1 Medical Clinic, Research Center Borstel, Medical University of Lübeck, Parkallee 35, 23845 Borstel, Germany; 2 Center for AIDS Research, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, OH, USA
Keywords: HIV, HAART, immune reconstitution
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Introduction |
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Restoration of the circulating CD4+ T-cell pool on ART |
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Restoration of the immune phenotype on ART is often incomplete, particularly if treatment initiation is delayed |
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Immune phenotypes in HIV disease may predict both outcome of infection and in vivo immune competence. As examples, expression of the activation marker CD38 on CD8+ T-cells is correlated with HIV RNA levels but may be a better predictor of disease outcome than plasma HIV RNA.10 CD28 is a critical co-receptor for T-cell activation that facilitates appropriate cellular activation after exposure to antigen.11 HIV infection is associated with diminished numbers, and proportions of CD4+ and CD8+ T-cells expressing CD28 and diminished CD28 levels predict a poor in vivo response to immunization in HIV infection.12
We recently investigated the effect of longstanding continuous suppression of viral replication on the restoration of the immune phenotype in HIV-infected patients treated with ART.13 We found that even patients who were able to normalize the numbers of circulating CD4+ T-cells after 3 years of therapy did not normalize numbers of memory-phenotype CD4+ T-cells or numbers of CD4+ T-cells co-expressing CD28. Additionally, numbers of CD8+ T-cells expressing HLA DR and CD38 remained elevated in persons who initiated ART at advanced stages of HIV-1 infection. Importantly, among these patients with excellent virological and numerical CD4+ T-cell responses to antiretroviral treatment for HIV-1 infection, the likelihood of more complete phenotypic normalization was directly correlated to the CD4+ T-cell count before initiation of ART. In a prospective study, AIDS Clinical Trials Group Protocol 375, patients with advanced HIV infection and suppressed viral replication were observed for a period of 3 years following the initiation of ART.14 Almost all immune restoration that was achieved in these patients with advanced disease occurred during the first year of therapy, whereas CD4+ T-cell rises in the peripheral blood during the second and third year were not significant. Although other patient groups have had better CD4 T-cell increases,15 the ACTG 375 group participants also had an extensive phenotypic examination, and in these subjects, normalization of CD28 expression on CD4+ T-cells and HLA DR CD38 expression on CD8+ T-cells was not achieved during the study period. The kinetics of the restoration of the immune phenotype as observed in these persons suggest that normalization of immune phenotypes may not be achieved by ART alone if therapy is initiated in advanced stages of HIV infection.
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Functional immune restoration depends upon timing of treatment initiation |
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We recently analysed a comprehensive panel of functional immune responses in a group of chronically HIV-1-infected patients with favourable responses to ART. Twenty-nine HIV-1-infected patients with ART-induced suppression of viral replication <400 copies/mL and normal CD4+ T-cell counts (median 730 cells/mm3) who started ART at a broad range of CD4+ T-cell nadirs (0618 cells/mm3) were included in this study.17 We used a new scoring system to summarize responses to immunization by measuring antibody titres, lymphoproliferation and delayed-type hypersensitivity skin reactions to the vaccine antigens. Patients with the lower pre-treatment CD4+ T-cell nadirs had diminished responses to immunization despite normal CD4+ T-cell numbers. The functional immune response score was significantly correlated with the pre-treatment CD4+ T-cell nadir and the number of CD28+ CD4+ T-cells at the time of immunization, but not to the current CD4+ T-cell count.
These results indicate that both phenotypic and functional immune restoration remain incomplete with currently available treatment regimes despite normalization of circulating CD4+ T-cell counts if initiation of ART is delayed. From a more clinical perspective, a collaborative analysis of 13 prospective cohort studies found that delaying ART as CD4+ T-cells fall is associated with a greater risk of opportunistic infection and death.18
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How much immune reconstitution is enough? |
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Restoration of HIV-1-specific immunity on ART |
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There is recent evidence that an effective endogenous HIV-1-specific T-cell immunity may be preserved with therapeutic interventions very early in the course of HIV-1 infection.29 As HIV-specific CD4+ T-cells are preferentially infected by HIV in vivo,30 immunological control of HIV decreases with ongoing viral replication. Persistence of an effective HIV-1-specific immunity does not appear to be common in persons who start ART in more advanced stages of the disease.
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Conclusions |
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Acknowledgements |
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Footnotes |
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References |
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