Evidence of Ongoing Immune Reconstitution in Subjects with Sustained Viral Suppression following 6 Years of Lopinavir-Ritonavir Treatment

Landay, Alan; Silva, Barbara A. da; King, Martin; Albrecht, Mary; Benson, Constance A.; Eron, Joseph J.; Glesby, Marshall J.; Gulick, Roy M.; Hicks, Charles B.; Kessler, Harold A.; Murphy, Robert L.; Thompson, Melanie; White, A. Clinton; Wolfe, Peter; McMillan, F; Hanna, George J.

doi:10.1086/511681

Cited by 41 publications

(23 citation statements)

References 27 publications

(27 reference statements)

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“…1A. As reported by others (21,22), both CD4 and CD8 cells showed increased CD38/ HLA-DR expression in ART 2 patients (p = 0.0007 and p , 0.0001, respectively), which was significantly decreased in ART + patients (p = 0.01 and p = 0.0005, respectively) (Fig. 1B).…”

Section: Nk Cell Activation Is Not Reduced By Artsupporting

confidence: 82%

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Lichtfuss

Cheng

Farsakoglu

et al. 2012

The Journal of Immunology

108

106

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FcRγ is an ITAM-containing adaptor required for CD16 signaling and function in NK cells. We have previously shown that NK cells from HIV patients receiving combination antiretroviral therapy (cART) have decreased FcRγ expression, but the factors causing this are unknown. We conducted a cross-sectional study of cART-naive viremic patients (ART−), virologically suppressed patients receiving cART (ART+), and HIV-uninfected controls. CD8+ T cells were activated, as assessed by CD38+HLA-DR+ expression, in ART− patients (p < 0.0001), which was significantly reduced in ART+ patients (p = 0.0005). In contrast, CD38+HLA-DR+ NK cells were elevated in ART− patients (p = 0.0001) but did not decrease in ART+ patients (p = 0.88). NK cells from both ART− and ART+ patients showed high levels of spontaneous degranulation in ex vivo whole blood assays as well as decreased CD16 expression (p = 0.0001 and p = 0.0025, respectively), FcRγ mRNA (p < 0.0001 for both groups), FcRγ protein expression (p = 0.0016 and p < 0.0001, respectively), and CD16-dependent Syk phosphorylation (p = 0.0001 and p = 0.003, respectively). HIV-infected subjects showed alterations in NK activation, degranulation, CD16 expression and signaling, and elevated plasma markers of inflammation and macrophage activation, that is, neopterin and sCD14, which remained elevated in ART+ patients. Alterations in NK cell measures did not correlate with viral load or CD4 counts. These data show that in HIV patients who achieve viral suppression following cART, NK cell activation persists. This suggests that NK cells respond to factors different from those driving T cell activation, but which are associated with inflammation in HIV patients.

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Section: Nk Cell Activation Is Not Reduced By Artsupporting

confidence: 82%

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Lichtfuss

Cheng

Farsakoglu

et al. 2012

The Journal of Immunology

108

106

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“…We have previously described patients with HIV infection who received an effective lopinavir and low-dose ritonavirbased ART regimen for 6 years, after which time, the proportions of activated (CD38 + , HLA-DR + ) CD4 + and CD8 + T cells were significantly lower than they were in untreated patients with HIV infection and comparable to what they were in HIVnegative subjects [8]. It is unknown what effect receiving ART for this length of time has on levels of serum immune activation markers or what relationship exists between serum immune activation markers and CD4 + T cell counts and T cell activation.…”

Section: B R I E F R E P O R Tmentioning

confidence: 98%

“…Serum levels of IgG, IgA, and IgM were assayed by immunoturbidimetry (Abbott Architect 8200 Chemical Analyzer). Total and activated CD4 + and CD8 + T cells were enumerated by flow cytometry, as described elsewhere [8].…”

Section: B R I E F R E P O R Tmentioning

confidence: 99%

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

et al. 2009

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The effect of long-term antiretroviral therapy on serum immune activation markers was assessed in a cohort of 63 patients before and after 6 years of boosted lopinavir-based antiretroviral therapy. High levels of most markers were associated with lower CD4(+) T cell counts at baseline and at year 6, with the exception of soluble cytotoxic T lymphocyte antigen-4 (sCTLA-4); high levels of sCTLA-4 were associated with higher CD4(+) T cell counts at year 6. Abnormalities of serum immune activation markers persisted after 6 years of ART but probably had different causes. Further investigation of the clinical usefulness of assaying immunoglobulin A, neopterin, and sCTLA-4 levels to assess the effectiveness of treatments for human immunodeficiency virus (HIV) disease are warranted.

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“…Lopinavir-ritonavir (LPV-r) is a PI combination well known for its potency and efficacy. In antiretroviral-naive adults, LPV-r demonstrates sustained virological suppression for up to 6 years in 195% of patients [3]. LPV-r use in children in resource-limited settings has also achieved good outcomes over sustained periods as long as 4 years [4].…”

mentioning

confidence: 99%

Virological Suppression Achieved with Suboptimal Adherence Levels among South African Children Receiving Boosted Protease Inhibitor–Based Antiretroviral Therapy

Müller¹,

Myer²,

Jaspan³

2009

CLIN INFECT DIS

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Sixty-six children who were receiving antiretroviral treatment were assessed for treatment adherence and virological outcome to compare boosted protease inhibitor-based regimens with nonnucleoside reverse-transcriptase inhibitor-based regimens. Children who were receiving protease inhibitor-based regimens demonstrated higher rates of virological suppression, even with poor treatment adherence (<80%). In children, boosted protease inhibitors seem to be more forgiving of poor adherence than do nonnucleoside reverse-transcriptase inhibitors.

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Evidence of Ongoing Immune Reconstitution in Subjects with Sustained Viral Suppression following 6 Years of Lopinavir-Ritonavir Treatment

Cited by 41 publications

References 27 publications

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

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

Virological Suppression Achieved with Suboptimal Adherence Levels among South African Children Receiving Boosted Protease Inhibitor–Based Antiretroviral Therapy

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Evidence of Ongoing Immune Reconstitution in Subjects with Sustained Viral Suppression following 6 Years of Lopinavir-Ritonavir Treatment

Cited by 41 publications

References 27 publications

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

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

Virological Suppression Achieved with Suboptimal Adherence Levels among South African Children Receiving Boosted Protease Inhibitor–Based Antiretroviral Therapy

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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