APOBEC3G: an intracellular centurion

The intrinsic antiretroviral factor APOBEC3G (A3G) is highly active against HIV-1 and other retroviruses. In different cell types, A3G is expressed in high-molecular-mass (HMM) RNA–protein complexes or low-molecular-mass (LMM) forms displaying different biological activities. In resting CD4 T cells, a LMM form of A3G potently restricts HIV-1 infection soon after virion entry. However, when T cells are activated, LMM A3G is recruited into HMM complexes that include Staufen-containing RNA granules. These complexes are probably nucleated by the induced expression of Alu/hY retroelement RNAs that accompany T-cell activation. HMM A3G sequesters these retroelement RNAs away from the nuclear long interspersed nuclear element-derived enzymes required for Alu/hY retrotransposition. Human immunodeficiency virus (HIV) exploits this ‘window of opportunity’ provided by the loss of LMM A3G in activated CD4 T cells to productively infect these cells. During HIV virion formation, newly synthesized LMM A3G is preferentially encapsidated but only under conditions where Vif is absent and thus not able to target A3G for proteasome-mediated degradation. Together, these findings highlight the discrete functions of the different forms of A3G. LMM A3G opposes the external threat posed by exogenous retroviruses, while HMM A3G complexes oppose the internal threat posed by the retrotransposition of select types of retroelements.

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Inconsistent Reversal of HIV-1 Latency Ex Vivo by Antigens of HIV-1, CMV, and Other Infectious Agents

10.21203/rs.3.rs-35386/v1 ◽

2020 ◽

Author(s):

Thomas Vollbrecht ◽

Aaron O. Angerstein ◽

Bryson Menke ◽

Nikesh M. Kumar ◽

Michelli Faria Oliveira ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Ex Vivo ◽

Latent Reservoir ◽

Antigen Specificity ◽

Pcr Assay ◽

Hiv 1

Abstract BackgroundA reservoir of replication-competent but latent virus is the main obstacle to a cure for HIV-infection. Much of this reservoir resides in memory CD4 T cells. We hypothesized that these cells can be reactivated with antigens from HIV and other common pathogens to reverse latency. ResultsWe obtained mononuclear cells from the peripheral blood of antiretroviral-treated patients with suppressed viremia. We tested pools of peptides and proteins derived from HIV and from other pathogens including CMV for their ability to reverse latency ex vivo by activation of memory responses. We assessed activation of the CD4 T cells by measuring the up-regulation of cell-surface CD69. We assessed HIV-expression using two assays: a real-time PCR assay for virion-associated viral RNA and a droplet digital PCR assay for cell-associated, multiply spliced viral mRNA. Reversal of latency occurred in a minority of cells from some participants, but no single antigen induced HIV-expression ex vivo consistently. When reversal of latency was induced by a specific peptide pool or protein, the extent was proportionally greater than that of T cell activation. ConclusionsIn this group of patients in whom antiretroviral therapy was started during chronic infection, the latent reservoir does not appear to consistently reside in CD4 T cells of a predominant antigen-specificity. Peptide-antigens reversed HIV-latency ex vivo with modest and variable activity. When latency was reversed by specific peptides or proteins, it was proportionally greater than the extent of T cell activation, suggesting partial enrichment of the latent reservoir in cells of specific antigen-reactivity.

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CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T cells to HIV-1 infection: a novel model of HIV-1 latency

Blood ◽

10.1182/blood-2007-06-097907 ◽

2007 ◽

Vol 110 (13) ◽

pp. 4161-4164 ◽

Cited By ~ 162

Author(s):

Suha Saleh ◽

Ajantha Solomon ◽

Fiona Wightman ◽

Miranda Xhilaga ◽

Paul U. Cameron ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Lymphocyte Migration ◽

