Determinants of Restoration of CD4 and CD8 Cell Counts and Their Ratio in HIV-1–Positive Individuals With Sustained Virological Suppression on Antiretroviral Therapy

Gras, Luuk; May, Margaret T; Ryder, Lars P.; Trickey, Adam; Helleberg, Marie; Obel, Niels; Thiébaut, Rodolphe; Guest, Jodie L; Gill, John; Crane, Heidi M.; Lima, Viviane D.; Monforte, Antonella d’Arminio; Sterling, Timothy R.; Miró, José M.; Moreno, Santiago; Stephan, Christoph; Smith, Colette; Tate, Janet P.; Shepherd, Leah; Saag, M; Rieger, Armin; Gillor, Daniel; Cavassini, Matthias; Montero, Marta; Ingle, Suzanne M; Reiss, Peter; Costagliola, Dominique; Wit, Ferdinand W. N. M.; Sterne, Jonathan A C; Wolf, Frank de; Geskus, Ronald B.

doi:10.1097/qai.0000000000001913

Cited by 28 publications

(37 citation statements)

References 44 publications

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“…In the general population an association between older age and inverted CD4+/CD8+ ratio <1 has been reported, and inverted CD4+/CD8+ ratio has been associated with altered T-cell subsets ( 41 ). In PWH, the CD4+/CD8+ ratio often remains inverted due to persistent high CD8+ T-cell count even in persons with early treatment start ( 42 ). CMV infection may contribute to CD8+ T-cell expansion and subsequently an inverted CD4+/CD8+ ratio, and high CMV seroprevalence has been described both in PWH and older uninfected persons ( 42 – 44 ).…”

Section: Discussionmentioning

confidence: 99%

“…In PWH, the CD4+/CD8+ ratio often remains inverted due to persistent high CD8+ T-cell count even in persons with early treatment start ( 42 ). CMV infection may contribute to CD8+ T-cell expansion and subsequently an inverted CD4+/CD8+ ratio, and high CMV seroprevalence has been described both in PWH and older uninfected persons ( 42 – 44 ). In our study, a CD4+/CD8+ ratio <1 was associated with having elevated proportion of CD8+ activated, CD4+ and CD8+ senescent, and CD4+ and CD8+ apoptotic T-cells in PWH.…”

Section: Discussionmentioning

confidence: 99%

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Impact of Age and HIV Status on Immune Activation, Senescence and Apoptosis

et al. 2020

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Introduction: Residual immune dysfunctions, resembling those that occur during normal aging, may persist even in well-treated people with HIV (PWH), and accelerated aging has been proposed. We aimed to determine if HIV infection is an independent risk factor for T-cell immune dysfunctions including increased immune activation, senescence and apoptosis. Moreover, in PWH we aimed to identify the associations between age and immune activation, senescence and apoptosis. Materials and Methods: We included 780 PWH with suppressed viral replication (<50 copies/mL) and absence of hepatitis B and hepatitis C co-infection and 65 uninfected controls from the Copenhagen Co-morbidity in HIV Infection (COCOMO) Study. Flow cytometry was used to determine T-cell activation (CD38+HLA-DR+), senescence (CD28-CD57+), and apoptosis (CD28-CD95+). T-cell subsets are reported as proportions of CD4+ and CD8+ T-cells. We defined an elevated proportion of a given T-cell subset as above the 75th percentile. Regression models were used to determine the association between HIV status and T-cell subset and in PWH to determine the association between age or HIV-specific risk factors and T-cell subsets. Furthermore, an interaction between HIV status and age on T-cell subsets was investigated with an interaction term in models including both PWH and controls. Models were adjusted for age, sex, BMI, and smoking status. Results: In adjusted models a positive HIV status was associated with elevated proportions of CD8+ activated (p = 0.009), CD4+ senescent (p = 0.004), CD4+ apoptotic (p = 0.002), and CD8+ apoptotic (p = 0.003) T-cells. In PWH a 10-year increase in age was associated with higher proportions of CD4+ and CD8+ senescent (p = 0.001 and p < 0.001) and CD4+ and CD8+ apoptotic T-cells (p < 0.001 and p < 0.001). However, no interaction between HIV status and age was found.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impact of Age and HIV Status on Immune Activation, Senescence and Apoptosis

et al. 2020

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“…Importantly, HIV-associated changes in circulating T cell numbers may also persist despite ART. This includes incomplete reversal of CD4 T cell depletion (25) and relatively elevated numbers of CD8 T cell counts (26,27) leading to a low CD4:CD8 ratio as a persistent immunological hallmark of PLHIV (28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

