Genetic testing and HIV dementia: teasing out the molecular mechanisms of disease
Year: 2010
Type: article
Abstract: Despite the substantial decline in virtually all the complications of HIV infection that followed the introduction of highly effective antiretroviral therapy 1.5 decades ago, HIV-associated neurocognitive disorders (HAND) remain a significant problem and among the most feared. Current estimates indicate that HAND is observed in approximately 30–50% of HIV-infected persons in the United States [1]. Understanding the mechanisms underpinning these neurocognitive problems is an important step in addressing this spectrum of disorders. In this issue, Spector et al.[2] report their observations regarding host genetic factors and HAND in a unique Chinese population. They demonstrate that in this population the apolipoprotein (ApoE)ε4 allele appears to increase the risk of HIV-cognitive deficits and that MBL2 O/O genotype increases the risk of progressive cognitive decline. Neurobehavioral studies in China and other parts of Asia have presented a difficult challenge for westernized testing methods and, until recently, few studies have utilized methods validated for accurate translation and cross-cultural equivalence [3]. Before embarking on this study, the authors conducted pilot feasibility studies that demonstrated that the neuropsychological effects of HIV are in fact similar in both China and the Unites States. These disorders represent a spectrum of cognitive abnormalities ranging from minor motor and neurocognitive impairment to frank dementia. The specific study population was Chinese individuals from the Anhui province infected during plasma donation. Ironically, it was China's efforts to protect itself from foreign blood products that had resulted in a large pool of persons infected with HIV. As a consequence of the former, the demand for local blood collection resulted in an enormous unregulated industry leading to the infection of large numbers of plasma donors, primarily in poor rural areas. According to 2005 estimates, approximately 10.7% of all HIV infections in China were attributable to blood donation or contaminated blood products [4] This cohort is of particular interest for genetic studies in view of the relative homogeneity of the population, the similar geographic location, and the known route of infection. The reduction of variables likely increases the power of genetic studies, but also raises questions regarding the generalizability of the findings. An attempt to demonstrate a link between ApoEε4 and HAND is a logical first step in light of the consistent association of this allele with Alzheimer's disease, other neurodegenerative disorders, and traumatic brain injury as well as preliminary evidence demonstrating a role for ApoE in modulating susceptibility to infection, including viral infection [5]. Some studies have failed to detect an effect of ApoEε4 on HAND. For instance, an autopsy study by Dunlop and her Norwegian colleagues detected no association between ApoEε4 and HIV dementia even after controlling for length of survival and antiretroviral therapy (Dunlop, 1997). Similarly, in a large HIV-positive cohort of European and African–American descent, no association between ApoEε4 and HAND was demonstrated, though ApoEε4 correlated with accelerated disease and death [6]. This contrasts with the results of this study and others [7–9]. The discordance in these studies with respect to the effect of the ApoEε4 allele on HAND remains unexplained. Possible explanations include differences in the populations, differences in the virus, means by which HAND was determined, or other factors. Age of the study population has been proposed as being a significant factor [8], but even the findings with respect to the influence of age are perplexing. Valcour et al.[9] demonstrated the impact of the ApoEε4 allele only in an older group (>50 years) for HAND expression and suggested that this observation was related to coexistent cerebrovascular disease or other age-related factors, prolonged immune activation, or extended exposure to HAART. In the Chinese cohort, the ApoEε4 allele was positively associated with cognitive impairment after adjusting for sex, age (40.8 years with an SD of 7.4 years), and education. After stratifying for age, however, the association held in the younger group (20–39 years of age), but not in the older group (50 or older). This finding is concordant with that of Corder et al.[7] who noted that the ApoEε4 allele doubled the risk of HIV dementia in a young cohort (average age 34.5 years) and suggested that there might be parallels in the pathogenesis of HIV dementia and Alzheimer's disease. In the studies presented here [2], the association between ApoEε4 remained significant after controlling for changes in viral load and CD4+ T-cell count. That ApoEε4 and neurocognitive impairment remained significant even in patients on antiretroviral therapy suggests the possibility that ApoEε4 predisposes to neurocognitive impairment in HIV infection by modulating host responses. Indeed ApoE exhibits immune modulatory properties and ApoE genetics appears to play a role in susceptibility to certain infections [10]. It is worth noting that CD16+ monocytes, expanded in patients with HIV infection [11], and contributing the central nervous system (CNS) reservoir of HIV infection [11,12], are also expanded relative to the total circulating monocyte pool in individuals with ApoEε4 polymorphism [13]. Despite being primarily produced in hepatic tissue and serving as a component of circulating lipoprotein complexes, other tissues such as brain, also express ApoE, [14], likely through expression in macrophages/microglia [15]. Expression at these sites may contribute to HAND by effects on macrophage function or by effects at the level of astrocytes and neurons. With respect to the former, APOEε4's contribution may be mediated by alteration of nitric oxide production in microglial cells and monocyte-derived macrophages resulting in cellular injury as has been demonstrated in Alzheimer's disease in human and animal studies [16,17]. Alternatively, ApoEε4 may contribute to HAND by enhancing the neurotoxic potential of the HIV protein Tat [18]. The observation by Singh et al.[19] regarding mannose binding lectin-2 polymorphisms and cognitive impairment dovetails with studies of the effect of the MBL-2 locus in HIV-infected children in the United States. Mannose-binding lectin (MBL) is involved in complement activation upon interaction with a variety of microbes including glycosylated virus particles [20]. MBL interaction with HIV has been demonstrated to reduce HIV infection in vitro via neutralization and/or opsonization [21–23]. This innate immune function could explain the observation whereby defective (O/O) MBL-2 genotypes appear to predispose HIV-infected individuals to more aggressive disease [24,25] and CNS impairment [19]. Here MBL-2 defective alleles are associated with an increased risk of cognitive impairment during 12 months of observation. These results are consistent with the protective role of the wild-type MBL-2 allele and might suggest the use of MBL-2 ligand as a therapeutic approach. Unquestionably, host genetic factors play a significant role in the expression of HAND. Although the observations regarding ApoEe4 polymorphisms and MBL-2 defective genotypes with respect to HAND reported in this paper are compelling, they have not been universally observed. Additional studies in other geographic areas will be necessary to confirm the generalizability of these findings and provide an explanation for the differences observed. Although the authors investigated other polymorphisms (CCR5, CCR2, interleukin-4, MCP-21, and CCL3L2) and detected no association with HAND, expanding the list of tested genes would be invaluable in teasing out the molecular mechanisms underpinning HAND. The authors have demonstrated a successful model in a relatively homogenous Chinese population that could potentially be generalized for use on a global scale to perform neurobehavioral/genetic studies for the study of the neurocognitive deficits of HIV.
Source: AIDS
Authors: Jay Rappaport, Joseph R Berger
Institutions: Temple University, University of Kentucky
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2051386192