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Changes in markers of T cell senescence and exhaustion with Atazanavir-, Raltegravir-, Darunavir-Based Initial Antiviral Therapy: ACTG 5260s
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from Jules: HIV can lead to accelerated aging, premature aging, increased numbers of & earlier onset of comorbidities including bone, heart, diabetes, mental & kidney diseases. Other viruses can contribute to this aging process so studies report CMV in HIV+ and HCV in HIV+ contribute to the aging process putting these patients at greater risk for inflammation, activation, and comorbidity onset. There is a little controversy in that a very few of researchers suggest aging is not accelerated but they prefer accentuation meaning it can increase comorbidity risk but not accelerate it, these few researchers do not accept acceleration. In my opinion they do not know what they are talking about, there are numerous studies reporting HIV accelerates aging & prematurely, and from knowing the research I think well from many years i firmly believe aging is accelerated in HIV- and this applies to immunity & some comorbid conditions - here is just 1 link .........
http://www.natap.org/2009/HIV/021009_01.htm
........http://www.natap.org/2015/HIV/060115_01.htm
Premature immunosenescence in HIV-infected patients on highly active antiretroviral therapy with low-level CD4 T cell repopulation.......
http://www.natap.org/2010/HIV/062310_02.htm.......To evaluate senescence, the relationship between CD57 expression and the percentage of naive CD4 T cells (CD4+ CD45RA+ CD27+) was analysed (Figure 2a). As shown in Figure 2(b), CD57 expression on naive CD4 T cells was statistically higher in the low-level CD4 T cell repopulation group compared with healthy controls (P = 0.006), while differences were not significant when compared with the high-level CD4 T cell repopulation group (P = 0.2).
from Jules: so this data suggests increased CD4 on ART & undetectable viral load might normalize senescences, but other studies find differently including this one- T cell Senescence and Proliferation Defects Persist in Treated HIV-infected Individuals Maintaining Viral Suppression and Are Associated with Poor CD4+ T Cell Recovery -
http://www.natap.org/2010/CROI/croi_88.htm
& the new study published in JID herein....the best antidote is exercise & diet: several diets discussed extensively in the literature are Mediterranean diet, Cretan diet, and plant-based diet:
Changes in markers of T cell senescence and exhaustion with Atazanavir-, Raltegravir-, Darunavir-Based Initial Antiviral Therapy: ACTG 5260s
Journal of Infectious Diseases Advance Access published June 28, 2016
Theodoros Kelesidis1, Carlee Moser2, James H. Stein3, Todd T. Brown4, Thuy Tien T. Tran2, Heather J. Ribaudo2, Michael P. Dube5, Otto O. Yang1, Judith S. Currier1, Grace A. McComsey6,7,
See below after next section just below
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Senescence in HIV - Immune Activation / Inflammation - older articles
In HIV-1-infected individuals, the majority of CD8+ T cells were CD28-, as compared with less than 10% within the CD4+ T-cell subset, similar to phenotypic changes in aging [28]. The differences in susceptibility of both T-cell subsets to aging can be attributed to differences in kinetics of loss of CD28 upon repeated antigenic stimulation or their differences in life-span [16, 29]. Therefore, despite a significant number of CD8+ T cells observed during HIV-1 infection, the CD8+ T-cell compartment is mostly comprised of functionally defective CD28- T cells......
http://www.natap.org/2010/HIV/021510_01.htm
CD8-Cell Activation, Senescence, Osteoprotegerin Tied to Atherosclerosis in Italian HIV Cohort....
(from jules: senescence marker higher in HIV+ & senescence marker associated with heart disease) / CD8+ T-cell activation (CD38+/HLADR+) and senescence (CD28-/CD57+) were higher in HIV+ patients than controls (p<0.001)......
