Erratum: Corrigendum: The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function

Abstract Despite the extraordinary success of HIV-1 antiretroviral therapy in prolonging life, infected individuals face lifelong therapy because of a reservoir of latently-infected cells that harbor replication competent virus. Recently, compounds have been identified that can reverse HIV-1 latency in vivo. These latency- reversing agents (LRAs) could make latently-infected cells vulnerable to clearance by immune cells, including cytolytic CD8+ T cells. We investigated the effects of two leading LRA classes on CD8+ T cell phenotype and function: the histone deacetylase inhibitors (HDACis) and protein kinase C modulators (PKCms). We observed that relative to HDACis, the PKCms induced much stronger T cell activation coupled with non-specific cytokine production and T cell proliferation. When examining antigen-specific CD8+ T cell function, all the LRAs except the HDACi Vorinostat reduced, but did not abolish, one or more measurements of CD8+ T cell function. Importantly, the extent and timing of these effects differed between LRAs. Panobinostat had detrimental effects within 10 hours of drug treatment, whereas the effects of the other LRAs were observed between 48 hours and 5 days. These observations suggest that scheduling of LRA and CD8+ T cell immunotherapy regimens may be critical for optimal clearance of the HIV-1 reservoir.

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Long-term evaluation of T-cell subsets and T-cell function after HAART in advanced stage HIV-1 disease

AIDS ◽

10.1097/00002030-199907090-00006 ◽

1999 ◽

Vol 13 (10) ◽

pp. 1187-1193 ◽

Cited By ~ 87

Author(s):

Ivano Mezzaroma ◽

Maurizio Carlesimo ◽

Elena Pinter ◽

Cecilia Alario ◽

Giovanna Sacco ◽

...

Keyword(s):

T Cell ◽

Cell Function ◽

T Cell Subsets ◽

Advanced Stage ◽

T Cell Function ◽

Term Evaluation ◽

Hiv 1

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Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics.

Journal of Experimental Medicine ◽

10.1084/jem.181.4.1365 ◽

1995 ◽

Vol 181 (4) ◽

pp. 1365-1372 ◽

Cited By ~ 467

Author(s):

M R Klein ◽

C A van Baalen ◽

A M Holwerda ◽

S R Kerkhof Garde ◽

R J Bende ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Function ◽

Cd4 Counts ◽

Rapid Progressors ◽

T Cell Function ◽

Hiv 1 ◽

Ctl Responses

To gain more insight into the role of HIV-1-specific cytotoxic T lymphocytes (CTL) in the pathogenesis of AIDS, we investigated temporal relations between HIV-1 Gag-specific precursor CTL (CTLp), HIV-1 viral load, CD4+ T cell counts, and T cell function. Six HIV-1-infected subjects, who were asymptomatic for more than 8 yr with CD4+ counts > 500 cells/mm3, were compared with six subjects who progressed to AIDS within 5 yr after HIV-1 seroconversion. In the long-term asymptomatics, persistent HIV-1 Gag-specific CTL responses and very low numbers of HIV-1-infected CD4+ T cells coincided with normal and stable CD4+ counts and preserved CD3 mAb-induced T cell reactivity for more than 8 yr. In five out of six rapid progressors Gag-specific CTLp were also detected. However, early in infection the number of circulating HIV-1-infected CD4+ T cells increased despite strong and mounting Gag-specific CTL responses. During subsequent clinical progression to AIDS, loss of Gag-specific CTLp coincided with precipitating CD4+ counts and severe deterioration of T cell function. The possible relationships of HIV-1 Gag-specific CTLp to disease progression are discussed.

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Expansion of Monocytic Myeloid-Derived Suppressor Cells Dampens T Cell Function in HIV-1-Seropositive Individuals

Journal of Virology ◽

10.1128/jvi.01759-12 ◽

2012 ◽

Vol 87 (3) ◽

pp. 1477-1490 ◽

Cited By ~ 111

Author(s):

Aiping Qin ◽

Weiping Cai ◽

Ting Pan ◽

Kang Wu ◽

Qiong Yang ◽

...

Keyword(s):

