- Molecular Mechanisms
- Neuroprotective Strategies
- Acute/Early (AEH) Infection
- Cofactors/HIV Associated Neurocognitive Disorder (HAND)
- Cross-Cultural Applications of Assessment Methods
- Optimal Antiviral Treatments/HIV Associated Neurocognitive Disorder (HAND)
From the standpoint of molecular mechanisms, several HNRC studies have focused on the problem of "protein mismanagement" in HIV diesease. For example, HNRC-associated investigators noticed increased frequency of alpha synuclein in the substantial nigra of persons dying with HIV disease (Khanlou et al., 2009) and electron microscopy and double labeling studies confirmed presence of aggregated A-proton in lysosomes and autophagosomes of such cases. Additional studies have suggested that in patients with HIV associated encephalitis (HIVE) autophagy is abnormally activated and that these alterations may be exacerbated with aging.
In the area of potential neuroprotective strategies, HNRC-associated investigators earlier noted the potential neuroprotective effects of lithium (Everall et al., 2002) in a small clinical study. Recent preclinical work suggests that two GSK 3 specific inhibitors appeared to prevent direct neurotoxicity in primary human neurons exposed to HIV (Nguyen et al., 2009).
On the theme of acute/early (AEH) infection events that may predispose to persistence of HIV associated neurocognitive disorder (HAND) despite antiretroviral (ARV) treatment, HNRC investigators noted that HAND was least likely in individuals who were virally suppressed and never had a CD4 count below 200 (Heaton et al., 2009). Additionally, Ances and colleagues noted abnormalities in brain perfusion among cases infected less than six months, using arterial spin labeling techniques (Ances et al., 2009). These findings are beginning to converge with data from other investigators suggesting that virological, immunological, and neurological events that may occur very soon after becoming infected may predispose to later HAND, and raises the issue whether early treatment might protect against future development of HAND.
The fact that several cofactors may exacerbate HAND has been widely suspected. HNRC-associated investigators extended earlier observations of increased cognitive impairment in methamphetamine using HIV infected persons (Rippeth et al., 2004) through more detailed neurocognitive and neurobiological studies. The latter revealed increased dendritic simplification and selective loss of calbindin immunostaining interneurons in methamphetamine users who died with HIV (Chana et al., 2006). Work in relation to another common copathogen, Hepatitis C virus (HCV), revealed increased likelihood of neurocognitive impairment in those with combined infection (Cherner et al., 2005); importantly, HNRC-associated projects provided some of the earliest work showing HCV localization in astroglia and macrophages suggesting that HCV may combine with HIV to induce inflammatory responses that augment synaptodendritic injury.
HNRC investigators have been at the forefront of refining assessment methods suitable for use in international settings. This has resulted in successful deployment of HNRC assessment tools in various countries, e.g., recent work in China indicates that similar levels of neurocognitive impairment are found in clade B HIV infected persons in that country, compared to USA, when similar methodologies of ascertainment are used (Cysique et al., 2007; Heaton et al., 2008). The demonstration of effective cross cultural applications of assessment methods, and further development of normative standards for classifying impairment and detecting disease-related cognitive change sets the stage for cross-clade comparisons and pursuit of other resesarch questions that would be difficult or impossible to address in the U.S. alone (e.g., assessing effects of co-factors such as infection with malaria; or achieving better experimental control in studying the effects of timing and nature of antiretroviral therapy initiation in relation to central nervous system outcomes). The impact of our work is attested by the growing acceptance of HNRC's approach to neurocognitive classification, which formed the basis for a new international consensus statement on HIV associated neurocognitive disorder that emerged from the NIMH sponsored Frascati conference (Antinori et al., 2007).
An additional area of HNRC-supported investigation has been the determination of optimal antiviral treatments to address HAND. These investigations have led to documenting the relationship of low level HIV persistence in the CSF to occurrence of HAND (Letendre et al., 2009) as well as the development of a practical system of classifying antiretrovirals (ARV) based on their central nervous system (CNS) penetration effectiveness (CPE) (Letendre et al., 2008). Because CNS penetration of ARV appears to be linked to better suppression of HIV in CSF, and possibly improved neurocognitive performance, the CPE approach is receiving increasing national and international recognition at the present time.