http://www.natap.org/2014/ICAAC/ICAAC_47.htm
.......The Sapienza University team proposed that "immune activation and immunosenescence of CD8 T cells together with osteoprotegerin plasma levels might contribute to development and progression of early atherosclerosis," even in antiretroviral-treated people with an undetectable viral load......"......c-IMT was higher in HIV+ than in controls (0.85 ± 0.17 mm vs 0.28 ± 0.24 mm, p<0,001) (Fig.1). ........CD8+ T-cell activation (CD38+/HLADR+) and senescence (CD28-/CD57+) were higher in HIV+ patients than controls (p<0.001) (Fig. 3A and B). ......Subjects with pathological c-IMT exhibited higher activated CD8+ CD38+HLADR+ (p=0.048), CD8+ CD28-CD57+ (p<0.001) (Fig. 3C and D) and OPG (p=0.053) (Fig.2B) than subjects with normal c-IMT......".....Osteoprotegerin levels in plasma were significantly higher in participants with than without HIV (6.59 versus 3.57 pmol/L, P < 0.001), as were levels of activated CD8 cells and senescent CD8 cells (P < 0.001). Study participants with pathologically elevated cIMT had significantly higher levels of activated CD8 cells (P = 0.048), senescent CD8 cells (P < 0.001), and osteoprotegerin (P = 0.053) than did people with normal cIMT.
High Inflammation/Activation Markers Before and During ART Predict Death in MACS - Mark Mascolini - (08/04/14)
Inflammation/Activation Markers Drop With ATV, DRV, RAL, But Not Completely - ACTG Study - written by Mark Mascolini - (07/23/14)
Monocyte activation markers remain significantly elevated in virologically suppressed HIV+ individuals to a level equivalent to an additional 4 years of normal ageing (07/30/14)
Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence - Review......
http://www.natap.org/2012/HIV/020712_01.htm
Immunosenescence and aging in HIV.....
http://www.natap.org/2014/HIVAGE/061614_05.htm
Premature Aging and Immune Senescence in HIV-1-Infected Children.....
http://www.natap.org/2015/CROI/croi_146.htm
we contend that frequent T-cell shifts with acute exercise also could have accumulative long-term restorative effects on systemic immunity.".....
http://www.natap.org/2011/HIV/070411_01.htm
....."A hallmark of aging and persistent CMV infection is the accumulation of terminally differentiated senescent T cells, which are incapable of further cell division in response to antigenic stimuli and drastically contribute to the shrinking of the naïve T-cell repertoire.......
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Changes in markers of T cell senescence and exhaustion with Atazanavir-, Raltegravir-, Darunavir-Based Initial Antiviral Therapy: ACTG 5260s
"Overall, sustained declines over time were evident in all treatment groups for CD4+ T cell markers of senescence and exhaustion..... In contrast, there was no apparent change from baseline to 96 weeks in levels of % CD28-CD57+ of CD8+ T cells. ....... The age-associated remodeling of the immune system, through accumulation of senescent T cells may contribute to numerous aging-related pathologies [2].....CD4+ T cells are rare long-lived senescent T cells with proatherogenic properties [12] that may result from persistent antigenic stimulation[12] and play a critical role in the development of age-related pathologies [2]. HIV-infected patients with low-level CD4+ T cell count on ART have more senescent CD4+ T cells compared to those with increased CD4+ T cell levels [13]."
DISCUSSION
In this prospective study of ART-naïve participants who achieved virologic suppression after initiation of TDF/FTC along with RAL, ATV/r or DRV/r, RAL did not have a more favorable effect on decreasing immunosenescence or exhaustion compared to the PIs. To our knowledge, this is the largest prospective study describing changes in markers of immune senescence and exhaustion after initiation of successful ART. We also describe associations with markers of immune activation and inflammation that have been associated with serious clinical events in HIV-1 infected persons, including CVD and mortality [8]. Of note, although sustained and similar declines over time from baseline were evident in all treatment groups for all CD4+ T cell markers of senescence and exhaustion, consistent reductions in markers of CD8+ T cell senescence were not apparent. Overall, these results add to the current literature outlining the incomplete reversal of inflammation, senescence and immune activation in the setting of effective treatment [9].
The age-associated remodeling of the immune system, through accumulation of senescent T cells may contribute to numerous aging-related pathologies [2]. Senescent T cells have been associated with CVD [3] but the differential role of CD4+ compared to CD8+ T cell senescence in development of chronic comorbidities such as CVD and bone disease remain unclear. CD8+ T cell senescence has been associated with progression of numerous diseases [2] including CVD in a study of HIV-infected patients [4] but this was not confirmed by others [5]. Senescent CD4+ T cells are rare long-lived senescent T cells with proatherogenic properties [12] that may result from persistent antigenic stimulation[12] and play a critical role in the development of age-related pathologies [2]. HIV-infected patients with low-level CD4+ T cell count on ART have more senescent CD4+ T cells compared to those with increased CD4+ T cell levels [13]. The lack of change in markers of CD8+ T cell senescence in our study may be due to our cohort having overall a relatively high pre-ART CD4+ T cell count and may be overall lower pre-ART levels of senescent CD8+ T cells than other studies [4, 5, 9]. Together, these prior studies highlight possible differential roles of senescent CD4+ versus CD8+ T cells [14] in the pathogenesis of HIV and its comorbidities, and are consistent with our results that effective ART reduced differentially CD4+ (and not CD8+) T cell senescence.
