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NeuroAids Vol. 2, Issue 8 (September 1999)

Replication of HIV-1 in Human Astrocytes

R. Brack-Werner1 and J. E. Bell2

1GSF-National Research Center for Environment and Health, Institute of Molecular Virology
Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany.

2Neuropathology Laboratory, Dep. of Pathology, The University of Edinburgh,
Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK.

Keywords: Glial cells, astrocytes, HIV, reservoir, Rev, dormant infection.

Abstract Introduction in vitro Infection in vivo Infection Conclusions References

The human immunodeficiency virus (HIV) invades the central nervous system (CNS) and can cause progressive combined cognitive and motor impairment in infected individuals. This review focuses on current knowledge regarding HIV infection and replication in astrocytes.

HIV infection of astrocytic cells has been demonstrated with various cell culture systems. HIV enters astrocytes in a CD4-independent manner, establishing chronic infection with very limited virus production and predominant expression of nonstructural HIV components. Despite these restrictions, infected astrocytic cells initiate highly productive infection of HIV-permissive blood-derived cells in co-culture experiments. Various alterations in the biology of HIV indicate that the astrocytic intracellular milieu differs from that of classic HIV producer cells. Inefficient Rev function is a common feature of human astrocyte cultures and is likely to play a major role in limiting virus replication in these cells. Several studies addressing cellular localization of HIV in brain tissue sections have identified nonstructural HIV markers in astrocytes, whereas HIV structural components are rarely observed. These observations support semi-dormant infection of astrocytes in vivo.

The potential of astrocytes to provide HIV sanctuary from antiviral attacks makes astrocytes important cellular targets for HIV. Future challenges entail understanding how and when astrocytes are infected by HIV in vivo, identification of HIV-suppressive cellular factors in astrocytes and development of strategies to prevent formation of the astrocytic reservoir in HIV-infected individuals.

Abstract Introduction in vitro Infection in vivo Infection Conclusions References

The human immunodeficiency virus has an undoubted capacity to establish a long-term chronic infection of the central nervous system (CNS), and invasion is presumed to occur from the circulation. Although virus production takes place mainly in brain macrophages and microglial cells, other neural cell types may harbor HIV in a more dormant state, contributing to the viral burden in the brain.

Astrocytes constitute the most abundant cell type in the brain, greatly outnumbering microglial cells and neurons. By means of their stellate processes they insulate neurons, enwrap blood vessels and interface with the pia mater. This extensive astrocytic network regulates the concentrations of ions, metabolites and neurotransmitters (particularly glutamate in the neuronal microenvironment). Astrocytes act as entry cells to the brain, controlling the entry of compounds into brain parenchyma by maintaining physiological barriers between neural tissue and the blood or cerebrospinal fluid. They also have an essential role in development and neural cell migration. Astrocytes respond to pathological insults to the CNS by producing a number of immunomodulatory and neurotrophic factors. They express different levels of the cell-specific glial fibrillary acidic protein (GFAP), depending on their location and state of activation. The wide range of astrocyte functions and morphological appearances (1) indicate that the astrocytic cell population is very heterogeneous and may be composed of several different subtypes.

In summary, astrocytes fulfill many functions in the CNS, disturbances of which are likely to have serious consequences. This review outlines current knowledge concerning astrocytes as target cells for HIV.

HIV-1 Infection & Replication in Cultured Astrocytes
Abstract Introduction in vitro Infection in vivo Infection Conclusions References

Cellular model systems for HIV infection of astrocytes.
Interactions of HIV with human astrocytes have been studied in two main types of cell culture systems, namely astrocytoma cell lines and cultures derived from human fetal CNS. These astrocytic model systems consist of mitotically active cells and no experimental system is available yet which mimics fully differentiated, non-dividing astrocytes. Significant diversity of cultured astrocytes (2) necessitates validation of experimental observations with more than one culture system. Despite these caveats, the combined observations from many cellular models and from a number of laboratories have consistently shown HIV infection of astrocytes, involving virus-cell interactions different from events in other cell types.

Evidence for HIV infection of cultured astrocytes.
HIV infection of cultured astrocytes has been demonstrated with at least 10 different astrocytoma tumor-derived cell lines, and for primary cultures of fetal astrocytes from various donors (reviewed in 3). Confirmation of astrocyte infection has been achieved in these studies by a comprehensive range of methods, including productive infection of co-cultured CD4-positive cells, PCR-detection of proviral DNA, detection of Tat stimulatory function, in situ hybridization, single-cell immunostaining and Gag antigen capture. Infection of astrocyte cultures has been shown for T-cell line tropic and monocytotropic strains of HIV-1 and recently also for HIV-2 (4).

