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T Cell Subsets in HIV Infected Patients after Successful Combination Antiretroviral Therapy: Impact on Survival after 12 Years

T Cell Subsets in HIV Infected Patients after Successful Combination Antiretroviral Therapy: Impact on Survival after 12 Years

  • Frederikke Falkencrone Rönsholt, 
  • Sisse Rye Ostrowski, 
  • Terese Lea Katzenstein, 
  • Henrik Ullum, 
  • Jan Gerstoft
PLOS
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Abstract

Objectives

Immune activation is decreased by combination antiretroviral therapy (cART) in patients infected with human immunodeficiency virus (HIV), but residual activation remains and has been proposed as a cause of premature aging and death, but data are lacking. We analyzed the relationship between T-cell subsets after 18 months of cART and overall survival during 12 years of follow up.

Methods

A cohort of 101 HIV infected patients who had undetectable plasma HIV after starting cART was included in 1997–1998. T cell subsets were analyzed by flowcytometry after 18 months of cART. Relation to survival was calculated using Kaplan-Meier curves and multiple Cox regression.

Results

Seventeen patients died during the observation period. The leading causes of death were non-AIDS cancer and cardiovascular disease. Higher levels of CD8 memory T cells (CD8+,CD45RO+,CD45RA-) showed a significant beneficiary effect on survival, HR of 0.95 (95% confidence interval 0.91–0.99, P = 0.016) when adjusted for age, nadir CD4 count, CD4 count, and AIDS and hepatitis C status. T cell activation was not associated with increased risk of death.

Conclusions

Larger and longitudinal studies are needed to accurately establish prognostic factors, but overall results seem to suggest that prognostic information exists within the CD8 compartment.

Introduction

Since the discovery and implementation of combination antiretroviral therapy (cART) the prognosis of human immunodeficiency virus (HIV) infected patients has improved enormously. As the HIV-infected patients’ life-expectancy increases and the risk of developing AIDS decreases the focus of attention is moving toward a documented excess non-AIDS morbidity and mortality due to cardiovascular disease and certain types of cancer. Several, probably coexistent, factors have been suggested as contributors to this, including excess of risk factors such as smoking, cART toxicity and foremost the theory that ongoing immune activation/dysfunction leads to chronic inflammation that causes comorbidity and mimics natural aging at the cellular level (“inflamm-aging” or “immunosenescence”) [1], [2].

Studies in patients nor receiving cART have convincingly shown that increased levels of cellular and soluble markers of immune activation are linked to higher risk of progression to AIDS, lower CD4 counts and poorer prognosis [3][6]. Among the cellular markers particularly measurements of CD8+CD38+ T cells have demonstrated prognostic value in untreated patients [7], [8]. cART effectively induces viral suppression and a partial restoration of immune function and composition, but residual immune activation is the rule [9], [10]. This residual immune activation has also been shown to impair immune reconstitution [11][14]. However, the clinical importance of this residual immune activation, microbial translocation and T cell senescence remains undetermined as most of the studies addressing this crucial question are either cross-sectional, longitudinal with limited follow-up time or relies on surrogate laboratory endpoints.

We aimed to address the relationship between T cell subsets measured in 1997-98 18 months after start of successful cART and the overall survival during 12 years of follow-up in a cohort of HIV infected patients.

Materials and Methods

Population

The study was conducted at the Department of Infectious Diseases and the Department of Clinical Immunology at Rigshospitalet (Copenhagen, Denmark). The study population consisted of HIV infected patients included in the period September 1997–August 1998 on the basis of having reproducible plasma HIV RNA levels <200 copies/mL after starting cART. One-hundred-and-one patients with an immunological investigation done 18 months after cART initiation were included in this study. All patients gave written informed consent and the study was approved by the Ethics Committee.

As treatment interruptions have never been part of the Danish treatment guidelines, the patients in this cohort have been offered cART continuously since the inclusion in 1997, although the drug combinations may have changed over the years due to drug development, side effects etc.

This group of well treated patients underwent repetitive extensive immunological examinations at regular intervals for the first 24 months of treatment [15][19]. For the purpose of this study baseline was defined as the date of immunological evaluation done 18 months (+/−6 months) after cART initiation, which was the time point where most patients were represented.

The patients’ baseline data have been collected from medical records and the Danish HIV Cohort and are presented in table 1.