Major Barrier ◽

Memory Cd4 T Cells ◽

Novel Model ◽

Hiv 1

Latent HIV-1 infection of resting memory CD4+ T cells represents the major barrier to HIV-1 eradication. To determine whether the CCR7 ligands involved in lymphocyte migration can alter HIV-1 infection of resting CD4+ T cells, we infected purified resting CD4+ T cells after incubation with the chemokines CCL19 and CCL21. Incubation with CCL19 or CCL21 did not alter markers of T-cell activation or proliferation. However, after HIV-1 infection of CCL19- or CCL21-treated CD4+ T-cells, we observed low-level HIV-1 production but high concentrations of integrated HIV-1 DNA, approaching that seen in mitogen-stimulated T-cell blasts. Restimulation of CCL19-treated infected CD4+ T cells resulted in virus production consistent with establishment of postintegration latency. CCR7 ligands facilitate efficient entry of HIV-1 into resting CD4+ T cells. These studies demonstrate a unique action of the chemokines CCL19 and CCL21 and provide a novel model with which to study HIV-1 latency in vitro.

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

10.1101/526053 ◽

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.

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Costimulation of T-cell activation and virus production by B7 antigen on activated CD4+ T cells from human immunodeficiency virus type 1-infected donors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.90.23.11094 ◽

1993 ◽

Vol 90 (23) ◽

pp. 11094-11098 ◽

Cited By ~ 30

Author(s):

O K Haffar ◽

M D Smithgall ◽

J Bradshaw ◽

B Brady ◽

N K Damle ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Immunodeficiency Virus ◽

T Cell Lines ◽

Antigen Presenting ◽

Hiv 1

Infection with the human immunodeficiency virus type 1 (HIV-1) requires T-cell activation. Recent studies have shown that interactions of the T-lymphocyte receptors CD28 and CTLA-4 with their counter receptor, B7, on antigen-presenting cells are required for optimal T-cell activation. Here we show that HIV-1 infection is associated with decreased expression of CD28 and increased expression of B7 on CD4+ T-cell lines generated from seropositive donors by alloantigen stimulation. Loss of CD28 expression was not seen on CD4+ T-cell lines from seronegative donors, but up-regulation of B7 expression was observed upon more prolonged culture. Both T-cell proliferation and interleukin 2 mRNA accumulation in HIV-1-infected cultures required costimulation with exogenous B7 because these events were blocked by CTLA4Ig, a soluble form of CTLA-4 that binds B7 with high avidity. In contrast, levels of HIV-1 RNA were not affected by CTLA4Ig, indicating that regulation of virus transcription in these cultures did not depend upon CD28-B7 engagement. Infected T cells could present alloantigen to fresh, uninfected CD4+ T cells, leading to increased proliferation and virus spread to the activated cells. Both of these events were blocked by CTLA4Ig. Thus, chronic activation of HIV-1-infected CD4+ T cells reduces expression of CD28 and increases expression of B7, thereby enabling these T cells to become antigen-presenting cells for uninfected CD4+ T cells; this might be another mechanism for HIV-1 transmission via T-cell-T-cell contact.

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Inconsistent reversal of HIV-1 latency ex vivo by antigens of HIV-1, CMV, and other infectious agents

10.21203/rs.3.rs-35386/v2 ◽

2020 ◽

Author(s):

Thomas Vollbrecht ◽

Aaron O. Angerstein ◽

Bryson Menke ◽

Nikesh M. Kumar ◽

Michelli Faria Oliveira ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Ex Vivo ◽

Latent Reservoir ◽

Antigen Specificity ◽

Pcr Assay ◽

Hiv 1

Abstract BackgroundA reservoir of replication-competent but latent virus is the main obstacle to a cure for HIV-1 infection. Much of this reservoir resides in memory CD4 T cells. We hypothesized that these cells can be reactivated with antigens from HIV-1 and other common pathogens to reverse latency. ResultsWe obtained mononuclear cells from the peripheral blood of antiretroviral-treated patients with suppressed viremia. We tested pools of peptides and proteins derived from HIV-1 and from other pathogens including CMV for their ability to reverse latency ex vivo by activation of memory responses. We assessed activation of the CD4 T cells by measuring the up-regulation of cell-surface CD69. We assessed HIV-1 expression using two assays: a real-time PCR assay for virion-associated viral RNA and a droplet digital PCR assay for cell-associated, multiply spliced viral mRNA. Reversal of latency occurred in a minority of cells from some participants, but no single antigen induced HIV-1 expression ex vivo consistently. When reversal of latency was induced by a specific peptide pool or protein, the extent was proportionally greater than that of T cell activation. ConclusionsIn this group of patients in whom antiretroviral therapy was started during chronic infection, the latent reservoir does not appear to consistently reside in CD4 T cells of a predominant antigen-specificity. Peptide-antigens reversed HIV-1 latency ex vivo with modest and variable activity. When latency was reversed by specific peptides or proteins, it was proportionally greater than the extent of T cell activation, suggesting partial enrichment of the latent reservoir in cells of specific antigen-reactivity.

