The prevalence of HIV-associated neurocognitive disorder has not changed from the pre- to the potent antiretroviral therapy era, remaining at approximately 50%. In research settings, mild ...neurocognitive disorder (MND) and so-called asymptomatic neurocognitive impairment (ANI) are now more common than HIV-associated dementia. The diagnosis of ANI is misleading because functional deficits, when tested in a laboratory, and degree of neuropsychologic testing abnormalities are often comparable in patients with ANI and those with symptomatic MND. Age-related comorbidities increase the risk of cognitive impairment in HIV infection. In a cohort of patients aged 60 years or older with excellent antiretroviral therapy adherence, correlates to cognitive impairment were apolipoprotein (Apo) E4 genotype and a novel measure of the effectiveness of antiretroviral drugs in monocytes, the monocyte efficacy (ME) score, with trend associations for diabetes and nadir CD4+ cell count. Management of impairment includes ensuring that patients are on and adhere to antiretroviral therapy and addressing comorbidities. Switching from effective and well-tolerated antiretroviral therapy for patients with mild cognitive impairment is not routinely recommended, but this must still be addressed on a case-by-case basis. This article summarizes a presentation by Victor G. Valcour, MD, at the IAS-USA continuing education program held in Atlanta, Georgia, in April 2013.
Background. Serious non-AIDS events cause substantial disease and death despite human immunodeficiency virus (HIV) suppression with antiretroviral therapy (ART). Biomarkers of inflammation, ...coagulation cascade activation, and fibrosis predict these end-organ events. We aimed to determine whether ART initiation during acute HIV infection would attenuate changes in these biomarker levels. Methods. Plasma samples were obtained from participants starting ART during acute or chronic HIV infection and from HIV-uninfected participants from Bangkok, Thailand. Biomarkers of inflammation (C-reactive protein CRP, interleukin 6, soluble interleukin 6 receptor sIL-6R, soluble gp130, tumor necrosis factor TNF), enterocyte turnover (intestinal fatty acid binding protein I-FABP), lipopolysaccharide-induced monocyte activation (soluble CD14 sCD14), coagulation cascade activation D-dimer, and fibrosis (hyaluronic acid HA) were measured at baseline and through 96 weeks of ART. Results. CRP, TNF, sIL-6R, I-FABP, sCD14, D-dimer, and HA levels were elevated in acute HIV infection. Early ART was associated with increased I-FABP levels but normalization of TNF, sIL-6R, and D-dimer levels. CRP, sCD14, and HA levels decreased during ART but remained elevated compared with HIV-uninfected participants. Higher sCD14, CRP, and D-dimer levels were associated with higher peripheral blood mononuclear cell and gut integrated HIV DNA levels. Decreases in sCD14 and CRP levels were correlated with increases in CD4 T-cell counts. Conclusions. ART initiated in early acute HIV infection was associated with normalization of the coagulation cascade and several systemic inflammatory biomarkers, but the acute-phase response, enterocyte turnover, monocyte activation, and fibrosis biomarkers remained elevated. Additional interventions to attenuate inflammation may be needed to optimize clinical outcomes in persons with HIV infection.
Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the ...virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14(+) enriched monocytes predicted cognitive impairment and brain injury.
We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14(+) enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF).
The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14(+) HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14(+) HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions.
Reservoir burden of HIV DNA in monocyte-enriched (CD14(+)) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Failure of potent antiretroviral therapy to eradicate this HIV reservoir may be responsible for the continued occurence of dementia in HIV‐infected individuals.
It is broadly accepted that HIV DNA in ...lymphoid and myeloid cells persists despite combination antiretroviral therapy. Recognized as the Achilles heel to HIV eradication, the role of these peripheral reservoirs in HIV morbidity is less well developed. The burden of HIV DNA in peripheral mononuclear cells is linked to HIV disease outcomes such as time to AIDS diagnosis, survival, and CD4 T‐lymphocyte counts. Monocytes are a minor HIV DNA reservoir, and the burden of HIV DNA in these cells appears to be linked to dementia, suggesting that residual infection in this subset is linked to tissue‐related HIV complications. Since monocytes are likely involved in trafficking virus to the brain, there is a strong mechanistic link underlying this discovery. Herein, we summarize our current understanding of monocyte HIV DNA and central nervous system dysfunction in humans. We present a model to understand these relationships and suggest possible treatment approaches to be tested.
