold in treated individuals and 4.3-fold in viremics), and CD32−PD-1+(2.2-fold in ART-treated individuals and 4.6-fold in viremics) cell populations. Similar levels of HIV-1 transcription were found in CD32+PD-1−and CD32−PD-1+CD4 T cells. Interestingly, the proportion of CD32+and PD-1+CD4 T cells negatively correlated with CD4 T cell counts and length of therapy. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and coexpression of CD32 and PD-1, the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.IMPORTANCEThe existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.

scholarly journals Induction of HIV-1 Replication in Latently Infected CD4+ T Cells Using a Combination of Cytokines

1998 ◽  
Vol 188 (1) ◽  
pp. 83-91 ◽  
Author(s):  
Tae-Wook Chun ◽  
Delphine Engel ◽  
Stephanie B. Mizell ◽  
Linda A. Ehler ◽  
Anthony S. Fauci
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Viral Replication ◽  
Proinflammatory Cytokines ◽  
Cd4 T Cells ◽  
Lymphoid Tissues ◽  
Tnf Α ◽  
Latently Infected ◽  
Hiv 1

Although it has been demonstrated that certain cytokines, particularly proinflammatory cytokines, can enhance ongoing viral replication in peripheral blood mononuclear cells (PBMCs) of HIV-1–infected individuals, it is unclear what role these cytokines play in the induction of HIV-1 replication in latently infected, resting CD4+ T cells. This study demonstrates that the in vitro combination of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α together with the immunoregulatory cytokine IL-2 are potent inducers of viral replication in highly purified, latently infected, resting CD4+ T cells derived from HIV-infected individuals who are antiretroviral therapy–naive as well as those who are receiving highly active antiretroviral therapy (HAART). Viral replication induced by this combination of cytokines was completely suppressed in the presence of HAART in vitro. Given that an array of cytokines, including IL-6, TNF-α, and IL-2, are copiously expressed in the microenvironment of the lymphoid tissues, which harbor the latent viral reservoirs, induction of HIV by this combination of cytokines may in part explain the commonly observed reappearance of detectable plasma viremia in HIV-infected individuals in whom HAART was discontinued. Moreover, since it is likely that these infected cells die upon activation of virus and that HAART prevents spread of virus to adjacent cells, the observation that this combination of cytokines can markedly induce viral replication in this reservoir may have important implications for the activation-mediated diminution of the latent reservoir of HIV in patients receiving HAART.

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