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Table 1. Baseline data (18 months (+/−) cART initiation) of the 101 patients who entered the study in 1997–1998 separated into groups based on survival until 1/1-2010.

https://doi.org/10.1371/journal.pone.0039356.t001

T cell Analysis and Proviral DNA

The immunological parameters used in survival analysis (proportions of naïve, memory and activated CD4 and CD8 cells, and proviral DNA) are derived from blood samples collected 18 months after initiation of cART (+/−6 months).

T cell subsets were analyzed in fresh whole blood using 4-color flowcytometry and were defined as naïve CD4/8(CD45RA+, CD62+), memory CD4/8 (CD45RA-, CD45RO+) and activated CD4 (HLA-DR+), and activated CD8 (HLA-DR+, CD38+). Proviral HIV DNA copies per 106 peripheral blood mononuclear cells were quantified by a prototype assay (Amplicor HIV DNA assay; Roche Diagnostic Systems), in accordance with the manufacturer’s recommendations.

All immunological and virological methods have been described in greater detail elsewhere [20], [21].

Statistics

Statistical analyses were conducted using SPSS 11.5.

The 101 subjects were divided into two groups, a survivor group that consisted of patients who were alive by 1/1-2010 (n = 84) and a deceased group of patients who had died before this time (n = 17) (table 1).

For comparison of means in table 1, Chi Square or Fischer’s exact tests were used for categorical data as appropriate and independent variables T test was used for nominal data. Data were log 10 transformed to obtain normal distribution. Data are presented as medians and interquartile ranges.

In order to identify risk factors for overall mortality in the population Kaplan-Meier analysis was used to construct survival curves and Cox regression analyses to estimate hazard ratios (HRs). Person years at risk were computed in an observation period from the day of the patient’s blood sample 18 months after initiation of cART (+/−6 months) till 1/1-2010 or death, whichever came first.

Kaplan-Meier plots (Figure 1) were made by dividing the population into the highest and lowest 50th percentile of the given variables. Analysis of survival linked to T cell subsets are made with proportions of CD4+ and CD8+ cells respectively.

thumbnail
Figure 1. Kaplan-Meier plots.

The observation period (days) is from 18 months (+/−6 months) after initiation of cART till death or 01/01/2010. The dotted line depicts the highest 50th percentile and the full line depicts the lowest 50th percentile. Analysis of survival linked to T cell subset are made with proportions of CD4+ and CD8+ cells respectively. Analysis using concentrations instead of proportions yielded similar results. Subsets were defined as naïve CD4/8(CD45RA+, CD62+), memory CD4/8 (CD45RA-, CD45R0+) and activated CD4 (HLA-DR+), and activated CD8 (HLA-DR+, CD38+).

https://doi.org/10.1371/journal.pone.0039356.g001

Uni- and multivariate Cox regression analysis was preformed only for patients with complete data for multivariate analysis (n = 90). In the multivariate analysis the T cell subsets – given as proportions of CD4 or CD8 T cells respectively - were adjusted for age, CD4 count at the time of T cell subset measurement, nadir CD4 count, as well as AIDS and hepatitis C status (Table 2). Hazard ratios (HR), 95% confidence intervals (CI) and p-values are presented.

Nadir CD4 count was defined as the lowest CD4 cell count measured before or during the first 18 months of cART.

P-values <0.05 were considered significant.

Results

Baseline Characteristics

One-hundred-and-one patients entered the study in 1997-98. On the 1/1-2010 seventeen of those had died.

The baseline data of the two groups (Table 1) differed somewhat in that the deceased group tended towards having more independent risk factors of morbidity and mortality; higher age, more smokers, higher prevalence of AIDS and hepatitis. Eighteen months after cART initiation the two groups showed largely similar total CD4 and CD8 counts, but the deceased group had a significantly lower proportion of CD4 and CD8 cells being naïve, and a lower concentration of naïve CD8 cells. Significant differences were not observed with respect to CD8 memory cells or activated CD8 cells but the deceased group tended to have lower concentrations of these subsets.

All patients had HIV RNA measured approximately 4 times a year as part of standard care and in the survivor group measurements were below detectable limits in a mean of 81% of measurements vs. 72% in the deceased group.

Mortality

The causes of the seventeen deaths were: non-AIDS cancer (n = 5), cardiovascular disease (n = 5), hepatitis C (n = 3), one case of suicide, one case of pneumonia, one case most likely linked to alcoholism, and only one AIDS related case which was non-Hodgkin lymphoma. Three of the deceased patients had hepatitis C and they all died from liver failure due to this disease.

