Highly active antiretroviral therapy of cognitive dysfunction and neuronal abnormalities in SCID mice with HIV encephalitis

Abstract

Our objective was to determine if highly active antiretroviral therapy (HAART), previously shown to ameliorate several pathological features of HIV encephalitis (HIVE) in a SCID mouse model, would also reduce additional established pathological features of HIV: cognitive dysfunction, TNF-alpha, production, and reduced MAP-2 expression. SCID mice with HIVE and control mice inoculated with uninfected monocytes were administered HAART or saline. The HIV pathological features evaluated included astrogliosis, viral load, neuronal apoptosis, MAP-2 expression, mouse TNF-alpha mRNA production and learning acquisition and retention. HAART reduced the HIV-induced viral load, and the astro- and microgliosis as previously observed; this effect was extended to HIV-induced increases in TNF-alpha mRNA production. In contrast, although HIV produced the cognitive deficits previously observed and also decreased MAP-2 expression in the area surrounding the injected HIV-infected human monocytes, HAART did not attenuate these effects. Interestingly, there was no neuronal apoptosis evident at the time point reflecting the above pathology. The results of this study combined with previous reports indicate that HAART reduces TNF-alpha mRNA, viral load and astrogliosis; however, HAART does not improve HIV-induced cognitive dysfunction or MAP-2 decreases. These results suggest that viral load, astrogliosis, TNF- alpha and apoptosis are not prominent in the pathogenesis of early functional deficits related to decreased MAP-2 expression or cognitive dysfunction in HIVE in SCID mice.

Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: Current status of dopamine system vulnerability in NeuroAIDS

“…The brain pathology of SCID mice infected with HIV-monocytes has been demonstrated to be similar to that of humans infected with HIV, including prominent characteristics of encephalitis (e.g., multinucleated giant cells, astrogliosis, and neuronal toxicity) , cytokine and chemokine upregulation (Persidsky et al, , 1997, and even behavioral abnormalities (Avgeropoulos et al, 1998). To date, researchers continue to use the SCID model not only for characterization of HIV pathology, but for studying therapeutic interventions of HIV (Cook-Easterwood et al, 2007;Spitzenberger et al, 2007). Even before the use of the SCID mouse model, transgenic mice which express various HIV-proteins have been used to study HIV related syndromes (Klotman et al, 1995), and the effect of HIV-proteins on the CNS (Keswani et al, 2006;Toneatto et al, 1999) (see Persidsky et al, 2005 for review of rodent HIV models).…”

Humanized mice for HIV and AIDS research

“…CD8 + T cell depletion results in increased HIV Gag expression in the cerebellum and an increased inducible nitrous oxide synthase (iNOS) expression in both the cerebellum and cortex [82,83]. These models have been extensively used to evaluate novel therapeutic approaches aimed at suppressing viremia in the brain with the goal of ameliorating disease [84–87]. One of the important limitations of these models is the lack of HIV-infected microglia since these cells have been postulated to be an important source of HIV in the CNS [88–90].…”

Development and in vivo evaluation of an implantable nano-enabled multipolymeric scaffold for the management of AIDS dementia complex (ADC)

“…The dementia is also responsible for declined intellectual scores in children and is the leading cause of dementia in young adults worldwide (Wu et al, 2007;Akhtar et al, 2010). ADC is responsible for a host of cognitive, motor and behavioural symptoms, ranging in severity from minor cognitive symptoms, such as forgetfulness, lack of attention and disturbed sleep patterns, to severe dementia and paralysis (Cook-Easterwood et al, 2007).…”