Harnessing CD8+ T Cells Under HIV Antiretroviral Therapy.

Nilu Goonetilleke,Joanna A Warren,Genevieve Clutton

doi:10.3389/fimmu.2019.00291

Nilu Goonetilleke, Joanna A Warren + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2019.00291

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Abstract

Antiretroviral therapy (ART) has transformed HIV from a fatal disease to a chronic condition. In recent years there has been considerable interest in strategies to enable HIV-infected individuals to cease ART without viral rebound, either by purging all cells infected harboring replication-competent virus (HIV eradication), or by boosting immune responses to allow durable suppression of virus without rebound (HIV remission). Both of these approaches may need to harness HIV-specific CD8+ T cells to eliminate infected cells and/or prevent viral spread. In untreated infection, both HIV-specific and total CD8+ T cells are dysfunctional. Here, we review our current understanding of both global and HIV-specific CD8+ T cell immunity in HIV-infected individuals with durably suppressed viral load under ART, and its implications for HIV cure, eradication or remission. Overall, the literature indicates significant normalization of global T cell parameters, including CD4/8 ratio, activation status, and telomere length. Global characteristics of CD8+ T cells from HIV+ART+ individuals align more closely with those of HIV-seronegative individuals than of viremic HIV-infected individuals. However, markers of senescence remain elevated, leading to the hypothesis that immune aging is accelerated in HIV-infected individuals on ART. This phenomenon could have implications for attempts to prime de novo, or boost existing HIV-specific CD8+ T cell responses. A major challenge for both HIV cure and remission strategies is to elicit HIV-specific CD8+ T cell responses superior to that elicited by natural infection in terms of response kinetics, magnitude, breadth, viral suppressive capacity, and tissue localization. Addressing these issues will be critical to the success of HIV cure and remission attempts.

Highlights

Typical controllersb controllersb progressorsbNaïve Central memory Effector memory TEMRA % CD38+ HLA-DR+ % PD-1 expression Telomere length T cell receptor (TCR) diversity %CD27− CD28+ %CD57+ %CD27− CD28− CMV-specific Peripheral blood Gut mucosa
Literature are limited on whether checkpoint inhibitor levels remain elevated relative to the HIV seronegative population; Tauriainen et al report that HIV-specific CD8+ TIGIThi cells were associated with lower function in durably treated participants and co-expressed other exhaustion markers, suggesting some ongoing T cell exhaustion in durably suppressed individuals [173]
A small clinical study found evidence that low level anti-PD-1 treatment increase CD8+ T cell functionality in a subset of durably ART-suppressed HIV seropositive participants, and more recently CTLA-4 blockade was reported to be well tolerated in HIV-infected individuals [191, 192]

Summary

Typical controllersb controllersb progressorsb

Naïve Central memory Effector memory TEMRA % CD38+ HLA-DR+ % PD-1 expression Telomere length TCR diversity %CD27− CD28+ %CD57+ %CD27− CD28− CMV-specific Peripheral blood Gut mucosa. With co-morbidities such as elevated risk of cardiovascular disease, cancer, fragility and tissue damage resulting from dysregulated inflammation [74] The incidence of these comorbidities is increased in HIV+ART+ individuals [47]. Untreated HIV infection is characterized by an inverted, low CD4/CD8 ratio [75], that results from both ongoing CD4+ T cell depletion and the persistent elevation of peripheral CD8+ T cells. While HCMV-specific CD8+ T cell responses do not themselves exhibit functional impairment in HIV+ART+ individuals [22], HCMV infection may indirectly impact CD8+. The failure to fully restore the CD8+ naïve compartment combined with elevated total CD8+ T cell frequencies described above suggests that, similar to observations in older people, induction of de novo CD8+ T cell responses in HIV+ART+ individuals may be more limited. Whether it will be possible to induce potent de novo HIV-specific T cell responses in HIV+ART+ individuals, important for both HIV eradication and remission approaches, is a key question in the current era of CD8+ T cell immunotherapy

Immune Activation Under ART

Summary

Survival factorsc

IMMUNOTHERAPY IN CURE