Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: age inversely predicts naive CD4 cell count increase

Lederman, Michael M.; McKinnis, Ray A.; Kelleher, Dennis; Cutrell, Amy; Mellors, John W.; Neisler, Mike; Cooney, Elizabeth; Haas, David W.; Haubrich, Richard; Stanford, James; Horton, James M.; Landay, Alan; Spreen, William

doi:10.1097/00002030-200012010-00002

Cited by 74 publications

(53 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Older participants were predicted to have a higher CD4/CD8 ratio during ART. This is inconsistent with previous reports, which suggested that older HIV-infected people have a worse immune recovery [24,25]. This analysis was biased by the narrow age range in our cohort (only 9 people aged >50 years), which might have affected our ability to determine the effect of older age on CD4/CD8 ratio.…”

Section: Discussioncontrasting

confidence: 99%

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

et al. 2016

View full text Add to dashboard Cite

Background. A low CD4/CD8 ratio in human immunodeficiency virus (HIV)-infected individuals is associated with inflammation and higher risk of non-AIDS morbidity and mortality. In this study, we investigated the effect of subclinical cytomegalovirus (CMV) and Epstein-Barr virus (EBV) replication on CD4 + and CD8 + T-cell dynamics when antiretroviral therapy (ART) is started during early infection.Methods. We investigated 604 peripheral blood mononuclear cell samples from 108 CMV-and EBV-seropositive HIV-infected men who have sex with men, who started ART within a median of 4 months from their estimated date of infection and were followed for a median of 29.1 months thereafter. Levels of CMV and EBV DNA were measured at each timepoint. Mixed-effects asymptotic regression models were applied to characterize CD4 + and CD8 + T-cell dynamics, and Bayesian hierarchical models were used to quantify individual differences in CMV and EBV DNA replication.Results. Higher levels of subclinical CMV replication were associated with lower predicted maximum levels of CD4/CD8 ratio (P < .05), which was driven by higher levels of CD8 + T-cell counts (P < .05), without affecting CD4 + T-cell counts (P > .1). Age was negatively associated with CD4/CD8 levels (P < .05), and this effect was independent of the CMV association (P < .05 for both CMV and age in a multivariate model).Conclusions. Subclinical CMV replication in blood cells during early HIV infection and younger age were associated with lower CD4/CD8 ratios during suppressive ART. These findings suggest that active CMV infection in the setting of treated HIV may represent an attractive potential target for therapeutic intervention.

show abstract

Section: Discussioncontrasting

confidence: 99%

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The response to IL-7 may depend on thymic function and age. Reconstitution of naive T cells with ART is decreased in older HIV ϩ patients, 44 and a relation between T-cell counts and IL-7 in patients with low thymic volume has been observed. 45 It has also been shown that T-cell responsiveness to IL-7 may be impaired by HIV infection 34 because of overstimulation and desensitization of the pSTAT5 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Decreases in IL-7 levels during antiretroviral treatment of HIV infection suggest a primary mechanism of receptor-mediated clearance