In the survivor group there were two patients with a history of malignant non-AIDS cancer and two patients with a history of acute myocardial infarction.

T Cell Subsets and Relation to Survival

Kaplan-Meier survival analysis (Figure 1) revealed significantly lower mortality among the patients who belonged to the highest 50th percentile of memory CD8 cell (CD45RA-,CD45RO+) proportions (P = 0.004). Nadir CD4 count, proviral DNA, and total CD4 and CD8 counts did not influence on mortality.

Multivariate Cox regression (Table 2) confirmed the protective effects of high proportions of memory CD8 cells, with a HR of 0.95 (P = 0.016), reflecting that a one percentage-point increase in CD8+CD45RO+CD45RA- T cells decreased the relative risk of death during follow up by 5%. The same CD8 subset was borderline significant in the univariate model (HR = 0.97, P = 0.064).

When removing the three deceased patients who died of suicide, alcoholism and AIDS/lymphoma respectively these results remained largely unchanged (Kaplan Meier log rank test: p = 0.0032, multivariate Cox regression: HR = 0.944, p = 0.019).

Age was a significant factor in several of the multivariate models with HR = 1.07−1.08, but none of the chosen adjusting factors were univariately significant.

Discussion

The present study exclusively included patients who had immunological studies done during fully suppressive cART and followed them for more than 10 years. The main findings were i) a high level of memory CD8+ T cells, defined as CD45RA-CD45RO+, was an independent predictor of increased overall survival and ii) immune activation defined as proportions of CD4+HLA-DR+ and CD8+HLA-DR+CD38+ showed no prognostic value.

The causes of death among the subjects in the present study are largely consistent with those found in a Danish nationwide study of patients who were virally suppressed for more than 3 years, in which the primary causes of death were cancer, sudden death of unspecified cause, and liver disease, and very few deaths were due to AIDS related illness [22]. A large multicenter, multinational study reported 435 deaths in 11,593 HIV-infected and found similarly only 10% of death related to AIDS defining disease, primarily non-Hodgkin lymphoma, and 21% related to non-AIDS cancers, 9% cardiovascular disease, and 9% liver disease [23].

It is generally accepted that CD8 T cells play a role in controlling untreated HIV infection, but the exact role of CD8 cells displaying memory phenotype (CD45RA-CD45RO+) is only incompletely understood during cART.

As the CD8+CD45RA-CD45RO+ subset in this study is not sub-characterized further, the specific subtype and function cannot be determined, and the subset most likely represents a mixture of early, antigen experienced CD8 cells, including central memory, effector memory and HIV specific CD8 cells (CD45RA+/−CD28-CD27+CCR7-) with specific cytokine releasing properties [24], [25]. Therefore it is not possible to conclude from these data which subtype of memory CD8 T cells is associated with reduced mortality.

In accordance with the present results we have previously reported a protective effect of high CD8+CD45RA-CD45RO+ levels among untreated patients [26]. However a recent study found no prognostic value of central memory CD8 T cells defined as CD45RO+CD28+CCR7+CCR5- in treatment naïve patients, but a decreased risk of disease progression and death with higher levels of CD127+ CD8 T cells [27] that are important for homeostasis of T cells and differentiation into memory CD8 phenotype [28], [29].

Our results failed to demonstrate the expected positive association between early immune activation and all-cause mortality. High levels of CD4 and CD8 cells expressing the activation markers CD38 and HLA-DR did not show any prognostic value.

Most previous studies that have shown prognostic value of cellular immune activation markers differ from this study in that they primarily included treatment naïve patients as well as treated patients, were cross sectional or with shorter follow up periods.

A study from Uganda recently showed that higher proportions of CD8+CD38+HLA-DR+ T cells six months after initiation of successful treatment was an independent predictor of increased mortality, but the same subset pre-cART had no significant impact [30]. However, the samples were taken earlier after cART at a time when pre-cART immune activation could still be declining, the follow up was shorter, and the mortality significantly higher suggesting differences in causes of death and the frequency of co-infections i.e. tuberculosis.

It has been suggested that even in the well controlled cART treated HIV infection the immune system has similarities to that of old people and it has further been suggested that these changes formed the basis for the morbidity and mortality observed [31]. These changes include poor T-cell regeneration, elevated levels of activated CD38+HLA-DR+ T cells and accumulation terminally differentiated CD8 memory cells [32][34]. We did find that those who died during follow-up had fewer naïve cells - significantly different for CD4 cell and borderline for CD8 cells (Table 1) – but these findings were not significant in survival analysis, and neither immune activation nor expansion of CD8 cell subsets were associated with increased risk of death.

