Head of Neurosciences Program St Vincent's Centre for Applied Medical Research and Director of the Peter Duncan Neurosciences Unit St Vincent's Centre for Applied Medical Research, St. Vincent's Hospital Sydney
Infection with human immunodeficiency virus type 1 (HIV-1) is frequently complicated in its late stages by the AIDS dementia complex, a neurological syndrome characterized by abnormalities in cognition, motor performance, and behavior. This dementia is due partially or wholly to a direct effect of the virus on the brain rather than to opportunistic infection, but its pathogenesis is not well understood. Productive HIV-1 brain infection is detected only in a subset of patients and is confined largely or exclusively to macrophages, microglia, and derivative multinucleated cells that are formed by virus-induced cell fusion. Absence of cytolytic infection of neurons, oligodentrocytes, and astrocytes has focused attention on the possible role of indirect mechanisms of brain dysfunction related to either virus or cell-coded toxins. Delayed development of the AIDS dementia complex, despite both early exposure of the nervous system to HIV-1 and chronic leptomeningeal infection, indicates that although this virus is "neurotropic," it is relatively nonpathogenic for the brain in the absence of immunosuppression. Within the context of the permissive effect of immunosuppression, genetic changes in HIV-1 may underlie the neuropathological heterogeneity of the AIDS dementia complex and its relatively independent course in relation to the systemic manifestations of AIDS noted in some patients.
"Moreover, the expression of CCR5 on brain microvascular endothelial cells might also facilitate CNS entry . Subsequently, HIV-1 has been shown to infect other cells in the brain, most commonly microglia cells, which express both CCR3 and CCR5   . The upregulation of CCR5 expression may also contribute to the spread of HIV-1 within the brain during the course of viral disease   . "
[Show abstract][Hide abstract] ABSTRACT: The evolution of human immunodeficiency virus type 1 (HIV-1) with respect to co-receptor utilization has been shown to be relevant to HIV-1 pathogenesis and disease.The CCR5-utilizing (R5) virus has been shown to be important in the very early stages of transmission and highly prevalent during asymptomatic infection and chronic disease.In addition, the R5 virus has been proposed to be involved in neuroinvasion and central nervous system (CNS) disease.In contrast, the CXCR4-utilizing (X4) virus is more prevalent during the course of disease progression and concurrent with the loss of CD4+Tcells.The dual-tropic virus is able to utilize both co-receptors (CXCR4 and CCR5) and has been thought to represent an intermediate transitional virus that possesses properties of both X4 and R5 viruses that can be encountered at many stages of disease. The use of computationaltools and bioinformatic approaches in the prediction of HIV-1 co-receptor usage has been growing in importance with respect to understanding HIV-1 pathogenesis and disease, developingdiagnostic tools,and improving the efficacy of therapeutic strategies focused on blocking viral entry.Current strategies have enhanced the sensitivity, specificity, and reproducibility relative to the prediction of co-receptor use; however, these technologies need to be improved with respect to their efficient and accurate use across the HIV-1 subtypes. The most effective approach may center on the combined use of different algorithms involving sequences within and outside of the env-V3 loop. This review focuses on the HIV-1 entry process and on co-receptor utilization, including bioinformatic tools utilized in the prediction of co-receptor usage. It also provides novel preliminary analyses for enabling identification of linkages between amino acids in V3 with other components of the HIV-1 genome and demonstrates that these linkages are different between X4 and R5 viruses.
Current HIV Research 05/2014; 12(2). DOI:10.2174/1570162X12666140526121746 · 1.76 Impact Factor
"As a consequence of the invasion of the CNS, various neuropathological disorders may occur, with the most prominent being AIDS dementia complex (ADC). ADC occurs in about 20–50% of HIV-1-infected individuals (Atwood et al., 1993; McArthur et al., 1993) and is characterized by a range of cognitive, motor, and behavioral changes that vary in severity as the disease progresses (Michaels et al., 1988; Price et al., 1988). Apart from CD4 ϩ T-lymphocytes, which are major targets for infection with HIV, cells of the mononuclear phagocyte system, including macrophages, microglia, and multinucleated giant cells of the brain, also play a critical role, both as host cells and as reservoirs, for HIV in vivo. "
"While seemingly innocent over much of this course and indeed clinically silent despite detectable HIV RNA and an inflammatory response in the cerebrospinal fluid (CSF), this infection may nevertheless impact brain function. Most notably, in some patients CNS infection evolves into a more invasive encephalitic form that presents clinically as HIV-associated dementia (HAD) (Navia et al. 1986; Price et al. 1988). The detailed characteristics and pathogenesis of this shift from ‘benign’ meningitis to devastating encephalitis remain poorly defined, though changes in both the viral pathogen and host immune responses likely contribute in concert (Schnell et al. 2011; Arrildt et al. 2012). "
[Show abstract][Hide abstract] ABSTRACT: Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.
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