Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease.

Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
PLoS ONE (Impact Factor: 3.53). 01/2010; 5(1):e8886. DOI: 10.1371/journal.pone.0008886
Source: PubMed

ABSTRACT In healthy, HIV seronegative, CMV seropositive adults, a large proportion of T cells are CMV-specific. High-level CMV-specific T cell responses are associated with accelerated immunologic aging ("immunosenesence") in the elderly population. The impact of untreated and treated HIV infection on the frequency of these cells remains undefined.
We measured the proportion of CD4+ and CD8+ T cells responding to CMV pp65 and IE proteins was measured using flow cytometry in 685 unique HIV seronegative and seropositive individuals. The proportion of CMV-specific CD8+ T cells was consistently higher in the HIV-seropositive subjects compared to the HIV-seronegative subjects. This HIV effect was observed even in patients who lacked measurable immunodeficiency. Among the HIV-seropositive subjects, CMV-specific CD8+ T cell responses were proportionately lower during recent infection, higher during chronic untreated infection and higher still during long-term antiretroviral treated infection. The CD8+ T cell response to just two CMV proteins (pp65 and IE) was approximately 6% during long-term therapy, which was over twice that seen in HIV-seronegative persons. CMV-specific CD4+ T cell responses followed the same trends, but the magnitude of the effect was smaller.
Long-term successfully treated HIV infected patients have remarkably high levels of CMV-specific effector cells. These levels are similar to that observed in the elderly, but occur at much younger ages. Future studies should focus on defining the potential role of the CMV-specific inflammatory response in non-AIDS morbidity and mortality, including immunosenescence.

  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: HIV-infection is characterized by aberrant immune activation and ongoing inflammation. Markers of inflammation are now recognized to have prognostic value for adverse events, independent of viral loads and CD4 counts. This study aimed to delineate a panel of affordable markers of immune activation in untreated HIV-infection that may have an impact on the management of HIV in resource-limited settings. METHODS: This was a cross-sectional study of 86 untreated newly diagnosed HIV-infected patients and 54 matched controls attending a voluntary testing clinic in Cape Town, South Africa. Serum levels of adenosine deaminase (ADA), total immunoglobulin G (IgG), soluble CD14 and lipopolysaccharide-binding protein (LBP) were measured and correlated with CD4 counts, viral loads and expression of CD38 on CD8+ T cells. RESULTS: ADA, IgG and LBP were all significantly increased in the HIV infected group (p < 0.0001) compared with uninfected controls. Soluble CD14 was also significantly increased (p = 0.0187). Furthermore, all these parameters correlated inversely with CD4 counts (r = -0.481 p < 0.0001; r = -0.561; p < 0.0001; r = -0.387 p = 0.0007 and r = -0.254 p = 0.0240, respectively). Only ADA correlated with viral load (r = 0.260 p = 0.0172). Importantly, ADA, IgG and LBP correlated directly with %CD38 on CD8+ T cells (r = 0.369 p < 0.0001; r = 0.284 p = 0.001; r = 0.408 p = 0.0006, respectively). CONCLUSION: Affordable parameters such as serum ADA and IgG correlated significantly with immune activation levels and markers of disease progression in untreated HIV-infection and therefore may add value to the management of these patients in resource-limited settings.
    Journal of Clinical Immunology 11/2012; · 3.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Persistent immune activation and inflammation despite sustained antiretroviral therapy (ART)-mediated viral suppression has emerged as a major challenge of the modern HIV treatment era. While immune activation, inflammatory, and coagulation markers typically decline during suppressive ART, they remain abnormally elevated in many HIV-infected individuals and predict subsequent mortality and non-AIDS morbidities including cardiovascular disease. The goal of this review is to summarize the current state of our knowledge regarding the underlying causes of persistent immune activation during ART-mediated viral suppression as well as the link between persistent immune activation and morbidity and mortality in this setting. Several recent studies have linked surrogate markers of this persistent inflammatory state to clinical outcomes, validating persistent immune activation as a viable therapeutic target. Other recent studies have helped clarify the roles of persistent HIV expression and/or replication, microbial translocation, and co-infections in driving this persistent inflammatory state, identifying targets for novel interventions.
    Current HIV/AIDS Reports 04/2012; 9(2):139-47.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Restoration of Cytomegalovirus-specific-CD4 T cell (CMV-Sp-CD4) responses partly accounts for the reduction of CMV-disease with antiretroviral-therapy (ART), but CMV-Sp-CD4 may also drive immune activation and immunosenescence. This study characterized the dynamics of CMV-Sp-CD4 after ART initiation and explored associations with CD4 T cell recovery as well as frequency of naïve CD4 T cells at week 96. Fifty HIV-infected, ART-naïve Thai adults with CD4 T cell count ≤350cells/µL and starting ART were evaluated over 96 weeks ( identifier NCT01296373). CMV-Sp-CD4 was detected by co-expression of CD25/CD134 by flow cytometry after CMV-antigen stimulation. All subjects were CMV sero-positive, 4 had quantifiable CMV-DNA (range 2.3-3.9 log10 copies/mL) at baseline but none had clinically apparent CMV-disease. Baseline CMV-Sp-CD4 response was positive in 40 subjects. Those with CD4 T cell count <100cells/µL were less likely to have positive baseline CMV-Sp-CD4 response (P=0.003). Positive baseline CMV-Sp-CD4 response was associated with reduced odds of quantifiable CMV-DNA (P=0.022). Mean CD4 T cell increase at week 96 was 213 cells/µL. This was associated positively with baseline HIV-VL (P=0.001) and negatively with age (P=0.003). The frequency of CMV-Sp-CD4 increased at week 4 (P=0.008), then declined. Those with lower baseline CMV-Sp-CD4 (P=0.009) or CDC category C (P<0.001) had greater increases in CMV-Sp-CD4 at week 4. At week 96, CD4 T cell count was positively (P<0.001) and the frequency of CMV-Sp-CD4 was negatively (P=0.001) associated with the percentage of naïve CD4 T cells. Increases in CMV-Sp-CD4 with ART occurred early and were greater in those with more advanced immunodeficiency. The frequency of CMV-Sp-CD4 was associated with reduced naïve CD4 T cells, a marker associated with immunosenescence.
    PLoS ONE 01/2013; 8(10):e77479. · 3.53 Impact Factor

Full-text (3 Sources)

Available from
May 26, 2014