Whereas human immunodeficiency virus (HIV) persists in tissue macrophages during antiretroviral therapy (ART), the role of circulating monocytes as HIV reservoirs remains controversial. Three ...magnetic bead selection methods and flow cytometry cell sorting were compared for their capacity to yield pure CD14
monocyte populations. Cell sorting by flow cytometry provided the purest population of monocytes (median CD4
T-cell contamination, 0.06%), and the levels of CD4
T-cell contamination were positively correlated with the levels of integrated HIV DNA in the monocyte populations. Using cell sorting by flow cytometry, we assessed longitudinally the infection of monocytes and other cell subsets in a cohort of 29 Thai HIV-infected individuals. Low levels of HIV DNA were detected in a minority of monocyte fractions obtained before and after 1 year of ART (27% and 33%, respectively), whereas HIV DNA was readily detected in CD4
T cells from all samples. Additional samples (2 to 5 years of ART) were obtained from 5 individuals in whom monocyte infection was previously detected. Whereas CD4
T cells were infected at high levels at all time points, monocyte infection was inconsistent and absent in at least one longitudinal sample from 4/5 individuals. Our results indicate that infection of monocytes is infrequent and highlight the importance of using flow cytometry cell sorting to minimize contamination by CD4
T cells.
The role of circulating monocytes as persistent HIV reservoirs during ART is still controversial. Several studies have reported persistent infection of monocytes in virally suppressed individuals; however, others failed to detect HIV in this subset. These discrepancies are likely explained by the diversity of the methods used to isolate monocytes and to detect HIV infection. In this study, we show that only flow cytometry cell sorting yields a highly pure population of monocytes largely devoid of CD4 contaminants. Using this approach in a longitudinal cohort of HIV-infected individuals before and during ART, we demonstrate that HIV is rarely found in monocytes from untreated and treated HIV-infected individuals. This study highlights the importance of using methods that yield highly pure populations of cells as flow cytometry cell sorting to minimize and control for CD4
T-cell contamination.
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 HIV-infected 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.
OBJECTIVE:To determine whether persistent viral suppression alters cognitive trajectories among HIV-infected (HIV+) women on combination antiretroviral therapy (cART) by investigating performance ...longitudinally in uninfected (HIV−) and 3 groups of HIV+ womenthose with consistent viral suppression after continuous cART use (VS), those without consistent virologic suppression despite continuous cART use (NVS), and those without consistent virologic suppression after intermittent cART use (Int NVS).
METHODS:Two hundred thirty-nine VS, 220 NVS, 172 Int NVS, and 301 HIV− women from the Womenʼs Interagency HIV Study (WIHS) completed neuropsychological testing every 2 years for 3 visits between 2009 and 2013. Mixed-effects regressions were used to examine group differences on continuous T scores and categorical measures of impairment (T score <40).
RESULTS:On global function, VS women demonstrated lower scores and were more likely to score in the impaired range than HIV− women (p = 0.01). These differences persisted over time (group × time, p > 0.39). VS women demonstrated lower learning and memory scores than HIV− women (p < 0.05) and lower attention/working memory and fluency scores than HIV− and NVS women (p < 0.05). Group differences in scores persisted over time. Categorically, VS women were more likely to be impaired on attention/working memory and executive function than HIV− women (p < 0.05). On motor skills, VS and NVS women showed a greater decline and were more likely to be impaired than HIV− women (p < 0.05).
CONCLUSIONS:Cognitive difficulties remain among HIV+ women despite persistent viral suppression. In some instances, VS women are worse than NVS women, reinforcing the need for novel adjunctive therapies to attenuate cognitive problems.
Background
Often, global health programs are designed to train individuals from low‐ and middle‐income countries (LMICs) with training provided in more resourced regions. Subsequently, the trainees ...return to their home community with limited additional resources. When research is funded, capacity‐building is rarely prioritized and partnership for core administrative and study management needs is absent. A program of ‘accompaniment’ where programs partner with trainees after their training period is less frequent and could alter the landscape of research capacity building for dementia.
Methods
The Atlantic Fellows for Equity in Brain Health program provides both a one‐year in‐residence learning experience and seeks to accompany fellows as they return to their home community. Resources and activities in the post‐training period include funding for small pilot projects, networking and community building, training in grants management, support for logistic and administrative activities related to grants, partnering with grant and manuscript writing and assistance with data collection and management.
Results
Over seven years, Atlantic Fellows have received 137 Pilots Awards ($25k each) for activities in 41 countries. Many of these awards serve as launching pads for future funding. For example, the Multi‐Partner Consortium for Dementia Research in Latin America (ReDLat) grew out of a Pilot awarded to an Atlantic Fellow from Latin America uniting 14 research centers across six Latin American countries aiming to identify the unique genetic and social determinants of health that drive Alzheimer’s disease and related dementias. Work is underway and includes prominent capacity building activities with more than $12M in committed from global partners. More than 1454 individuals have been enrolled. Eleven Atlantic Fellows are directly involved in the project. Other examples include work in Brazil that has now been transformed into US National Institutes of Health funding. New work is currently launched in East Africa leading to competitive research applications under review.
Conclusions
An intentional model of accompaniment can achieve substantial impact on dementia research in LMICs.
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