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Nadir Cd4 Count May Predict Immunity: Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection
  AIDS 2003; 17(14):2015-2023
Christoph G. Lange; Michael M. Lederman; Kathy Medvik; Robert Asaad; Mary Wild a; Robert Kalayjian a; Hernan Valdez
From the Center for AIDS Research, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, and aMetroHealth Medical Center, Cleveland, Ohio, USA.
Objective: To ascertain whether delaying the initiation of highly active antiretroviral therapy (HAART) compromises functional immune reconstitution in HIV-1 infection in persons who regain 'normal' CD4 T-cell counts after suppressive antiretroviral therapies.
Design: Prospective open-label study carried out at two University-affiliated HIV-outpatient clinics in the USA.
Subjects and methods: Response to immunization was used as a model for in vivo functional immune competence in 29 HIV-1 infected patients with CD4 T-cell counts > 450 x 106cells/l and HIV-RNA < 400 copies/ml for > 12 months after HAART and nine HIV-1 seronegative controls. After immunization with tetanus toxoid, diphtheria-toxoid, and keyhole limpet hemocyanin, immune response scores (IRS) were calculated using postimmunization antibody concentrations, lymphocyte proliferation, and delayed-type hypersensitivity responses to vaccine antigens.
Results: Despite normal numbers of circulating CD4 T-cells, the CD4 T-cell nadir before HAART initiation predicted the immune response to immunization ([rho] = 0.5; P < 0.005) while current CD4 T-cell count did not. Likewise, CD4 T-lymphocyte expression of the co-stimulatory molecule CD28 was also an independent predictor of response to immunization ([rho] = 0.5; P < 0.005).
Conclusions: Even among persons who controlled HIV replication and normalized CD4 T-cell counts with HAART, pretreatment CD4 T-cell count and numbers of circulating CD4+CD28+ T-cells at immunization, but not current CD4 T-cell count, predict the ability to respond to vaccination. Delaying the initiation of HAART in chronic HIV-1 infection results in impaired functional immune restoration despite normalization of circulating CD4 T-cell numbers.
Using a model of in vivo immune response to immunization challenge, we analyzed functional and phenotypic indicators of immune recovery in patients with chronic HIV-1 infection who initiated suppressive antiretroviral therapies at a broad range of CD4 T-cell count nadirs and who experienced 'normalization' of circulating CD4 T-cell numbers thereafter.
In contrast to previous investigations that compared the pretreatment CD4 T-cell nadir and immune-phenotype and -function in the response to HAART we here performed a comprehensive examination of in vivo immune function, including measurement of antibody concentrations, LP and DTH, in response to vaccination with recall antigens and a presumed neo-antigen. We found that analyses of responses to immunization can discriminate functional differences in immune status even in persons with comparable circulating CD4 T-cell counts. HAART-treated patients with normal CD4 T-lymphocyte counts exhibited a broad range of responses to immunization. These responses to immunization could be predicted by the number or percentage of CD4 T lymphocytes co-expressing CD28 at the time of immunization and by the nadir pretreatment CD4 T-cell count. Our results suggest that even when CD4 T-cell counts have 'normalized' prior immune decline determines current immune competence. Changes in the immune phenotype persist in HIV-1 infected patients even after years of suppressive antiviral therapy.
It should be noted that we studied a highly selected group of chronically HIV-1 infected patients, each of whom had a very favorable and durable response to antiretroviral treatment and an associated normalization of CD4 T-cell counts. Thus in an unselected patient population who initiate HAART, even more profound effects of CD4 T-cell nadir on functional restoration might be expected. Whether longer duration of suppressive therapy will result in greater enhancement of functional immune reserve remains to be determined.
While CD4 T-cell counts provide an indicator of immune competence in HIV disease, reasonably predicting short-term risk for opportunistic infection, the relationship between CD4 T-cell nadir and functional immune competence is incompletely understood. Several cross-sectional studies and a recently reported collaborative analysis of 13 prospective cohort studies show that delaying antiretroviral therapy is associated with a greater risk of opportunistic infection and death [34]. In these studies CD4 T-cell counts at the time of infection or deaths have not been reported.
Our results are in agreement with earlier studies that failed to show normalization of antibody and cellular responses to immunization in HIV-1 infected patients with moderately advanced disease. We show here a linear relationship between the immune response scores and the nadir CD4 T-cell count suggesting that functional immune restoration is attenuated by prior depletion of the CD4 T-cell pool without an apparent threshold for complete immune reconstitution. Whether such a threshold exists should be determined in prospective studies enrolling larger numbers of patients.