Hodge

Srinivasula

Hu³

et al. 2011

Blood

View full text Add to dashboard Cite

IL-7 is essential for T-cell homeostasis.Elevated serum IL-7 levels in lymphopenic states, including HIV infection, are thought to be due to increased production by homeostatic feedback, decreased receptor-mediated clearance, or both. The goal of this study was to understand how immune reconstitution through antiretroviral therapy (ART) in HIV ؉ patients affects IL-7 serum levels, expression of the IL-7 receptor (CD127), and T-cell cycling.Immunophenotypic analysis of T cells from 29 HIV ؊ controls and 43 untreated HIV ؉ patients (30 of whom were followed longitudinally for < 24 months on ART) was performed. Restoration of both CD4 ؉ and CD8 ؉ T cells was driven by increases in CD127 ؉ naive and central memory T cells. CD4 ؉ T-cell subsets were not fully restored after 2 years of ART, whereas serum IL-7 levels normalized by 1 year of ART. Mathematical modeling indicated that changes in serum IL-7 levels could be accounted for by changes in the receptor concentration. These data suggest that T-cell restoration after ART in HIV infection is driven predominantly by CD127 ؉ cells and that decreases of serum IL-7 can be largely explained by improved CD127-mediated clearance. IntroductionT-cell homeostasis tightly regulates the composition of the T-cell compartment, 1 but many aspects of these homeostatic mechanisms in humans remain unclear. IL-7 is a cytokine produced by stromal cells in the BM, thymus, and lymph node 2 and is critical for T-cell thymopoiesis. Through the JAK-STAT5 signaling pathway, IL-7 is essential for the development, maturation, and survival of naive and memory T cells in the periphery. [2][3][4][5][6] The IL-7 receptor (IL-7R) consists of 2 chains: the ␣ chain (IL-7R␣/CD127) and the common ␥ chain shared by IL-2, IL-4, IL-9, Previous studies have found that, in addition to T cells, dendritic cells and monocytes also express CD127. 8,9 Elevated levels of serum or plasma IL-7 have been observed in CD4 T-cell lymphopenia, including HIV infection, idiopathic CD4 lymphocytopenia, and after chemotherapy and BM transplantation. [10][11][12][13] A strong inverse association has been observed between serum IL-7 levels and CD4 T-cell counts, especially in severe CD4 T-cell lymphopenia (Ͻ 200 cells/L). 10,11 Two possible hypotheses have been proposed to explain this association: increased production of IL-7 as part of a compensatory homeostatic response (possibly regulated by the presence of CD127 receptor on dendritic cells) or decreased receptor-mediated clearance from reduced availability of CD127 in lymphopenic conditions [14][15][16][17] leading to accumulation of IL-7. It has been previously described that CD8 T-cell proliferation is more effective than CD4 proliferation in recovering depleted populations in response to homeostatic signals. 18 Some studies have further suggested that very high IL-7 levels may negatively affect CD4 T-cell homeostatic proliferation, 9 although in other animal models of lymphopenia-induced proliferation, excess IL-7 led to improved restoration of the T-cell pool, des...

show abstract

“…13 The second phase of CD4 ϩ T-cell increase, of about 5 to 10 cells/L monthly, lasts until the end of the second year of therapy, and the third phase, of about 2 to 5 cells/L monthly, extends beyond this second year for at least 7 years. 10,12,[14][15][16] Various mechanisms account for the rise in mostly naive CD4 ϩ T cells 12,17 during these 2 phases: first, de novo production of T lymphocytes by the thymus; second, the homeostatic proliferation of the residual CD4 ϩ T cells, and third, the extension of CD4 ϩ T-cell half life, a mechanism responsible for sustaining the number of naive CD4 ϩ T cells in older individuals in whom thymic production is impaired. 18 From a qualitative point of view, these 3 mechanisms of reconstitution are not equivalent.…”

Section: Immunologic Responses To Haart: Both Quality and Quantity Mamentioning

confidence: 99%

Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection

Corbeau

Reynes

2011

Blood

177

165

View full text Add to dashboard Cite

Although highly active antiretroviral therapy has enabled constant progress in reducing HIV-1 replication, in some patients who are "aviremic" during treatment, the problem of insufficient immune restoration remains, and this exposes them to the risk of immune deficiencyassociated pathologies. Various mechanisms may combine and account for this impaired immunologic response to treatment. A first possible mechanism is immune activation, which may be because of residual HIV production, microbial translocation, co-infections, immunosenescence, or lymphopenia per se. A second mechanism is ongoing HIV replication. Finally, deficient thymus output, sex, and genetic polymorphism influencing apoptosis may impair immune reconstitution. In this review we will discuss the tools at our disposal to identify the various mechanisms at work in a given patient and the specific therapeutic strategies we could propose based on this etiologic diagnosis. (Blood. 2011;117(21): 5582-5590)

show abstract

Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: age inversely predicts naive CD4 cell count increase

Cited by 74 publications

References 30 publications

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

Decreases in IL-7 levels during antiretroviral treatment of HIV infection suggest a primary mechanism of receptor-mediated clearance

Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection

Contact Info

Product

Resources

About