Understanding how different initial ART regimens reduce chronic immune dysfunction in successfully treated HIV-1 infection is an ongoing research priority. Other studies have suggested that integrase inhibitors may reduce inflammation and viral load more effectively than other antiretroviral agents[10][11]. Intensification with the integrase inhibitor RAL has shown variable effects on immune activation[10]. Despite this limited evidence, the differential effects of integrase inhibitors compared to other ART on T cell senescence remain unknown. We did not find any benefit of RAL over PIs on reducing immunosenescence or exhaustion during the first 96 weeks of successful treatment. This is consistent with a study by Kaplan et al, in which no differential effect of PIs were seen compared to NNRTIs on T cell senescence [4]. A strength of our study is that, in contrast to prior RAL switch or intensification-related studies, our data are not confounded by prior ART.
ABSTRACT
It is unclear whether differential roles of CD4+ vs CD8+ T cell senescence/exhaustion and effects of antiretroviral therapy (ART) on these processes may contribute to morbidity in treated HIV-1 infection. In a prospective 96-week trial, 328 HIV-1-infected/ART-naïve participants were randomized to receive tenofovir-emtricitabine plus: atazanavir/ritonavir, darunavir/ritonavir, or raltegravir. Markers of CD4+ senescence (%CD28-CD57+) and CD4+/CD8+ T cell exhaustion (% PD1+) decreased after ART. There were no changes in markers of CD8+ T cell senescence after ART and no differential changes in all markers in ART groups. Senescent CD4+ and CD8+ T cells may have differential roles in HIV-1 pathogenesis.
The objective of this analysis was to characterize the changes in biomarkers of T cell senescence longitudinally among treatment-naïve individuals initiating these randomized ART regimens. In this paper, we describe for the first time in the setting of a large randomized ART initiation trial, the effects of different successful ART regimens on T cell senescence and exhaustion. In addition, associations between key biomarkers of T cell exhaustion, immune senescence and activation, and inflammation were explored in ART-naïve HIV-infected participants at entry, and through 96 weeks of a successful ART regimen.
Changes in markers of immunosenescence and exhaustion
Sustained decreases (about 31% or more) from baseline in levels of % CD28-CD57+ of CD4+ T cells were evident among all treatment groups (Figure 1, Table 1). In contrast, there was no apparent change from baseline to 96 weeks in levels of % CD28-CD57+ of CD8+ T cells. For exhaustion markers, declines from baseline were evident for % PD1+ of both CD4+ and CD8+ T cells across all treatment groups, by week 24, with further apparent declines for CD4 + T cell exhaustion by week 96; week 96 levels were on average at least 56% lower than baseline levels. Treatment group differences were not apparent for any immunosenescence and exhaustion marker (p>0.1;Supplemental Table 1). Overall, sustained declines over time were evident in all treatment groups for CD4+ T cell markers of senescence and exhaustion.
Correlations between biomarkers of T cell senescence, exhaustion, inflammation and immune activation
At baseline, plasma viral load was correlated with markers of exhaustion (PD1+) (r=0.24-0.31; p<0.001), but not senescence (|r|<0.15, p>0.05). With regards to associations of baseline markers of immunosenescence with markers of T-cell and monocyte activation, or inflammation at baseline (Supplemental Table 2), the strongest associations were apparent between % of CD4+ CD38+DR+ and % of CD4+ CD28-CD57+ (r=0.42) and % of CD4+ PD1+(r=0.40) (Supplemental Figure 2). There was also a moderate association at baseline between monocyte activation (sCD163) and CD4+ exhaustion (% of CD4+ PD1+) (r=0.35). These moderate associations were also apparent when examining the concurrent changes over 96 weeks between these set of markers with correlations ranging from 0.33 to 0.55 (Supplemental Table 3); in contrast, a moderate association between the levels of these markers at week 96 was only apparent for CD4+ activation and senescence (r=0.44). All remaining associations between biomarkers were not apparent or weak (|r|<0.3) (Supplemental Tables 2, 3)
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