High level HIV-1 DNA concentrations in brain tissues differentiate patients with post-HAART AIDS dementia complex or cardiovascular disease from those with AIDS

Department of Laboratory Science of Virology, School of Public Health, Shandong University, Jinan, 250012, China.
Science in China Series C Life Sciences (Impact Factor: 1.61). 08/2009; 52(7):651-6. DOI: 10.1007/s11427-009-0085-5
Source: PubMed


Highly active antiretroviral treatment (HAART) has had a significant impact on survival of individuals with acquired immunodeficiency syndrome (AIDS); however, with the longer life-span of patients with AIDS, there is increasing prevalence of AIDS dementia complex (ADC) and other non-AIDS-defining illness, and cardiovascular diseases (CVD) are also common. The influence of these varied disease processes on HIV-1 DNA concentration in brain tissues has not been thoroughly assessed in the post-HAART era. The purpose of the current study is to clarify the impacts of ADC and other complications of HIV disease on the viral load in the brains in AIDS patients with post-HARRT. We examined autopsy specimens from the brains of thirteen patients who died from complications of AIDS with quantitative polymerase chain reaction (QPCR). All but one patient had received HAART prior to death since 1995. Two patients died with severe CVD, multiple cerebrovascular atherosclerosis (CVA) throughout the brain and five patients died with ADC. Six patients had no ADC/CVA. A QPCR was used to measure the presence of HIV-1 DNA in six brain tissues (meninges, frontal grey matter, frontal white matter, temporal subcortex, cerebellum and basal ganglia). In the post-HARRT era, for non-ADC/CVA patients, HIV-1 DNA concentration in brain tissues was statistically higher than that in patients with ADC. In a new finding, two patients who suffered from severe CVD, especially CVA, also had high concentrations of HIV-1 in brain compartments not showing ADC related changes. To our knowledge, this is the first report of a relationship between the CVA and HIV-1 viral burden in brain. The current observations suggest that HAART-resistant HIV reservoirs may survive within ADC lesions of the brain as well as the macrophage rich atherosclerosis, which needs to be confirmed by more AIDS cases with CVA.

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    • "In particular, we were interested in two patients who died due to HAD and questioned if they harbored unique HIV nef structures within the macrophage-associated tissues of the brain. In an earlier study, we noted that many HIV-infected patients did not have significant amounts of HIV within brain tissues at death [4]. Other patients have HIV within the brain, but do not develop symptoms related to HAD. "
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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.
    PLoS ONE 02/2011; 6(2):e16659. DOI:10.1371/journal.pone.0016659 · 3.23 Impact Factor
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    • "c o m / l o c a t e / m e e g i d pathologies showed that both models are possible (Lamers et al., 2010). An additional study by Zhao et al. (2009) showed that 46% of 13 patients were qPCR-negative for HIV within the brain at the time of death, indicating that many patients never develop an active infection in the brain. The biological mechanism(s) responsible for the wide spectrum of potential outcomes remains unclear. "
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    ABSTRACT: Brain infection by the human immunodeficiency virus type 1 (HIV-1) has been investigated in many reports with a variety of conclusions concerning the time of entry and degree of viral compartmentalization. To address these diverse findings, we sequenced HIV-1 gp120 clones from a wide range of brain, peripheral and meningeal tissues from five patients who died from several HIV-1 associated disease pathologies. High-resolution phylogenetic analysis confirmed previous studies that showed a significant degree of compartmentalization in brain and peripheral tissue subpopulations. Some intermixing between the HIV-1 subpopulations was evident, especially in patients that died from pathologies other than HIV-associated dementia. Interestingly, the major tissue harboring virus from both the brain and peripheral tissues was the meninges. These results show that (1) HIV-1 is clearly capable of migrating out of the brain, (2) the meninges are the most likely primary transport tissues, and (3) infected brain macrophages comprise an important HIV reservoir during highly active antiretroviral therapy.
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