HIV can damage neurons leading to cognitive impairment. Epidemiological observations suggest that neuropsychological impairment might progress despite successful HAART therapy, but available prevalence estimates are based on populations that were selected for impairment.
Of 433 advanced AIDS patients with documented immune reconstitution (CD4 lymphocyte counts < 50 before and > 100 cells/microl after HAART), 286 had brief assessments of cognition (Trailmaking A/B and Digit Symbol Tests) at least once, no confounding neurological conditions, and available neuropsychological norms with comprehensive demographic corrections. At entry, most were immune reconstituted on HAART (median CD4 cell count 230 cells/microl) and HIV was suppressed (65% < 500; only 14% > 20 000 RNA copies/ml).
Over one quarter (27%) of participants exhibited impairment at their initial neuropsychological assessment, a rate nearly twice that expected in a normal (HIV-uninfected) reference population (14%). These impaired participants did not differ from the unimpaired group with respect to age, sex, education, race, CD4 lymphocyte counts, or HIV-RNA levels. Improved performance on neuropsychological tests was documented over a 2-year period 3-5 years after initiating HAART. This improvement was marginally associated with the continued or improving control of plasma HIV-RNA levels, but not with concurrent levels of immune recovery (CD4 lymphocyte counts).
Most advanced AIDS patients responding to HAART for prolonged periods have stable or improving cognition, but remain more likely to be impaired than the general population. During HAART, improving test performance probably reflects both practice effects and continuing neurological recovery after more than 3 years of HAART.
"With the introduction of highly active antiretroviral therapy (HAART), the morbility and mortality in HIV positive patients have been significantly reduced. Although HAART has lessen the incidence of HIV-associated dementia (HAD; McCutchan et al. 2007; Nath 2010), HIV positive patients continue to suffer from HIV-associated neurocognitive disorders (HAND) and the prevalence of HAD actually increased due to the extended lifespan in HIV positive patients and the resistance to HAART in some patients (Antinori et al. 2007; Gonzalez-Scarano and Martin-Garcia 2005; McArthur et al. 2003; Nath 2010). In addition, recent studies suggest that the greater incidence of drug abuse among HIV-positive patients may exacerbate the progression of HAD as the psychoactive drugs and the products of the HIV-1 virus interact additively or synergistically on common brain regions. "
[Show abstract][Hide abstract] ABSTRACT: The HIV-1 transgenic (HIV-1Tg) rat shows a deficit in learning to locate a submerged platform in a multiple-trial water maze task compared to transgenic littermate and F344 control rats (Vigorito et al., J.Neuroimmune Pharmacol 2:319-328, 2007; Lashomb et al., J.Neurovirol 15:14-24, 2009). Nicotine is known to have neuroprotective effects possibly by minimizing cytotoxic effects of glutamate or by modulating a cholinergic anti-inflammatory pathway. Nicotine also improves performance in a variety of learning tasks by enhancing attention and short-term memory (STM). The purpose of this study was to determine if the learning deficit in HIV-1Tg is ameliorated by repeated nicotine treatment independent of its effects on STM. HIV-1Tg and F344 rats were treated (subcutaneous) with nicotine (0.25 mg/kg/injection) or saline twice daily and tested in a single-trial-per-day procedure which precludes the impact of STM on the acquisition of the spatial learning task. HIV-1Tg rats showed a deficit in the acquisition of the task and in the long-term retention for the platform location in a probe test. Nicotine did not ameliorate the deficit in HIV-1Tg rats and slightly worsened performance during acquisition. Analysis of individual differences in performance during the probe test suggested that nicotine improved performance in some F344 rats but not in HIV-1Tg rats. These results indicate that a deficit in the consolidation of long-term memory contributes to the acquisition deficit of HIV1-Tg rats. The results, however, do not provide any evidence of the amelioration of the learning deficit observed in this behavioral model at least with the nicotine dose tested.