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HIV-1 Nef Enhances Dendritic Cell-Mediated Viral Transmission to CD4+ T Cells and Promotes T-Cell Activation

PLoS ONE ◽

10.1371/journal.pone.0034521 ◽

2012 ◽

Vol 7 (3) ◽

pp. e34521 ◽

Cited By ~ 19

Author(s):

Corine St. Gelais ◽

Christopher M. Coleman ◽

Jian-Hua Wang ◽

Li Wu

Keyword(s):

T Cells ◽

T Cell ◽

Dendritic Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Viral Transmission ◽

Hiv 1

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FOXP3 expressing CD127lo CD4+ T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 infection

Journal of Leukocyte Biology ◽

10.1189/jlb.0507281 ◽

2007 ◽

Vol 83 (2) ◽

pp. 254-262 ◽

Cited By ~ 64

Author(s):

Lishomwa C. Ndhlovu ◽

Christopher P. Loo ◽

Gerald Spotts ◽

Douglas F. Nixon ◽

Frederick M. Hecht

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Cd8 T Cell ◽

Hiv 1

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Low SAMHD1 expression following T-cell activation and proliferation renders CD4+ T cells susceptible to HIV-1

AIDS ◽

10.1097/qad.0000000000000594 ◽

2015 ◽

pp. 1 ◽

Cited By ~ 15

Author(s):

Nicolas Ruffin ◽

Vedran Brezar ◽

Diana Ayinde ◽

Cécile Lefebvre ◽

Julian Schulze Zur Wiesch ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Samhd1 Expression ◽

Hiv 1

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A subgroup of Ugandan elite and viremic controllers naturally control HIV-1 infection by blocking R5-tropic viral entry.

10.21203/rs.3.rs-86395/v1 ◽

2020 ◽

Author(s):

Alex Kayongo ◽

Derrick Semugenze ◽

Mary Nantongo ◽

Fred Semitala ◽

Anxious Jackson Niwaha ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Viral Entry ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Cell Activation ◽

Cd4 T Cell ◽

Controlled Study ◽

Hiv 1

Abstract Background: World over, there are antiretroviral therapy naïve individuals infected with HIV who maintain their CD4+T cell count above 500 cells/µl over 7-10 years and viral loads well controlled below undetectable levels (termed elite controllers, ECs) or at least 2,000 copies/mL (termed viremic controllers, VCs) for at least 12 months. Mechanisms responsible for HIV control in these individuals have not been fully elucidated. We hypothesized that CD4+T cells from elite and viremic controllers are naturally resistant to HIV-1 infection by blocking R5-tropic viral entry. We conducted a case-controlled study in which archived peripheral blood from 31 ECs/VCs and 15 progressors were investigated using in vitro HIV-1 infectivity assays. Results: Briefly, we purified CD4+T cells from peripheral blood using EasySep CD4+ positive selection kit followed by CD4+T cell activation using IL-2, anti-CD28 and anti-CD3. Three days post-activation, CD4+T cells were spinoculated and co-cultured with vesicular stomatitis virus G (VSV-G)-pseudotyped HIV, R5 (ADA-enveloped)- and X4 (NL4.3-enveloped v)-tropic HIV-1. Three days post infection, we quantified and compared the percentage infection of CD4+T cells in cases and controls. We demonstrate that a subgroup of Ugandan elite and viremic controllers possess CD4+T cells that are specifically resistant to R5-tropic virus, remaining fully susceptible to X4-tropic virus. Conclusion: Our study suggests that a subgroup of Ugandan elite and viremic controllers naturally control HIV-1 infection by blocking R5-tropic viral entry. Further research is needed to explore mechanisms of HIV control in the African population.

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