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: 3.23). 01/2010; 5(1):e8886. DOI: 10.1371/journal.pone.0008886
Source: PubMed


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.

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    • "CMV, a ubiquitous herpes virus, establishes a lifelong latent infection in humans [31],[32]. Naeger et al found that CMV-specific CD8+ T-cell responses are high in successfully treated HIV-positive patients [33]. Interestingly, CMV prevalence was highest among Group I and Group II patients. "
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    ABSTRACT: Successful combination antiretroviral therapy (cART) increases levels of CD4+ T-cells, however this increase may not accurately reflect long-term immune recovery since T-cell dysregulation and loss of T-cell homeostasis often persist. We therefore assessed the impact of a decade of effective cART on immune regulation, T-cell homeostasis, and overall T-cell phenotype. We conducted a retrospective study of 288 HIV+ cART-naïve patients initiating therapy. We identified 86 individuals who received cART for at least a decade, of which 44 consistently maintained undetectable plasma HIV-RNA levels throughout therapy. At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4<200 cells/mm3); Group II (CD4: 200-350 cells/mm3); Group III (CD4>350 cells/mm3). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm3); (2) normalization of CD4:CD8 T-cell ratio (1.2-3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%-85% of peripheral lymphocytes); (4) normalization of the complete T-cell phenotype (TCP). Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm3). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio. Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count <200 cells/mm3. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated.
    PLoS ONE 04/2014; 9(4):e94018. DOI:10.1371/journal.pone.0094018 · 3.23 Impact Factor
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    • "After resolution of acute infection, a T cell activation ''steady state'' is achieved that is predicted in part by degree of HIV replication and innate immune responses (Chevalier et al., Immunity 39, October 17, 2013 ª2013 Elsevier Inc. 633 2013; Deeks et al., 2004). Decades of intense research into this phenomenon has led to a number of conclusions regarding the potential root causes of inflammation: (1) HIV replication contributes directly to T cell activation (however, the frequency of HIVspecific T cells is only a small proportion of the activated cell population, suggesting other less-direct mechanisms) (Papagno et al., 2004); (2) other pathogens—including common herpes viruses such as CMV—contribute to high level T cell activation, although why the percentage of antigen-specific T cells is dramatically elevated is not known (Doisne et al., 2004; Naeger et al., 2010; Smith et al., 2013; Wittkop et al., 2013); (3) HIV-mediated breakdown in the gut mucosa and chronic exposure to gut microbial products like lipopolysaccharide (LPS) is also a key factor driving inflammation (Brenchley et al., 2006); and (4) dysfunctional immunoregulatory factors probably contribute to persistent inflammation. This chronic inflammatory environment appears to cause fibrosis in lymphoid tissues, which in turn causes CD4 + T cell regenerative failure and disease (Figure 1; Boulware et al., 2011; Schacker et al., 2002; Zeng et al., 2012). "
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    ABSTRACT: Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging.
    Immunity 10/2013; 39(4):633-45. DOI:10.1016/j.immuni.2013.10.001 · 21.56 Impact Factor
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    • "The effect of ART on CMV-Sp-CD4 T cells has not been fully elucidated. The majority of published studies were cross-sectional in design [25,37-39] and those that were longitudinal had widely spaced visit intervals, some over years [24,40]. Comparisons of CMV-Sp-CD4 T cell frequency were made between subgroups with different CMV disease status or across widely different CD4 T cell counts. "
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    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 10/2013; 8(10):e77479. DOI:10.1371/journal.pone.0077479 · 3.23 Impact Factor
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