Lamers SL, Salemi M, Galligan DC, et al. Human immunodeficiency virus-1 evolutionary patterns associated with pathogenic processes in the brain

BioInfoExperts, Thibodaux, Louisiana, USA.
Journal of NeuroVirology (Impact Factor: 2.6). 04/2010; 16(3):230-41. DOI: 10.3109/13550281003735709
Source: PubMed


The interplay between pathology and human immunodeficiency virus (HIV) expansion in brain tissues has not been thoroughly assessed in the highly active antiretroviral therapy (HAART) era. HIV-associated dementia (HAD) is marked by progressive brain infection due to recruitment and migration of macrophages in brain tissues; however, the cellular and viral events occurring prior to HAD development and death are under debate. In this study, 66 brain tissues from 11 autopsies were analyzed to assess HIV-1 DNA concentration in brain tissues. In most patients without HAD, it was impossible to amplify HIV-1 from brain tissues. Amplifiable DNA was obtained from three cases of patients on HAART who died due to primary pathology other than HAD: (1) cardiovascular disease, a disease associated with HAART therapy; (2) bacterial infections, including Mycobacterium avium complex, rapid occurrence of extreme dementia; and (3) acquired immunodeficiency syndrome (AIDS)-related lymphoma with meningeal involvement. HIV-1 DNA was also amplified from multiple tissues of two HAD patients. Analysis of HIV-1 nef, gp120, and gp41 sequences showed reduced viral evolution within brain tissues for the non-HAD cases relative to patients with clinical and histological HAD. The present study is the first to show a potential correlation between HIV-1 evolutionary patterns in the brain and different neuropathologies.

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    • "These findings suggest that some HIV variants may be more capable of entering the CNS, but are less pathogenic in the brain environment, whereas other HIV variants might be more efficient in both brain infiltration and in setting up the HAD self-inflammatory macrophage environment. Another explanation for the finding of HIV in the brain without HAD development, could be late-stage HIV infiltration, which could arise from atherosclerosis or breakdown of the blood brain barrier near death [3], [5], [6]. "
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    ABSTRACT: The difference between regional rates of HIV-associated dementia (HAD) in patients infected with different subtypes of HIV suggests that genetic determinants exist within HIV that influence the ability of the virus to replicate in the central nervous system (in Uganda, Africa, subtype D HAD rate is 89%, while subtype A HAD rate is 24%). HIV-1 nef is a multifunctional protein with known toxic effects in the brain compartment. The goal of the current study was to identify if specific three-dimensional nef structures may be linked to patients who developed HAD. HIV-1 nef structures were computationally derived for consensus brain and non-brain sequences from a panel of patients infected with subtype B who died due to varied disease pathologies and consensus subtype A and subtype D sequences from Uganda. Site directed mutation analysis identified signatures in brain structures that appear to change binding potentials and could affect folding conformations of brain-associated structures. Despite the large sequence variation between HIV subtypes, structural alignments confirmed that viral structures derived from patients with HAD were more similar to subtype D structures than to structures derived from patient sequences without HAD. Furthermore, structures derived from brain sequences of patients with HAD were more similar to subtype D structures than they were to their own non-brain structures. The potential finding of a brain-specific nef structure indicates that HAD may result from genetic alterations that alter the folding or binding potential of the protein.
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    • "The section shown in Fig. 1 is typical of HIV p24 large vessel staining of a HAD brain section. P24 staining of the meninges for the other patients was very low, presumably due to the late stage of disease; however, as previously reported (Lamers et al., 2010), frontal lobe tissues for all patients stained positive for p24 with varying degrees of intensity. "
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