Complete normalization of lymphocyte phenotoypes was not achieved in these successfully treated patients as numbers of circulating CD4+CD45RA+CD62L+ naive T-cells and CD4 T-cells expressing the CD28 co-receptor for activation were lower and numbers of circulating CD8 T-cells and CD8 HLA-DR+, CD38+ activated T-cells were elevated in patients when compared to HIV-1 seronegative persons. Ongoing activation of CD8 T-cells and lower numbers of naïve CD4 T-cells were observed in HIV infected individuals regardless of the CD4 T-cell nadir and there was no relationship among the numbers of HLA-DR+, CD38+CD8+ T-cells and CD4+CD45RA+ CD62L+ T-cells or the IRS. Since naive T-cell restoration may be delayed yet persistent, the on-treatment period in this study may have been insufficient to permit 'complete' naive T-cell reconstitution. Longer duration of follow-up in these patients will be needed to learn if subclinical immune deficiency persists and predicts long-term morbidities or if it progressively normalizes.
CD28 expression on CD4 T-cells is diminished in untreated HIV-1 infection and failure of co-stimulation through this receptor may contribute to decreased lymphocyte proliferation and anergy after T-cell receptor engagement. Cellular proliferation is a critical factor in immunization responses. We have demonstrated earlier a profound defect in proliferation after T-cell receptor engagement among CD4 and CD8 T-cells in HIV infection that is also predicted by CD4 T-cell nadir and is at least in part related to diminished CD28 expression (S.F. Sieg and M.M. Lederman, unpublished data).
Sustained suppression of viral replication results in increases in the frequency of CD28 expression. Here we confirmed a previous finding of our group that CD28 expression on CD4 T-cells is an important predictor of the ability to respond to immunization in HIV-1 infection. We suspect, therefore, that proliferation failure of T-cells in HIV disease, in part related to diminished expression of CD28, is an important determinant of suboptimal responses to immunization. Our results suggest that quantification of CD28 expression on CD4 T-cells may be superior to the enumeration of absolute circulating CD4 T-cells alone as a surrogate marker of the functional immune status in HIV-1 infected patients.
It remains unclear why the numbers of activated CD8 T-cells expressing HLA-DR and CD38 do not return to normal levels despite longstanding suppression of viral replication. Whether this activation state is sustained by low level viral replication or whether the activation and survival of these cells persists without antigen exposure needs to be further explored.
We here show that even after normalization of CD4 T-lymphocyte numbers, in vivo immune function as measured by responses to immunization is significantly impaired in persons who delayed therapy initiation. Although this study was not designed primarily to evaluate the optimal timing of treatment initiation in chronic HIV-1 infection, our data suggest that delaying treatment significantly increases the risk of a persistent functional immune defect. Our data demonstrate that even in those persons who normalize CD4 T-cell numbers and are largely protected from opportunistic infection, immune deficits persist.
Interpretation of our results is limited in several ways. Detailed pretreatment phenotypic and functional analyses were not available. Only patients with longstanding suppression of viral replication and 'normalization' of CD4 T-cell counts (> 450 x 106/l) on HAART were included in the study and only a fraction of the patients with low CD4 T-cell nadirs were likely to reach a CD4 T-cell count > 450 x 106/l permitting inclusion in this study. In this regard our findings probably underestimate the magnitude of the persistent immune defect attributable to delayed treatment initiation. Since persons with CD4 T-cell restoration on HAART have to date been protected from major AIDS-defining complications, the long-term clinical relevance of a persistent partial immune deficiency remains to be determined. The clinical significance of our findings regarding decisions for the timing of treatment initiation is therefore unclear.
In summary, we found that even in persons with longstanding suppression of viral replication who achieve normalization of circulating CD4 T-cell counts, functional immune-reconstitution is incomplete in patients who start HAART at more advanced stages of HIV-1 infection. Complete functional immune reconstitution is progressively attenuated by CD4 T-cell depletion prior to the initiation of HAART and is also predicted by the expression of the CD28 co-receptor for T-cell activation on CD4 T-lymphocytes. Thus, delay in initiation of therapy results in impaired functional immune restoration. The long-term consequences of persistent subclinical immune deficiency in this setting are not known and should be monitored prospectively.
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