Persistent T Cell Repertoire Perturbation and T Cell Activation in HIV After Long Term Treatment

et al. 2021

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ObjectiveIn people living with HIV (PLHIV), we sought to test the hypothesis that long term anti-retroviral therapy restores the normal T cell repertoire, and investigate the functional relationship of residual repertoire abnormalities to persistent immune system dysregulation.MethodsWe conducted a case-control study in PLHIV and HIV-negative volunteers, of circulating T cell receptor repertoires and whole blood transcriptomes by RNA sequencing, complemented by metadata from routinely collected health care records.ResultsT cell receptor sequencing revealed persistent abnormalities in the clonal T cell repertoire of PLHIV, characterized by reduced repertoire diversity and oligoclonal T cell expansion correlated with elevated CD8 T cell counts. We found no evidence that these expansions were driven by cytomegalovirus or another common antigen. Increased frequency of long CDR3 sequences and reduced frequency of public sequences among the expanded clones implicated abnormal thymic selection as a contributing factor. These abnormalities in the repertoire correlated with systems level evidence of persistent T cell activation in genome-wide blood transcriptomes.ConclusionsThe diversity of T cell receptor repertoires in PLHIV on long term anti-retroviral therapy remains significantly depleted, and skewed by idiosyncratic clones, partly attributable to altered thymic output and associated with T cell mediated chronic immune activation. Further investigation of thymic function and the antigenic drivers of T cell clonal selection in PLHIV are critical to efforts to fully re-establish normal immune function.

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“…Other studies classify patients as good or poor responders according to a fixed arbitrary increase in CD4 T cell counts [23]. It is well described that initial counts predict end point ones [5,6]. In contrast to end-point counts, our work studies the net increment in CD4 T cell counts (delta CD4 T cells), which also determines reconstitution.…”

Section: Discussionmentioning

confidence: 97%

“…These patients remain mostly free of opportunistic infections, but they have an increased incidence of non-AIDS defining illnesses [4]. CD4 T cell count at ART initiation is today the most usual predictor of the magnitude of recovery of CD4 T cells under ART [5,6]. It is thus likely that a person with HIV initiating ARV at a late phase of infection will recover CD4 T cells deficiently.…”

Section: Introductionmentioning

confidence: 99%

Machine learning-selected variables associated with CD4 T cell recovery under antiretroviral therapy in very advanced HIV infection

et al. 2020

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Background: A considerable portion of the HIV pandemic is composed of people under antiretroviral therapy, many of whom get a late diagnosis. Patients starting antiretroviral therapy (ART) at a very advanced stage of HIV disease attain a low recovery of CD4 T cells. Factors associated with poor recovery are incompletely described. This study aimed at finding variables associated with CD4 T cell recovery in late-presenting HIV patients. Methods: We studied a cohort of HIV + patients initiating ART with very low basal CD4 T cell counts. We defined immune recovery as the net increase in circulating CD4 T cell counts after one year on ART. We analyzed diverse routine laboratory determinations at different times using Least Absolute Shrinkage and Selection Operator (LASSO), adaptive LASSO and Conditional Inference Random Forest. Results: CD4/CD8 ratio, % CD4 T cells and CD8 T cell counts at different times were the main recovery correlates, validated by all approaches. Unexpectedly, basal hematocrit was a consistent predictor. Additionally, week 24 creatinine had a high lasso coefficient, and alkaline phosphatase had a high conditional inference random forest coefficients, although neither was verified by other tests. Conclusions: CD4 T cell proportions are associated with CD4 T cell recovery, independently of cell counts. Inflammation-related variables could also affect reconstitution. These accessible variables may reflect underlying mechanisms and could improve the follow up of patients starting ART with an advanced HIV infection.

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Determinants of Restoration of CD4 and CD8 Cell Counts and Their Ratio in HIV-1–Positive Individuals With Sustained Virological Suppression on Antiretroviral Therapy

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 28 publications

References 44 publications

Impact of Age and HIV Status on Immune Activation, Senescence and Apoptosis

Impact of Age and HIV Status on Immune Activation, Senescence and Apoptosis

Persistent T Cell Repertoire Perturbation and T Cell Activation in HIV After Long Term Treatment

Machine learning-selected variables associated with CD4 T cell recovery under antiretroviral therapy in very advanced HIV infection

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