Biomarkers of Immune Dysfunction Following Combination Antiretroviral Therapy for HIV Infection

Lichtfuss, Gregor F.; Hoy, Jennifer; Rajasuriar, Reena; Kramski, Marit; Crowe, Suzanne; Lewin, Sharon R.

doi:10.2217/bmm.11.15

Cited by 68 publications

(61 citation statements)

References 154 publications

(152 reference statements)

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“…However, no differences in IL-6, or any other cytokines or chemokines measured, were observed in the plasma between PP and VNP patients (data not shown). Thus, the differences in cytokine signaling and/or leukocyte activation observed by microarray may reflect overt immunological dysfunction in the PPs compared to the VNPs, consistent with progressive HIV phenotype [34], [35].…”

Section: Resultsmentioning

confidence: 81%

Limited HIV Infection of Central Memory and Stem Cell Memory CD4+ T Cells Is Associated with Lack of Progression in Viremic Individuals

et al. 2014

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A rare subset of HIV-infected individuals, designated viremic non-progressors (VNP), remain asymptomatic and maintain normal levels of CD4+ T-cells despite persistently high viremia. To identify mechanisms potentially responsible for the VNP phenotype, we compared VNPs (average >9 years of HIV infection) to HIV-infected individuals who have similar CD4+ T-cell counts and viral load, but who are likely to progress if left untreated (“putative progressors”, PP), thus avoiding the confounding effect of differences related to substantial CD4+ T cell depletion. We found that VNPs, compared to PPs, had preserved levels of CD4+ stem cell memory cells (TSCM (p<0.0001), which was associated with decreased HIV infection of these cells in VNPs (r = −0.649, p = 0.019). In addition, VNPs had decreased HIV infection in CD4+ central memory (TCM) cells (p = 0.035), and the total number of TCM cells was associated with increased proliferation of memory CD4+ T cells (r = 0.733, p = 0.01). Our results suggest that, in HIV-infected VNPs, decreased infection of CD4+ TCM and TSCM, cells are involved in preservation of CD4+ T cell homeostasis and lack of disease progression despite high viremia.

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Section: Resultsmentioning

confidence: 81%

Limited HIV Infection of Central Memory and Stem Cell Memory CD4+ T Cells Is Associated with Lack of Progression in Viremic Individuals

et al. 2014

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“…Biomarkers of immune activation, inflammation, and microbial translocation remain elevated in virologically suppressed HIV-infected patients compared to HIV-negative individuals (81)(82)(83)(84) and may be a pathway to noninfectious morbidities (85,86). The cellular markers of immune activation appear to remain elevated during persistent LLV.…”

Section: Figmentioning

confidence: 99%

Significance and Clinical Management of Persistent Low-Level Viremia and Very-Low-Level Viremia in HIV-1-Infected Patients

Ryscavage

Kelly

et al. 2014

Antimicrob Agents Chemother

115

101

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A goal of HIV therapy is to sustain suppression of the plasma viral load below the detection limits of clinical assays. However, widely followed treatment guidelines diverge in their interpretation and recommended management of persistent viremia of low magnitude, reflecting the limited evidence base for this common clinical finding. Here, we review the incidence, risk factors, and potential consequences of low-level HIV viremia (LLV; defined in this review as a viremia level of 50 to 500 copies/ml) and verylow-level viremia (VLLV; defined as a viremia level of <50 copies/ml detected by clinical assays that have quantification cutoffs of <50 copies/ml). Using this framework, we discuss practical issues related to the diagnosis and management of patients experiencing persistent LLV and VLLV. Compared to viral suppression at <50 or 40 copies/ml, persistent LLV is associated with increased risk of antiretroviral drug resistance and overt virologic failure. Higher immune activation and HIV transmission may be additional undesirable consequences in this population. It is uncertain whether LLV of <200 copies/ml confers independent risks, as this level of viremia may reflect assay-dependent artifacts or biologically meaningful events during suppression. Resistance genotyping should be considered in patients with persistent LLV when feasible, and treatment should be modified if resistance is detected. There is a dearth of clinical evidence to guide management when genotyping is not feasible. Increased availability of genotypic assays for samples with viral loads of <400 copies/ml is needed.

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“…However, CD4 T cell depletion in the gut mucosa also occurs during non-pathogenic SIV infection but gut barrier function is not compromised (Marchetti et al, 2013). Another area of uncertainty pertains to the natural history of HIV-infected patients, who continue to exhibit low levels chronic inflammation despite effective long-term combination antiretroviral therapy and full suppression of plasma HIV RNA levels (Hunt et al, 2003; Kuller et al, 2008; Lichtfuss et al, 2011). As these subjects grow older, they appear to experience a higher-than-expected risk for a number of diseases typically associated with aging, including cardiovascular disease, cancer, osteoporosis, and other end-organ diseases (Deeks, 2011).…”

Section: Pyroptosis Can Breed More Pyroptosismentioning

confidence: 99%

Dissecting How CD4 T Cells Are Lost During HIV Infection

Doitsh

Greene

2016

Cell Host & Microbe

198

156

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Although the replicative life cycle of HIV within CD4 T cells is understood in molecular detail, less is known about how this human retrovirus promotes the loss of CD4 T lymphocytes. It is this cell death process that drives clinical progression to acquired immune deficiency syndrome (AIDS). Recent studies have highlighted how abortive infection of resting and thus nonpermissive CD4 T cells in lymphoid tissues triggers a lethal innate immune response against the incomplete DNA products generated by inefficient viral reverse transcription in these cells. Sensing of these DNA fragments results in pyroptosis, a highly inflammatory form of programmed cell death, that potentially further perpetuates chronic inflammation and immune activation. As discussed here, these studies cast CD4 T cell death during HIV infection in a different light. Further, they identify drug targets that may be exploited to both block CD4 T cell demise and the chronic inflammatory response generated during pyroptosis.

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Biomarkers of Immune Dysfunction Following Combination Antiretroviral Therapy for HIV Infection

Cited by 68 publications

References 154 publications

Limited HIV Infection of Central Memory and Stem Cell Memory CD4+ T Cells Is Associated with Lack of Progression in Viremic Individuals

Limited HIV Infection of Central Memory and Stem Cell Memory CD4+ T Cells Is Associated with Lack of Progression in Viremic Individuals

Significance and Clinical Management of Persistent Low-Level Viremia and Very-Low-Level Viremia in HIV-1-Infected Patients

Dissecting How CD4 T Cells Are Lost During HIV Infection

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