HIV DNA in CD14+ reservoirs is associated with regional brain atrophy in patients naive to combination antiretroviral therapy

Kallianpur, Kalpana J.; Valcour, Victor; Lerdlum, Sukalaya; Busovaca, Edgar; Agsalda, Melissa; Sithinamsuwan, Pasiri; Chalermchai, Thep; Fletcher, James; Tipsuk, Somporn; Shikuma, Cecilia; Shiramizu, Bruce; Ananworanich, Jintanat

doi:10.1097/qad.0000000000000306

Cited by 19 publications

(22 citation statements)

References 31 publications

(34 reference statements)

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“…The more robust findings for sCD163 as compared to sCD14 suggests that the impact is more likely due to specific monocyte infection than gut microbial translocation. This is consistent with prior studies linking HIV DNA in CD14 + reservoirs to cognition, brain atrophy, and brain inflammation through cytokine analyses and magnetic resonance spectroscopy [40,41]. This study also informs clinical practice in cases where successfully treated patients achieve viral suppression yet have cognitive symptoms.…”

Section: Discussionsupporting

confidence: 77%

Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression

et al. 2016

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Background. Cognitive impairment persists despite suppression of plasma human immunodeficiency virus (HIV) RNA. Monocyte-related immune activation is a likely mechanism. We examined immune activation and cognition in a cohort of HIVinfected and uninfected women from the Women's Interagency HIV Study (WIHS).Methods. Blood levels of activation markers, soluble CD163 (sCD163), soluble CD14 (sCD14), CRP, IL-6, and a gut microbial translocation marker (intestinal fatty acid binding protein (I-FABP)) were measured in 253 women (73% HIV-infected). Markers were compared to concurrent (within ± one semiannual visit) neuropsychological testing performance.Results. Higher sCD163 levels were associated with worse overall performance and worse verbal learning, verbal memory, executive function, psychomotor speed, and fine motor skills (P < .05 for all comparisons). Higher sCD14 levels were associated with worse verbal learning, verbal memory, executive function, and psychomotor speed (P < .05 for all comparisons). Among women with virological suppression, sCD163 remained associated with overall performance, verbal memory, psychomotor speed, and fine motor skills, and sCD164 remained associated with executive function (P < .05 for all comparisons). CRP, IL-6, and I-FABP were not associated with worse cognitive performance.Conclusions. Monocyte activation was associated with worse cognitive performance, and associations persisted despite viral suppression. Persistent inflammatory mechanisms related to monocytes correlate to clinically pertinent brain outcomes.Keywords. CD163; CD14; women; HIV infection; cognition disorders; intesticial fatty acid-binding protein (1-19).Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is a debilitating condition that affects up to 50% of people living with HIV, despite access to combination antiretroviral therapy (cART) [1]. Understanding the cellular and molecular mechanisms leading to HAND is of clinical importance, particularly among those adherent to treatment, as HAND is associated with loss of employment [2], decreased ability to multitask [3], impaired medication self-management [4], and shorter time to virologic failure.[5] These factors influence health and quality of life [6]. Chronic immune activation is a common theme in describing potential mechanisms underlying persistence of HAND despite suppression of plasma viremia [7]. Two postulated sources of this immune activation are intracellular HIV DNA in tissues and circulating cells (eg, monocytes, lymph nodes, and, potentially, the brain) and gut microbial translocation [8,9]. However, published work describing HAND is frequently based on the evaluation of study participants who have a mixture of suppressed or unsuppressed plasma HIV RNA levels, a factor that limits our understanding of persistent impairment despite suppressive therapy [10].Circulation of activated CD14 + /CD16 + monocytes containing HIV contribute to chronic immune activation. These monocytes are theorized to carry HIV into the brain [7]....

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Section: Discussionsupporting

confidence: 77%

Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression

et al. 2016

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“…Our cross-sectional analyses confirm limited volumetric reductions in HIV-infected participants with cognitive impairment compared to healthy controls, including regions previously noted to be affected in the setting of HIV, such as the cerebellum, nucleus accumbens and brainstem. 36–38 These findings were driven by HIV-infected participants with HAND and we did not identify differences by HIV serostatus alone. Among the HIV infected group, the baseline volume of the nucleus accumbens and its association to executive functioning is notable.…”

