Astrocyte infection by HIV-1: mechanisms of restricted virus replication, and role in the pathogenesis of HIV-1-associated dementia.
Astrocytes are the most numerous cell type in the brain, and their physiological roles are essential for normal brain function. Studies of post-mortem brain tissue samples from individuals with AIDS have revealed that a small proportion of astrocytes are infected by HIV-1 which is linked to the development of HIV-associated dementia (HIVD), a frequent clinical manifestation of HIV-1 disease affecting up to 20% of infected adults. However, astrocyte infection by HIV-1 in vivo is generally non-productive, and can only be readily detected by sensitive techniques that detect HIV-1 RNA or proviral DNA. Similarly, primary astrocyte cultures and astrocytic cell lines can be permissive to infection by HIV-1 strains, but are refractory to efficient HIV-1 expression. In efforts to delineate the molecular mechanisms underlying the "restricted" infection, several studies have demonstrated that efficient HIV-1 replication is blocked in astrocytes at different steps of the virus life cycle, including virus entry, reverse transcription, nucleocytoplasmic HIV-1 RNA transport, translation of viral RNA, and maturation of progeny virions. However, the relative importance of each of these possible replication blocks in restricting HIV-1 replication in astrocytes is unclear. Moreover, how restricted astrocyte infection contributes to the development of HIVD is unknown. This review surveys the current in vitro models of restricted HIV-1 replication in astrocytes, and provides an analysis of the available evidence supporting a role for astrocyte infection in the pathogenesis of HIVD. A greater understanding of the fate of HIV-1 in astrocytes may assist in the identification of viral reservoirs in the central nervous system, novel therapies for the treatment of HIVD, and also novel strategies to suppress HIV-1 replication in CD4+ cells of the immune system.
Gorry
Paul R
PR
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia. gorry@burnet.edu.au
Ong
Chi
C
Thorpe
Janine
J
Bannwarth
Sylvie
S
Thompson
Katherine A
KA
Gatignol
Anne
A
Vesselingh
Steven L
SL
Purcell
Damian F J
DF
D015526:AIDS Dementia Complex / Q000821:virology*; D001253:Astrocytes / Q000821:virology*; D016207:Cytokines; D015694:Gene Products, rev / Q000502:physiology; D016325:HIV Long Terminal Repeat / Q000502:physiology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009498:Neurotoxins; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins / Q000502:physiology; D015728:Receptors, HIV / Q000502:physiology; D014158:Transcription, Genetic; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism; D054321:rev Gene Products, Human Immunodeficiency Virus; D000099253:Trans-Activation Responsive RNA-Binding Protein
D016207:Cytokines; D015694:Gene Products, rev; D009498:Neurotoxins; D016601:RNA-Binding Proteins; D015728:Receptors, HIV; D019892:eIF-2 Kinase; D054321:rev Gene Products, Human Immunodeficiency Virus; D000099253:Trans-Activation Responsive RNA-Binding Protein