Phylodynamic Analysis of Human Immunodeficiency Virus Type 1 in Distinct Brain Compartments Provides a Model for the Neuropathogenesis of AIDS

Abstract

"Phylodynamic" analysis combines various statistical procedures that can be used to correlate the epidemiological and evolutionary behavior of viral pathogens with the immune system of the host. We utilized this approach to examine human immunodeficiency virus type 1 (HIV-1) gp120 envelope DNA sequences (V1, V2, and V3) isolated from different brain compartments of a T-cell-depleted patient diagnosed with severe HIVassociated dementia at the time of death. In agreement with previous reports, phylogenetic analysis showed distinct virodemes but also revealed a significant amount of viral gene flow among different brain compartments. Local-molecular-clock analysis showed that HIV-1 meninges and temporal lobe subpopulations evolve about 30 and 100 times faster, respectively, than the other viral populations in the brain. However, maximum likelihood codon-based substitution models did not detect any site under significant positive selective pressure, and the main cause of HIV-1 genetic variation appeared to be random genetic drift. Therefore, the higher evolutionary rate in the meninges and temporal lobe could be due to an enhanced infection/expansion rate of macrophages as a consequence of the immune system failure. In conclusion, in this case study, viral infection in the brain progressed with a nonspecific genetic evolution, recurrent migration events, and an expansion of macrophage-tropic sequences. The data suggest that after immune failure newly produced viral variants, which would be rapidly cleared under normal conditions, begin to productively infect macrophages in a "selfamplifying" cycle of infection/inflammatory response that could be at the origin of HIV-associated dementia.

Towards an understanding of the migration of Crimean-Congo hemorrhagic fever virus

“…Such analysis has been used successfully to determine migration patterns of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) within and between countries (Nakano et al, 2004;Salemi et al, 2008a, b) and to analyse the migration of HIV-1 between different compartments in the brain (Salemi et al, 2005) and between lymphoid and non-lymphoid tissues (Salemi et al, 2007).…”

“…The worldwide migration of CCHFV was analysed by using a modified version of the Slatkin-Maddison test (Slatkin & Maddison, 1989), which counts migration events to and from subpopulations. Such analysis has been used successfully to determine the migration patterns of HIV-1 and HCV within and between countries (Nakano et al, 2004;Salemi et al, 2008a, b) and to analyse the migration of HIV-1 between different compartments in the brain (Salemi et al, 2005) and between lymphoid and nonlymphoid tissues (Salemi et al, 2007).…”

Molecular Epidemiology of HIV Type 1 CRF02_AG in Cameroon and African Patients Living in Italy

“…The hypothesis of metapopulation structure, i.e., the existence within each clade of different subpopulations linked to different Cameroon geographic regions, was tested with a modified version of the Slatkin and Maddison test 45,46 using the MCC trees. A one-character matrix was obtained from the original dataset by assigning to each taxon in the tree a one-letter code indicating its geographic region of origin.…”

HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads

“…Moreover, resident tissue macrophages are long-lived and may naturally produce low levels of virus. HIV ϩ perivascular macrophages and macrophage-like microglia (39,40) in the brain have been associated with the emergence of antiretroviral drug resistance (41,42) and HIV-associated neurocognitive disorders (HAND) (43,44). HIV ϩ patients may also harbor viral populations in cerebrospinal fluid (CSF) that are genetically distinct from virus in the blood (45)(46)(47)(48)(49)(50) and that exhibit characteristics of macrophage/microglia tropism (51).…”