The strengths of this study are the un-interrupted, long-term treatment of the patients, a very long observation period combined with the accessibility of data on T cell subsets during cART. The weaknesses are the relatively small number of patients and the broad definitions of T cell subsets, primarily due to the limited amount of colors available for flowcytometry at the time, and the absence of data on the functional properties of the cells. Due to these factors the presented data should be interpreted with caution.

In summary, the study demonstrated a significant survival benefit of high levels of CD8+CD45RO+CD45RA- T cells. T cell activation as defined as CD4+HLA-DR+ and activated CD8+ CD38+HLA-DR+ did not show prognostic value in this group of long term viraemically suppressed HIV patients.

Larger and longitudinal studies including more specific T-cell subset analyses such as CD28 and CD57 are needed to accurately establish prognostic factors, but overall the results suggest that prognostic information exists within the CD8 compartment.

Author Contributions

Conceived and designed the experiments: SRO HU TLK JG. Performed the experiments: FFR. Analyzed the data: FFR SRO HU TLK JG. Wrote the paper: FFR.

References

  1. 1. Deeks SG (2010) HIV Infection, Inflammation, Immunosenescence, and Aging. Annu Rev Med. SG Deeks2010HIV Infection, Inflammation, Immunosenescence, and Aging.Annu Rev Med
  2. 2. Desai S, Landay A (2010) Early immune senescence in HIV disease. Curr HIV/AIDS Rep 7: 4–10.S. DesaiA. Landay2010Early immune senescence in HIV disease.Curr HIV/AIDS Rep7410
  3. 3. Fahey JL, Taylor JM, Detels R, Hofmann B, Melmed R, et al. (1990) The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N Engl J Med 322: 166–172.JL FaheyJM TaylorR. DetelsB. HofmannR. Melmed1990The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1.N Engl J Med322166172
  4. 4. Fahey JL, Taylor JM, Manna B, Nishanian P, Aziz N, et al. (1998) Prognostic significance of plasma markers of immune activation, HIV viral load and CD4 T-cell measurements. AIDS 12: 1581–1590.JL FaheyJM TaylorB. MannaP. NishanianN. Aziz1998Prognostic significance of plasma markers of immune activation, HIV viral load and CD4 T-cell measurements.AIDS1215811590
  5. 5. Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, et al. (2003) Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS 17: 1881–1888.MD HazenbergSA OttoBH van BenthemMT RoosRA Coutinho2003Persistent immune activation in HIV-1 infection is associated with progression to AIDS.AIDS1718811888
  6. 6. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, et al. (2008) Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 197: 126–133.PW HuntJ. BrenchleyE. SinclairJM McCuneM. Roland2008Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy.J Infect Dis197126133
  7. 7. Liu Z, Cumberland WG, Hultin LE, Kaplan AH, Detels R, et al. (1998) CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J Acquir Immune Defic Syndr Hum Retrovirol 18: 332–340.Z. LiuWG CumberlandLE HultinAH KaplanR. Detels1998CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency.J Acquir Immune Defic Syndr Hum Retrovirol18332340
  8. 8. Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, et al. (1997) Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol 16: 83–92.Z. LiuWG CumberlandLE HultinHE PrinceR. Detels1997Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression.J Acquir Immune Defic Syndr Hum Retrovirol168392
  9. 9. Battegay M, Nuesch R, Hirschel B, Kaufmann GR (2006) Immunological recovery and antiretroviral therapy in HIV-1 infection. Lancet Infect Dis 6: 280–287.M. BattegayR. NueschB. HirschelGR Kaufmann2006Immunological recovery and antiretroviral therapy in HIV-1 infection.Lancet Infect Dis6280287
  10. 10. Steel A, John L, Shamji MH, Henderson DC, Gotch FM, et al. (2008) CD38 expression on CD8 T cells has a weak association with CD4 T-cell recovery and is a poor marker of viral replication in HIV-1-infected patients on antiretroviral therapy. HIV Med 9: 118–125.A. SteelL. JohnMH ShamjiDC HendersonFM Gotch2008CD38 expression on CD8 T cells has a weak association with CD4 T-cell recovery and is a poor marker of viral replication in HIV-1-infected patients on antiretroviral therapy.HIV Med9118125
