Profound metabolic, functional, and cytolytic differences characterize HIV-specific CD8 T cells in primary and chronic HIV infection

Trautmann, Lydie; Mbitikon-Kobo, Florentin Martial; Goulet, Jean-Philippe; Peretz, Yoav; Shi, Yu; Grevenynghe, Julien van; Procopio, Francesco A.; Boulassel, Mohamad Rachid; Routy, Jean Pierre; Chomont, Nicolas; Haddad, Elias K.; Sékaly, Rafick Pierre

doi:10.1182/blood-2012-04-422550

Cited by 71 publications

(87 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Streeck et al (43) reported that HIV-specific CD8 T-cell responses during acute but not chronic infection were associated with the subsequent viral set point and CD4 T-cell dynamics. The same group (42) also showed that HIVspecific CTLs have increased cytotoxicity early in HIV infection compared to that in chronic infection, though they are more prone to apoptosis as a result of sustained activation and metabolic stress (42).…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Pinzone

Graf

Lynch

et al. 2016

J Virol

View full text Add to dashboard Cite

The dynamics of HIV reservoir accumulation off antiretroviral therapy (ART) is underexplored. Levels of integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) were longitudinally monitored before and after antiviral therapy. HIV integration increased over time in both elite controllers (ECs; n ‫؍‬ 8) and noncontrollers (NCs; n ‫؍‬ 6) before ART, whereas integration remained stable in patients on ART (n ‫؍‬ 4). The median annual fold change was higher in NCs than in ECs and negatively correlated with CD4/CD8 T-cell ratio. Cytotoxic T lymphocyte (CTL) function as assessed by infected CD4 T-cell elimination (ICE) and granzyme B activity did not significantly change over time in ECs, suggesting that the gradual increase in integrated HIV DNA observed in ECs was not a result of progressive loss of immune-mediated control. Also, acutely infected (n ‫؍‬ 7) but not chronically infected (n ‫؍‬ 6) patients exhibited a significant drop in integrated HIV DNA 12 months after ART initiation. In conclusion, in the absence of ART, integrated HIV accumulates over time both in NCs and in ECs, at variable individual rates. Starting ART early in infection leads to a greater drop in integrated HIV DNA than does initiating treatment after years of infection. The increase in integrated HIV DNA over time suggests that early treatment may be of benefit in limiting HIV reservoirs. IMPORTANCEThe establishment of a latent reservoir represents a barrier to cure among HIV-infected individuals. The dynamics of HIV reservoir accumulation over time in patients before antiviral therapy is underexplored, in large part because it is difficult to accurately and reproducibly measure the size of HIV reservoir in this setting. In our study, we compared the dynamics of integrated HIV DNA over time in ECs and NCs before and after ART was initiated. We found that integrated HIV DNA levels progressively increase over time in the absence of ART, but with a higher, albeit variable, rate in NCs compared to ECs. In addition, integrated HIV DNA declines more dramatically when ART is initiated in acute rather than chronic HIV infection, suggesting important differences between acute and chronic infection. Our study highlights the role of HIV replication and CTL control in reservoir accumulation in sanctuary sites and why ART appears to be more effective in acute infection.

show abstract

Section: Discussionmentioning

confidence: 86%

“…In addition, CTL may be more functional early in infection (40,42). Several studies have investigated the functional profile of CD8 T cells during primary infection.…”

Section: Discussionmentioning

confidence: 99%

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Pinzone

Graf

Lynch

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9)(10)(11)(12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13)(14)(15)(16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.…”

Section: The Persistence Of Functional Memory Cd4 T Cells Represents mentioning

confidence: 94%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

show abstract

“…Trautmann et al who previously reported on progressive exhaustion of cytolytic function of HIV-specific CD8 T cells, after two to four months of HIV infection (17), now assessed such response within days of infection in participants of the Thai cohort. These participants received treatment during very early HIV infection and were grouped as stage 1, 2 and 3 with a median of 14, 16 and 19 days post-infection, respectively (18).…”

Section: Influence Of Early Art Initiation On the Dynamics Of Hiv Spementioning

confidence: 99%

Very early antiretroviral therapy permits CD8 T cells to keep HIV reservoirs at bay

Routy

Mehraj

2017

Ann. Transl. Med.

Self Cite

View full text Add to dashboard Cite

Profound metabolic, functional, and cytolytic differences characterize HIV-specific CD8 T cells in primary and chronic HIV infection

Cited by 71 publications

References 49 publications

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Very early antiretroviral therapy permits CD8 T cells to keep HIV reservoirs at bay

Contact Info

Product

Resources

About