T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy

Macatangay, Bernard; Gandhi, Rajesh T.; Jones, R. Brad; McMahon, Deborah; Lalama, Christina M.; Bosch, Ronald J.; Cyktor, Joshua C.; Thomas, Abu; Borowski, Luann; Riddler, Sharon A.; Hogg, Evelyn; Stevenson, Eva M.; Eron, Joseph J.; Mellors, John W.; Rinaldo, Charles R.

doi:10.1097/qad.0000000000002406

Cited by 25 publications

(27 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, elevated PD‐1 levels also persisted in TI of cART‐treated patients and were significantly elevated in comparison to non‐infected individuals. While persisting PD‐1 elevation in PB was previously observed [26,36,37], our study provides evidence that PD‐1 expression on memory CD4 T‐cells is also elevated in TI, and persists despite cART. Indeed, patients in this study had been treated for a median (IQR) of 8 (5–11) years, longer than in a previous study [36].…”

Section: Discussionsupporting

confidence: 78%

“…However, given the small number of subjects with detectable HIV DNA, in particular of treatment‐naïve patients, and the large spread of measured HIV DNA, the power to observe a correlation in our study was limited. Furthermore, in contrast to recent studies [26,37], we did not differentiate between high and low PD‐1 expression, which may have facilitated detection of correlations between highly PD‐1 expressing cells and HIV DNA. Further research is required to ascertain correlations, in particular including longitudinal data from pre‐ and post‐treatment initiation HIV‐positive patients, given the immense potential of immunotherapy to reverse HIV latency and T‐cell reconstitution.…”

Section: Discussioncontrasting

confidence: 61%

“…This suggests that even under prolonged treatment, PD‐1+ memory CD4 T‐cells remain stable in both PB and TI. As the up‐regulation of counter‐regulatory immunosuppressive responses in PB despite treatment is associated with lower HIV‐specific T‐cell responses [37], causative mechanisms need to be explored further. First, a higher presence of T follicular helper cells (Tfh) in lymphoid tissue may contribute to a general increase in PD‐1 expression in TI, also noted in uninfected individuals (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

HIV DNA reservoir and elevated PD‐1 expression of CD4 T‐cell subsets particularly persist in the terminal ileum of HIV‐positive patients despite cART

et al. 2021

View full text Add to dashboard Cite

Objectives Despite its importance as an HIV anatomic sanctuary, little is known about the characteristics of the HIV reservoir in the terminal ileum (TI). In blood, the immune checkpoint inhibitor programmed‐death‐1 (PD‐1) has been linked to the HIV reservoir and T‐cell immune dysfunction. We thus evaluated PD‐1 expression and cell‐associated HIV DNA in memory CD4 T‐cell subsets from TI, peripheral blood (PB) and rectum (RE) of untreated and treated HIV‐positive patients to identify associations between PD‐1 and HIV reservoir in other sites. Methods Using mononuclear cells from PB, TI and RE of untreated HIV‐positive (N = 6), treated (n = 18) HIV‐positive and uninfected individuals (n = 16), we identified and sorted distinct memory CD4 T‐cell subsets by flow cytometry, quantified their cell‐associated HIV DNA using quantitative PCR and assessed PD‐1 expression levels using geometric mean fluorescence intensity. Combined HIV‐1 RNA in situ hybridization and immunohistochemistry was performed on ileal biopsy sections. Results Combined antiretroviral therapy (cART)‐treated patients with undetectable HIV RNA and significantly lower levels of HIV DNA in PB showed particularly high PD‐1 expression in PB and TI, and high HIV DNA levels in TI, irrespective of clinical characteristics. By contrast, in treatment‐naïve patients HIV DNA levels in memory CD4 T‐cell subsets were high in PB and TI. Conclusion Elevated PD‐1 expression on memory CD4 T‐cells in PB and TI despite treatment points to continuous immune dysfunction and underlines the importance of evaluating immunotherapy in reversing HIV latency and T‐cell reconstitution. As HIV DNA particularly persists in TI despite cART, investigating samples from TI is crucial in understanding HIV immunopathogenesis.