  11. 11. Mildvan D, Bosch RJ, Kim RS, Spritzler J, Haas DW, et al. (2004) Immunophenotypic markers and antiretroviral therapy (IMART): T cell activation and maturation help predict treatment response. J Infect Dis 189: 1811–1820.D. MildvanRJ BoschRS KimJ. SpritzlerDW Haas2004Immunophenotypic markers and antiretroviral therapy (IMART): T cell activation and maturation help predict treatment response.J Infect Dis18918111820
  12. 12. Rodger AJ, Fox Z, Lundgren JD, Kuller LH, Boesecke C, et al. (2009) Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis 200: 973–983.AJ RodgerZ. FoxJD LundgrenLH KullerC. Boesecke2009Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection.J Infect Dis200973983
  13. 13. Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, et al. (2004) Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104: 942–947.SG DeeksCM KitchenL. LiuH. GuoR. Gascon2004Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load.Blood104942947
  14. 14. Hunt PW (2003) T cell activation is associated with lower CD4+ cell gains in human immudeficiency virus-infected patientswith sustained viral supression during antiretroviral therapy. J Infect Dis 1534–1543. PW Hunt2003T cell activation is associated with lower CD4+ cell gains in human immudeficiency virus-infected patientswith sustained viral supression during antiretroviral therapy.J Infect Dis 1534–1543
  15. 15. Katzenstein TL, Ullum H, Roge BT, Wandall J, Dickmeiss E, et al. (2003) Virological and immunological profiles among patients with undetectable viral load followed prospectively for 24 months. HIV Med 4: 53–61.TL KatzensteinH. UllumBT RogeJ. WandallE. Dickmeiss2003Virological and immunological profiles among patients with undetectable viral load followed prospectively for 24 months.HIV Med45361
  16. 16. Ostrowski SR, Katzenstein TL, Thim PT, Pedersen BK, Gerstoft J, et al. (2005) Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy. J Infect Dis 191: 348–357.SR OstrowskiTL KatzensteinPT ThimBK PedersenJ. Gerstoft2005Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy.J Infect Dis191348357
  17. 17. Ostrowski SR, Katzenstein TL, Pedersen BK, Gerstoft J, Ullum H (2008) Residual viraemia in HIV-1-infected patients with plasma viral load <or = 20 copies/ml is associated with increased blood levels of soluble immune activation markers. Scand J Immunol 68: 652–660.SR OstrowskiTL KatzensteinBK PedersenJ. GerstoftH. Ullum2008Residual viraemia in HIV-1-infected patients with plasma viral load <or = 20 copies/ml is associated with increased blood levels of soluble immune activation markers.Scand J Immunol68652660
  18. 18. Mens H, Pedersen AG, Jorgensen LB, Hue S, Yang Y, et al. (2007) Investigating signs of recent evolution in the pool of proviral HIV type 1 DNA during years of successful HAART. AIDS Res Hum Retroviruses 23: 107–115.H. MensAG PedersenLB JorgensenS. HueY. Yang2007Investigating signs of recent evolution in the pool of proviral HIV type 1 DNA during years of successful HAART.AIDS Res Hum Retroviruses23107115
  19. 19. Ostrowski SR, Ullum H, Pedersen BK, Gerstoft J, Katzenstein TL (2005) 2B4 expression on natural killer cells increases in HIV-1 infected patients followed prospectively during highly active antiretroviral therapy. Clin Exp Immunol 141: 526–533.SR OstrowskiH. UllumBK PedersenJ. GerstoftTL Katzenstein20052B4 expression on natural killer cells increases in HIV-1 infected patients followed prospectively during highly active antiretroviral therapy.Clin Exp Immunol141526533
  20. 20. Ostrowski SR, Katzenstein TL, Thim PT, Pedersen BK, Gerstoft J, et al. (2005) Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy. J Infect Dis 191: 348–357.SR OstrowskiTL KatzensteinPT ThimBK PedersenJ. Gerstoft2005Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy.J Infect Dis191348357
  21. 21. Katzenstein TL, Ullum H, Roge BT, Wandall J, Dickmeiss E, et al. (2003) Virological and immunological profiles among patients with undetectable viral load followed prospectively for 24 months. HIV Med 4: 53–61.TL KatzensteinH. UllumBT RogeJ. WandallE. Dickmeiss2003Virological and immunological profiles among patients with undetectable viral load followed prospectively for 24 months.HIV Med45361
