HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues
Introduction
One of the primary HIV-associated diseases caused by infection with the human immunodeficiency virus type 1 (HIV-1) is HIV-associated dementia (HAD). Since the institution of HAART therapy, the incidence of HAD has decreased, but the prevalence of HAD and neurocognitive dysfunction now exceeds 20% and may be increasing (McArthur, 2004). While some patients develop a slower, progressive form of HAD, others only develop neurological complications at advanced stages of AIDS and near the time of death. In the latter case, neurological complications are often secondary to other AIDS-associated diseases. In the brain, HIV infects macrophages that release cytokines that present a toxic environment for neurons. In the presence of HIV, astrocytes also synthesize complimentary factors that contribute to neuronal degeneration (Speth et al., 2002). Infected macrophages may also release sphingolipids (Campbell et al., 2002), which alter the functional plasticity of neurons in patients with Alzheimer's disease (Haughey et al., 2010), a disease with similarities to post-HAART HIV-associated neurocognitive dysfunction.
Despite what is known about the effect of HIV in the brain, some debate exists concerning the timing of HIV entry into the central nervous system. Phylogenetic analysis has shown that viral variants in the brain are more compartmentalized than in peripheral tissues (Haggerty and Stevenson, 1991, Salemi et al., 2007, van’t Wout et al., 1998, Wong et al., 1997). Other phylogenetic studies have identified a subset of brain viruses within the periphery (Liu et al., 2000, Wang et al., 2001). Early biological studies suggested that HIV enters the brain via monocyte trafficking in the early stages of infection (Kim et al., 2003) and begins to evolve independently from the virus in the periphery (i.e. compartmentalization) with subsequent viral entry into the brain inhibited by the establishment of an immune barrier (Williams and Hickey, 2002). Later studies suggested HIV enters the brain much later in infection due to general immune failure during the onset of AIDS (Fischer-Smith et al., 2008). A phylogenetic analysis of patients viruses with different disease 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. However, a recent study by Sacktor et al. (2009) showed that specific HIV-1 subtypes are associated with a higher incidence of HAD than infection with other subtypes in the same geographic region. This finding suggests that particular genetic variants have increased neuropathogenesis. A better understanding of brain and periphery viral transport is fundamental to the identification of the tissue or tissues involved in viral gene flow between the two compartments. In this study, we examined brain and peripheral tissues from five patients who died due to varied disease pathologies to determine the degree of compartmentalization within the brain and to follow up on our earlier finding that showed evidence of the meninges acting as a transit route between brain compartments in one patient (Salemi et al., 2005).
Section snippets
Samples
Frozen autopsy tissues from five patients and accompanying pathology records were obtained from the University of California, San Francisco AIDS and Cancer Specimen Resource (ACSR) (http://acsr.ucsf.edu). Tissues were obtained after appropriate consent and de-identification procedures were applied. Patient designations used throughout this study were generated randomly as shorthand used by technicians who performed the studies and names do not correlate to patient information. The ACSR is
P24 staining of HAD brain tissue
The tissue stains of the meninges for patient CX showed a background of HIV p24 positivity with intense staining localized to perivascular macrophages. 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
Discussion
In the current study, we amplified virus from brain and peripheral tissues, including the meninges, from five patients. Two patients died primarily from progressive HAD, whereas the other three patients died from lymphoma, systemic infection or atherosclerosis. In every patient, sequences from the meninges were interspersed within the brain, the periphery, or both tissue types, thus identifying the meninges as the primary supplier of HIV to and from the brain. Although there has been much
Acknowledgements
The project was funded by NIH grants U01 CA066529 and U19 MH081835. MS is supported by NIH grant R01 NS063897-01A2. RRG was supported by T32 NIH training grant_CA-09126. The authors would like to thank those who assisted in generation and proofing of the data: Derek Galligan, Li Zhao and Tulio de Oliveira.
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These authors equally contributed to this work.