Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute HIV Infection

Sereti, Irini; Krebs, Shelly J.; Phanuphak, Nittaya; Fletcher, James; Slike, Bonnie M.; Pinyakorn, Suteeraporn; O’Connell, Robert J.; Rupert, Adam; Chomont, Nicolas; Valcour, Victor; Kim, Jerome H.; Robb, Merlin L.; Michael, Nelson L.; Douek, Daniel C.; Ananworanich, Jintanat; Utay, Netanya S.

doi:10.1093/cid/ciw683

Cited by 224 publications

(172 citation statements)

References 33 publications

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“…49 Initiation of HAART can reduce immune mediated changes but microglial and macrophage activation remains elevated. 4,12,50 In addition, latent HIV viral antigen can instigate further immune activation leading to a proliferation of microglia and reactivation of virus. 51 Cellularity is sensitive to cellular proliferation and may reflect prominent microglial and macrophage induced inflammation that occurs in response to injury.…”

Section: Discussionmentioning

confidence: 99%

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Strain

Burdo

Song

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Inflammation occurs after HIV infection and persists despite highly active antiretroviral therapy (HAART). Diffusion tensor imaging (DTI), measures HIV associated white matter changes, but can be confounded by inflammation. Currently, the influence of inflammation on white matter integrity in well-controlled HIV+ patients remains unknown. We used diffusion basis Spectrum imaging (DBSI) derived cellularity to isolate restricted water diffusion associated with inflammation separated from the anisotropic diffusion associated with axonal integrity. Ninety-two virologically suppressed HIV+ patients on HAART and 66 HIV uninfected (HIV-) controls underwent neuropsychological performance (NP) testing and neuroimaging. NP tests assessed multiple domains (memory, psychomotor speed, and executive functioning). DTI and DBSI derived fractional anisotropy (FA) maps were processed with tract based spatial statistics for comparison between both groups. Cellularity was assessed with regards to age, HIV status, and NP. Within the HIV+ cohort, cellularity was compared to clinical (HAART duration) and laboratory measures of disease (e.g. CD4 cell current and nadir). NP was similar for both groups. DTI derived FA was lower in HIV+ compared to HIV- individuals. In contrast, DBSI derived FA was similar for both groups. Instead, diffuse increases in cellularity were present in HIV+ individuals. Observed changes in cellularity were significantly associated with age, but not NP, in HIV+ individuals. A trend level association was seen between cellularity and HAART duration. Elevated inflammation, measured by cellularity, persists in virologically well-controlled HIV+ individuals. Widespread cellularity changes occur in younger HIV+ individuals and diminish with aging and duration of HAART.

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Section: Discussionmentioning

confidence: 99%

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Strain

Burdo

Song

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…Accordingly, Sereti et al [117] have suggested that additional interventions, aimed at attenuating inflammation, may be required to optimize clinical outcomes in HIV patients treated with ART.…”

Section: Art and Inflammationmentioning

confidence: 99%

Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence

Franzese¹,

Barbaccia²,

Bonmassar³

et al. 2018

Chemotherapy

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Since the introduction of highly active antiretroviral therapy more than 2 decades ago, HIV-related deaths have dramatically decreased and HIV infection has become a chronic disease. Due to the inability of antiretroviral drugs to eradicate the virus, treatment of HIV infection requires a systemic lifelong therapy. However, even when successfully treated, HIV patients still show increased incidence of age-associated co-morbidities compared with uninfected individuals. Virus- induced immunosenescence, a process characterized by a progressive decline of immune system function, contributes to the premature ageing observed in HIV patients. Although antiretroviral therapy has significantly improved both the quality and length of patient lives, the life expectancy of treated patients is still shorter compared with that of uninfected individuals. In particular, while antiretroviral therapy can contrast some features of HIV-associated immunosenescence, several anti-HIV agents may themselves contribute to other aspects of immune ageing. Moreover, older HIV patients tend to have a worse immunological response to the antiviral therapy. In this review we will examine the available evidence on the role of antiretroviral therapy in the control of the main features regulating immunosenescence.

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“…Despite sustained undetectable viraemia during efficient cART, the virus persists in so‐called viral reservoirs . In addition, a residual chronic inflammation persists in treated patients . Indeed, while cART lowers chronic inflammation concomitantly with a reduction in viral load, in most patients the inflammation levels are not normalized and remain higher than in healthy persons .…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a residual chronic inflammation persists in treated patients . Indeed, while cART lowers chronic inflammation concomitantly with a reduction in viral load, in most patients the inflammation levels are not normalized and remain higher than in healthy persons . Even in spontaneous HIV controllers (HIC), the inflammation level remains most often higher as compared to healthy donors and those HIC with higher inflammatory scores have a higher risk for CD4 + T‐cell loss and disease progression .…”

Section: Introductionmentioning

confidence: 99%

Systemic DPP4 activity is reduced during primary HIV‐1 infection and is associated with intestinal RORC⁺CD4⁺ cell levels: a surrogate marker candidate of HIV‐induced intestinal damage

et al. 2018

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IntroductionCombined anti‐retroviral therapy (cART) transformed HIV‐1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV‐induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV‐induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV‐1 infection.MethodsBiomarker discovery approaches were performed in four independent cohorts, covering HIV‐1 primary and chronic infection in 496 naïve or cART‐treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre‐ and post‐infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non‐human primate models, representing pathogenic (macaque) and non‐pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4,RORC and TBX21 gene expression in sorted CD4+ cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV‐infected macaques treated with IL‐21.ResultsWe showed that sDPP4 levels were strongly decreased in primary HIV‐1 infection. Strikingly, sDPP4 levels in primary HIV‐1 infection predicted time to AIDS. They were not increased by cART in chronic HIV‐1 infection (median 36 months on cART). In the gut of SIV‐infected non‐human primates, DPP4 mRNA was higher in CD4+ than CD4− leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in CD4+ cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL‐21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine CD4+ cells positively correlated with circulating DPP4 activity.ConclusionThese data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV‐induced intestinal damage.

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Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute HIV Infection

Cited by 224 publications

References 33 publications

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence

Systemic DPP4 activity is reduced during primary HIV‐1 infection and is associated with intestinal RORC⁺CD4⁺ cell levels: a surrogate marker candidate of HIV‐induced intestinal damage

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Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute HIV Infection

Cited by 224 publications

References 33 publications

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence

Systemic DPP4 activity is reduced during primary HIV‐1 infection and is associated with intestinal RORC+CD4+ cell levels: a surrogate marker candidate of HIV‐induced intestinal damage

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Systemic DPP4 activity is reduced during primary HIV‐1 infection and is associated with intestinal RORC⁺CD4⁺ cell levels: a surrogate marker candidate of HIV‐induced intestinal damage