T Cell ◽

Cell Function ◽

Suppressor Cells ◽

Cell Contact ◽

Myeloid Derived Suppressor Cells ◽

Cell Dysfunction ◽

Arginase 1 ◽

T Cell Function ◽

T Cell Dysfunction ◽

Hiv 1

ABSTRACTT lymphocyte dysfunction contributes to human immunodeficiency virus type 1 (HIV-1) disease progression by impairing antivirus cellular immunity. However, the mechanisms of HIV-1 infection-mediated T cell dysfunction are not completely understood. Here, we provide evidence that expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) suppressed T cell function in HIV-1-infected individuals. We observed a dramatic elevation of M-MDSCs (HLA-DR−/lowCD11b+CD33+/highCD14+CD15−cells) in the peripheral blood of HIV-1-seropositive subjects (n= 61) compared with healthy controls (n= 51), despite efficacious antiretroviral therapy for nearly 2 years. The elevated M-MDSC frequency in HIV-1+subjects correlated with prognostic HIV-1 disease markers, including the HIV-1 load (r= 0.5957;P< 0.0001), CD4+T cell loss (r= −0.5312;P< 0.0001), and activated T cells (r= 0.4421;P= 0.0004). Functional studies showed that M-MDSCs from HIV-1+subjects suppressed T cell responses in both HIV-1-specific and antigen-nonspecific manners; this effect was dependent on the induction of arginase 1 and required direct cell-cell contact. Further investigations revealed that direct HIV-1 infection or culture with HIV-1-derived Tat protein significantly enhanced human MDSC generationin vitro, and MDSCs from healthy donors could be directly infected by HIV-1 to facilitate HIV-1 replication and transmission, indicating that a positive-feedback loop between HIV-1 infection and MDSC expansion existed. In summary, our studies revealed a novel mechanism of T cell dysfunction in HIV-1-infected individuals and suggested that targeting MDSCs may be a promising strategy for HIV-1 immunotherapy.

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Spontaneous HCV clearance in HCV/HIV-1 coinfection associated with normalized CD4 counts, low level of chronic immune activation and high level of T cell function

Journal of Clinical Virology ◽

10.1016/j.jcv.2007.11.005 ◽

2008 ◽

Vol 41 (2) ◽

pp. 160-163 ◽

Cited By ~ 23

Author(s):

Karolin Falconer ◽

Veronica D. Gonzalez ◽

Olle Reichard ◽

Johan K. Sandberg ◽

Annette Alaeus

Keyword(s):

T Cell ◽

Immune Activation ◽

Cell Function ◽

Chronic Immune Activation ◽

Cd4 Counts ◽

Low Level ◽

T Cell Function ◽

Spontaneous Hcv Clearance ◽

High Level ◽

Hiv 1

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Long‐Term Protease Inhibitor–Containing Therapy Results in Limited Improvement in T Cell Function but Not Restoration of Interleukin‐12 Production in Pediatric Patients with AIDS

The Journal of Infectious Diseases ◽

10.1086/322006 ◽

2001 ◽

Vol 184 (2) ◽

pp. 201-205 ◽

Cited By ~ 15

Author(s):

Claire Chougnet ◽

Shirley Jankelevich ◽

Keith Fowke ◽

David Liewehr ◽

Seth M. Steinberg ◽

...

Keyword(s):

T Cell ◽

Protease Inhibitor ◽

Pediatric Patients ◽

Cell Function ◽

Interleukin 12 ◽

T Cell Function

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Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells

Journal of Endocrinology ◽

10.1677/joe.1.05620 ◽

2004 ◽

Vol 183 (3) ◽

pp. 445-454 ◽

Cited By ~ 36

Author(s):

M Schütt ◽

J Zhou ◽

M Meier ◽

H H Klein

Keyword(s):

Insulin Secretion ◽

Protease Inhibitors ◽

Beta Cells ◽

Insulin Signaling ◽

Cell Function ◽

Long Term Effects ◽

Akt Phosphorylation ◽

Glucose Stimulated Insulin Secretion ◽

Hiv 1

The mechanism by which chronic treatment with HIV (human immunodeficiency virus)-1 protease inhibitors leads to a deterioration of glucose metabolism appears to involve insulin resistance, and may also involve impaired insulin secretion. Here we investigated the long-term effects of HIV-1 protease inhibitors on glucose-stimulated insulin secretion from beta cells and explored whether altered insulin secretion might be related to altered insulin signaling. INS-1 cells were incubated for 48 h with different concentrations of amprenavir, indinavir, nelfinavir, ritonavir or saquinavir, stimulated with 20 mM d-glucose, and insulin determined in the supernatant. To evaluate insulin signaling, cells were stimulated with 100 nM insulin for 2 min, and insulin-receptor substrate (IRS)-1, -2 and Akt phosphorylation determined. Incubation for 48 h with ritonavir, nelfinavir and saquinavir resulted in impaired glucose-induced insulin secretion at 2.5, 5 and 5 μM respectively, whereas amprenavir or indinavir had no effects even at 20 and 100 μM respectively. The impaired insulin secretion by ritonavir, nelfinavir and saquinavir was associated with decreased insulin-stimulated IRS-2 phosphorylation, and, for nelfinavir and saquinavir, with decreased insulin-stimulated IRS-1 and Thr308-Akt phosphorylation. No such effects on signaling were observed with amprenavir or indinavir. In conclusion, certain HIV-1 protease inhibitors, such as ritonavir, nelfinavir and saquinavir, not only induce peripheral insulin resistance, but also impair glucose-stimulated insulin secretion from beta cells. With respect to the long-term effect on beta-cell function there appear to be differences between the protease inhibitors that may be clinically relevant. Finally, these effects on insulin secretion after a 48 h incubation with protease inhibitor were associated with a reduction of the insulin-stimulated phosphorylation of insulin signaling parameters, particularly IRS-2, suggesting that protease inhibitor-induced alterations in the insulin signaling pathway may contribute to the impaired beta-cell function.

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