Section: Discussionmentioning

confidence: 68%

Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years

Clifford

Samboju

Cobigo

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Current HIV treatments are successful at suppressing plasma HIV RNA to undetectable levels for most adherent patients. Yet, emerging evidence suggests viral suppression will inadequately control inflammation and mitigate risk for progressive brain injury. We sought to quantify differences in longitudinal brain atrophy rates among older virally suppressed HIV-infected participants compared to that of healthy aging. Methods We examined longitudinal structural brain MRI atrophy rates employing region of interest assessments and voxel-wise tensor-based morphometry in HIV-infected participants over age 60 years (n=38) compared to age-matched HIV-uninfected healthy and cognitively normal controls (n=24). Results The mean age of participants was 63 years, the mean estimated duration of infection was 21 years and the median of duration of documented viral suppression was 3.2 years. Average proximal and nadir CD4 counts were 550 and 166, respectively; 15/38 (39%) met criteria for HIV-associated neurocognitive disorder. In models adjusting for age and sex, HIV serostatus was associated with more rapid average annualized rates of atrophy in the cerebellum (0.42% vs. 0.02%, p=0.016), caudate (0.74% vs. 0.03%, p=0.012), frontal lobe (0.48% vs. 0.01%, p=0.034), total cortical gray matter (0.65% vs. 0.16%, p=0.027), brain stem (0.31% vs. 0.01%, p=0.026), and pallidum (0.73% vs. 0.39%, p=0.046). Among those with HIV, atrophy rates did not differ statistically by cognitive status. Conclusion Despite persistent control of plasma viremia, these older HIV-infected participants demonstrate more rapid progressive brain atrophy when compared to healthy aging. Either HIV or other factors that differ between older HIV-infected participants and healthy controls could be responsible for these differences.

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“…With cART, VL usually decreases and thus it may be necessary to establish the reliability of other clinical markers of HAND. Recent work in this cohort also identified that HIV DNA reservoir levels in circulating CD14+ cells (enriched with monocytes) correlate with cognitive diagnosis and brain atrophy, specifically in the nucleus accumbens, brainstem, and total gray matter (Kallianpur, et al, 2014). …”

Section: Discussionmentioning

confidence: 77%

“…More recent MRS studies reveal elevations in metabolites suggestive of cellular inflammation during acute HIV infection (Valcour et al, 2012; Sailasuta et al, 2012) that resolved after early cART (Sailasuta et al, 2012). A separate Thai neuroimaging study reported reduced regional brain volumes in cART naïve HIV+ individuals who had higher levels of peripheral HIV DNA compared to HIV+ individuals with lower HIV DNA levels (Kallianpur, 2014). However, prior studies did not characterize HIV+ by HAND status or compare brain volumes in HIV+ individuals, with and without HAND to HIV− uninfected individuals in Thailand.…”

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confidence: 99%

Association between brain volumes and HAND in cART-naïve HIV+ individuals from Thailand

et al. 2015

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This study aimed to determine the effects of human immunodeficiency virus (HIV) on brain structure in HIV-infected individuals with and without HIV-associated neurocognitive disorders (HAND). Twenty-nine HIV-uninfected controls, 37 HIV+, treatment naïve, individuals with HAND (HIV+HAND+; 16 ANI, 12 MND, and 9 HAD) and 37 HIV+, treatment naïve, individuals with normal cognitive function (HIV+HAND−) underwent magnetic resonance imaging (MRI) and neuropsychological assessment. The HIV-infected participants had a mean (SD) age of 35(7) years, mean (IQR) CD4 count of 221(83-324) and mean (IQR) log10 plasma viral load of 4.81(4.39-5.48). Six regions of interest were selected for analyses including total and subcortical gray matter, total white matter, caudate, corpus callosum, and thalamus. The HIV+/HAND+ group exhibited significantly smaller brain volumes compared to the HIV-uninfected group in subcortical gray and total gray matter; however, there were no statistically significant differences in brain volumes between the HIV+HAND+ and HIV+HAND− groups or between HIV+/HAND− and controls. CD4 count at time of cART initiation was associated with total and subcortical gray matter volumes, but not with cognitive measures. Plasma viral load correlated with neuropsychological performance, but not brain volumes. The lack of significant differences in brain volumes between HIV+HAND+ and HIV+HAND− suggests that brain atrophy is not a sensitive measure of HAND in subjects without advanced immunosuppression. Alternatively, current HAND diagnostic criteria may not sufficiently distinguish patients based on MRI measures of brain volumes.

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HIV DNA in CD14+ reservoirs is associated with regional brain atrophy in patients naive to combination antiretroviral therapy

Cited by 19 publications

References 31 publications

Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression

Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression

Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years

Association between brain volumes and HAND in cART-naïve HIV+ individuals from Thailand

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