Journal of NeuroVirology 03/2013; 19(2). DOI:10.1007/s13365-013-0154-1 · 2.60 Impact Factor
"Secondly, cognitive decline in HAND may result as much from neuronal dysfunction as from neuronal loss, an idea supported by experimental results showing alterations in cell layer volume  and dendritic morphology  correlate with HAD . Indeed, extensive cell death is not always present when symptoms manifest  and antiretroviral therapy (ART) treatment has been known to lead to cognitive improvement , , , , suggesting the underlying pathology of HAD may be in part reversible. This is consistent with a channelopathy hypothesis originally described by Dr. Ben Gelman , which led our laboratory to investigate Kv channel involvement in HAND . "
[Show abstract][Hide abstract] ABSTRACT: Human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) usually occurs late in the course of HIV-1 infection and the mechanisms underlying HAD pathogenesis are not well understood. Accumulating evidence indicates that neuronal voltage-gated potassium (Kv) channels play an important role in memory processes and acquired neuronal channelopathies in HAD. To examine whether Kv channels are involved in HIV-1-associated neuronal injury, we studied the effects of HIV-1 glycoprotein 120 (gp120) on outward K+ currents in rat cortical neuronal cultures using whole-cell patch techniques. Exposure of cortical neurons to gp120 produced a dose-dependent enhancement of A-type transient outward K+ currents (IA). The gp120-induced increase of IA was attenuated by T140, a specific antagonist for chemokine receptor CXCR4, suggesting gp120 enhancement of neuronal IA via CXCR4. Pretreatment of neuronal cultures with a protein kinase C (PKC) inhibitor, GF109203X, inhibited the gp120-induced increase of IA. Biological significance of gp120 enhancement of IA was demonstrated by experimental results showing that gp120-induced neuronal apoptosis, as detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and caspase-3 staining, was attenuated by either an IA blocker 4-aminopyridine or a specific CXCR4 antagonist T140. Taken together, these results suggest that gp120 may induce caspase-3 dependent neuronal apoptosis by enhancing IA via CXCR4-PKC signaling.
PLoS ONE 10/2011; 6(10):e25994. DOI:10.1371/journal.pone.0025994 · 3.23 Impact Factor
"The alteration of disease progression has resulted in several positive consequences including increased life expectancy (Cameron et al., 1998; Hammer et al., 1997; Montaner et al., 1998) and the reduction in the severity of cognitive symptoms and/or rates of dementia (Dore et al., 1997; Ferrando et al., 1998; Robertson et al., 2004; Sacktor et al., 2006). Importantly, however, there are an increasing number of patients who clearly develop less severe cognitive symptoms in the mild to moderate range of dysfunction (McArthur et al., 2003; McCutchan et al., 2007; Sacktor et al., 2002; Ances & Ellis, 2007). The prevalence of milder forms of cognitive dysfunction range between 20% and 37% (Sacktor et al., 2002; Villa et al., 1996) and these milder forms of cognitive dysfunction are know to diminish their ability to successfully engage in many aspects of daily living (e.g., driving [Marcotte et al., 1999], cooking [Heaton et al., 2004], financial management [Heaton et al., 2004], and medication adherence [Hinkin et al., 2002, 2004]). "
[Show abstract][Hide abstract] ABSTRACT: This study examined the association between recent trends in CD4 and viral loads and cognitive test performance with the expectation that recent history could predict cognitive performance. Eighty-three human immunodeficiency virus (HIV)-infected patients with a mean CD4 count of 428 copies/ml were examined in this study (62% with undetectable plasma viral load [PVL]). We investigated the relationships between nadir CD4 cell count, 1-year trends in immunologic function/PVLs, and cognitive performance across several domains using linear regression models. Nadir CD4 cell count was predictive of current executive function (p = .004). One year clinical history for CD4 cell counts and/or PVLs were predictive of executive function, attention/working memory, and learning/memory measures (p < .05). Models that combined recent clinical history trends and nadir CD4 cell counts suggested that recent clinical trends were more important in predicting current cognitive performance for all domains except executive function. This research suggests that recent CD4 and viral load history is an important predictor of current cognitive function across several cognitive domains. If validated, clinical variables and cognitive dysfunction models may improve our understanding of the dynamic relationships between disease evolution and progression and CNS involvement.
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