show abstract

Section: Discussionsupporting

confidence: 78%

Section: Discussioncontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

HIV DNA reservoir and elevated PD‐1 expression of CD4 T‐cell subsets particularly persist in the terminal ileum of HIV‐positive patients despite cART

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Although ART is associated with a significant reduction in the incidence of TB irrespective of CD4 + T cell count status (9), the lifetime risk of TB reactivation in ART-adherent cases remains 4-to 7-fold higher than in HIV-uninfected populations (9,10). CD4 + T cell dysfunction and chronic immune activation are reported alongside CD4 + T cell restoration in ART-adherent PLHIV (11)(12)(13). Lung pathology was reported in 75%-85% of HIV/AIDS autopsies (14), and the plethora of opportunistic infections that can arise in the lung of HIV-infected individuals suggests that their lung environments remain immunologically impaired.…”

Section: Introductionmentioning

confidence: 99%

Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model

Ganatra¹,

Bucşan²,

Álvarez³

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We used Mycobacterium tuberculosis/simian immunodeficiency virus-coinfected (M. tuberculosis/SIV-coinfected) macaques to model M. tuberculosis/HIV coinfection and study the impact of ART on TB reactivation due to HIV infection. Although ART significantly reduced viral loads and increased CD4 + T cell counts in blood and bronchoalveolar lavage (BAL) samples, it did not reduce the relative risk of SIV-induced TB reactivation in ART-treated macaques in the early phase of treatment. CD4 + T cells were poorly restored specifically in the lung interstitium, despite their significant restoration in the alveolar compartment of the lung as well as in the periphery. IDO1 induction in myeloid cells in the inducible bronchus-associated lymphoid tissue (iBALT) likely contributed to dysregulated T cell homing and impaired lung immunity. Thus, although ART was indispensable for controlling viral replication, restoring CD4 + T cells, and preventing opportunistic infection, it appeared inadequate in reversing the clinical signs of TB reactivation during the relatively short duration of ART administered in this study. This finding warrants the modeling of concurrent treatment of TB and HIV to potentially reduce the risk of reactivation of TB due to HIV to inform treatment strategies in patients with M. tuberculosis/HIV coinfection.

show abstract

“…Day et al reported that HIV-infected individuals displayed increased expression of PD-1 and identified an association between the frequency of PD-1 + CD4 + T-cells and disease progression [ 26 ]. Moreover, another study showed that ART initiation does not change expression levels of PD-1 on CD8 + T cells, resulting in infective T cell-specific responses against HIV infection [ 27 ]. Hoffmann et al showed that the frequency of CD8 + T-cells expressing PD-1/CD38 was linked to an elevated number of viral copies in plasma and lower CD4 + T-cell count [ 28 ].…”

Section: Inflammatory Activation In Persons Living With Hiv and Irmentioning

confidence: 99%

Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV

Vinhaes

Araújo-Pereira

Tibúrcio

et al. 2021

Life

View full text Add to dashboard Cite

Antiretroviral therapy (ART) has represented a major advancement in the care of people living with HIV (PLWHH), resulting in significant reductions in morbidity and mortality through immune reconstitution and attenuation of homeostatic disruption. Importantly, restoration of immune function in PLWH with opportunistic infections occasionally leads to an intense and uncontrolled cytokine storm following ART initiation known as immune reconstitution inflammatory syndrome (IRIS). IRIS occurrence is associated with the severe and rapid clinical deterioration that results in significant morbidity and mortality. Here, we detail the determinants underlying IRIS development in PLWH, compiling the available knowledge in the field to highlight details of the inflammatory responses in IRIS associated with the most commonly reported opportunistic pathogens. This review also highlights gaps in the understanding of IRIS pathogenesis and summarizes therapeutic strategies that have been used for IRIS.

show abstract

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy

Cited by 25 publications

References 41 publications

HIV DNA reservoir and elevated PD‐1 expression of CD4 T‐cell subsets particularly persist in the terminal ileum of HIV‐positive patients despite cART

HIV DNA reservoir and elevated PD‐1 expression of CD4 T‐cell subsets particularly persist in the terminal ileum of HIV‐positive patients despite cART

Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model

Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV

Contact Info

Product

Resources

About