  22. 22. Engsig FN, Gerstoft J, Kronborg G, Larsen CS, Pedersen G, et al. (2010) Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: a cohort study. BMC Infect Dis 10: 318.FN EngsigJ. GerstoftG. KronborgCS LarsenG. Pedersen2010Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: a cohort study.BMC Infect Dis10318
  23. 23. Lifson AR, Belloso WH, Carey C, Davey RT, Duprez D, et al. (2008) Determination of the underlying cause of death in three multicenter international HIV clinical trials. HIV Clin Trials 9: 177–185.AR LifsonWH BellosoC. CareyRT DaveyD. Duprez2008Determination of the underlying cause of death in three multicenter international HIV clinical trials.HIV Clin Trials9177185
  24. 24. Appay V, van Lier RA, Sallusto F, Roederer M (2008) Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A 73: 975–983.V. AppayRA van LierF. SallustoM. Roederer2008Phenotype and function of human T lymphocyte subsets: consensus and issues.Cytometry A73975983
  25. 25. Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22: 745–763.F. SallustoJ. GeginatA. Lanzavecchia2004Central memory and effector memory T cell subsets: function, generation, and maintenance.Annu Rev Immunol22745763
  26. 26. Ostrowski SR, Gerstoft J, Pedersen BK, Ullum H (2003) A low level of CD4+CD28+ T cells is an independent predictor of high mortality in human immunodeficiency virus type 1-infected patients. J Infect Dis 187: 1726–1734.SR OstrowskiJ. GerstoftBK PedersenH. Ullum2003A low level of CD4+CD28+ T cells is an independent predictor of high mortality in human immunodeficiency virus type 1-infected patients.J Infect Dis18717261734
  27. 27. Ganesan A, Chattopadhyay PK, Brodie TM, Qin J, Gu W, et al. (2010) Immunologic and virologic events in early HIV infection predict subsequent rate of progression. J Infect Dis 201: 272–284.A. GanesanPK ChattopadhyayTM BrodieJ. QinW. Gu2010Immunologic and virologic events in early HIV infection predict subsequent rate of progression.J Infect Dis201272284
  28. 28. Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, et al. (2003) Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol 4: 1191–1198.SM KaechJT TanEJ WherryBT KoniecznyCD Surh2003Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.Nat Immunol411911198
  29. 29. Crawley AM, Angel JB (2011) Expression of gamma-chain cytokine receptors on CD8(+) T cells in HIV infection with a focus on IL-7Ralpha (CD127). Immunol Cell Biol. AM CrawleyJB Angel2011Expression of gamma-chain cytokine receptors on CD8(+) T cells in HIV infection with a focus on IL-7Ralpha (CD127).Immunol Cell Biol
  30. 30. Hunt PW, Cao HL, Muzoora C, Ssewanyana I, Bennett J, et al. (2011) Impact of CD8+ T Cell Activation on CD4+ T Cell Recovery and Mortality in HIV-infected Ugandans Initiating Antiretroviral Therapy. AIDS. PW HuntHL CaoC. MuzooraI. SsewanyanaJ. Bennett2011Impact of CD8+ T Cell Activation on CD4+ T Cell Recovery and Mortality in HIV-infected Ugandans Initiating Antiretroviral Therapy.AIDS
  31. 31. Deeks SG (2010) HIV Infection, Inflammation, Immunosenescence, and Aging. Annu Rev Med. SG Deeks2010HIV Infection, Inflammation, Immunosenescence, and Aging.Annu Rev Med
  32. 32. Pawelec G, Larbi A, Derhovanessian E (2010) Senescence of the human immune system. J Comp Pathol 142: S39–S44.G. PawelecA. LarbiE. Derhovanessian2010Senescence of the human immune system.J Comp Pathol142S39S44
  33. 33. Kalayjian RC, Landay A, Pollard RB, Taub DD, Gross BH, et al. (2003) Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: association of age and HIV infection with naive CD8+ cell depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic volumes. J Infect Dis 187: 1924–1933.RC KalayjianA. LandayRB PollardDD TaubBH Gross2003Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: association of age and HIV infection with naive CD8+ cell depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic volumes.J Infect Dis18719241933
  34. 34. Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, et al. (2000) Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev 121: 187–201.J. OlssonA. WikbyB. JohanssonS. LofgrenBO Nilsson2000Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study.Mech Ageing Dev121187201