Mechanisms of HIV entry into astrocytes.
Interaction of HIV with cellular receptors and mechanisms of HIV entry appear to be fundamentally different for astrocytes than for other target cells (Table 1). HIV does not appear to enter astrocytes via the CD4 molecule, using instead various alternate receptors for entry. Primary fetal astrocytes have been observed to express the HIV co-receptors CXCR4 and CCR5 for T-tropic and M-tropic strains of HIV-1, respectively (5, 4), but the relevance of these cell surface molecules for HIV infection of astrocytes is still unknown. A recent study suggests that entry of HIV into astrocytes may occur by a receptor-mediated endocytic pathway (6), rather than by fusion of HIV with cell surface membrane.

Table 1: Differences in virus-cell interactions observed in astrocytes compared with high-producer cells:
               Pre-integration processes.

Phase of virus life cycle Difference Evidence Astrocytic cell model Reference
Receptor interaction and entry CD4- independent entry No CD4-dependent blockage of gp120 binding or virus infection. *U138 MG
*U138 MG
(50, 51)
(50, 53)
Alternate (co) receptors No effect of stable CD4 expression on infection.


Candidate alternate receptors:
  Galactosyl ceramide
  65 kDa protein
  180 kDa protein
  260 kDa protein


(56, 57)

Virus uptake by endocytosis Virions in clathrin-coated pits and cytoplasmic vacuoles (electron microscopy). +PFA (6)
*Tumor-derived cell line. +Primary fetal astrocytes.

Limited virus production by infected astrocytes.
Astrocytic cultures may show transient low-level production of viral structural components for several days after exposure to HIV-1 (7, 8, 9) However, parallel infection experiments revealed that Gag production by fetal astrocytes was maximally 10% of that observed for microglial cultures (8). Synthesis of structural antigens occurs in about 1-5% of astrocytes (10). Transfection of astrocytes with molecular clones of HIV-1 increased Gag production in the transient productive phase, but did not fully overcome the astrocytic block to the establishment of a highly productive, spreading HIV infection (7).

After the brief initial productive phase, HIV may persist in astrocytic cultures for many months (11, 12, 13). Astrocytic cultures with dormant HIV can initiate productive infection of cocultured HIV susceptible blood-derived cells (10, 14, 15, 16), confirming presence of replication-competent HIV in astrocytes. Chronic HIV-infection of astrocytes is characterized by accumulation of early viral gene products, particularly Nef, and only very limited production of viral structural proteins (10, 17, 16, 9). These observations suggest that astrocytes tolerate chronic infection by HIV by attenuating virus replication, and are capable of transmitting the virus to suitable cells for full-scale production.

Molecular basis of restricted virus production in astrocytes.
Several studies addressing post-integration processes of the HIV life cycle in astrocytes have revealed differences from HIV-producer cells (Table 2), some of which may contribute to limiting HIV production by astrocytes.

Table 2: Differences in virus-cell interactions observed in astrocytes compared with high-producer cells:
               Post-integration processes.

Phase of virus life cycle Difference Evidence Astrocytic cell model Reference
Transcription of viral genes Altered LTR activity Reduced transcription activity and altered binding capacity *U373MG (19)
Additional pathway for stimulation by Tat *U87MG
(21, 23)
Suppression by extra-LTR sequences within nef *#TH4-7-5
Post-transcriptional regulation of viral gene expression Inefficient Rev function Selectively reduced expression of viral structural proteins *#TH4-7-5
(10, 16)
Severely reduced Rev-response; Abnormal accumulation of Rev in the cytoplasm *85HG66
Translation of viral proteins Inefficient translation Reduced production of viral antigens *U251MG (24)
Processing of viral proteins Abnormal cleavage Absence of Env-gp120
Absence of Gag-p24
*Tumor-derived cell line. +Primary fetal astrocytes. #Chronically HIV-1 infected derivative of 85HG66 astrocytoma cell line.

In all infected cells, transcription of the integrated provirus is directed by the viral long terminal repeat (LTR). In astrocytic cells, properties of the LTR may differ from HIV-producer nonglial cells with respect to levels of basal transcription, binding of cellular factors, pathways of stimulation by Tat, and negative modulation of LTR activity (18, 19, 20, 21, 22, 23). While these observations certainly indicate that the cellular factors influencing HIV transcription in astrocytes may be different from other cells, it is not clear at this stage to what extent transcriptional processes contribute to restriction of virus production in astrocytes.

So far as post-transcriptional control of viral gene expression is concerned, selectively reduced expression of viral structural proteins in chronically infected astrocytes (see above) suggests restrictions of Rev functions in these cells. Indeed, the compiled results of numerous experiments with tumor-derived and fetal cell cultures indicate that Rev stimulates HIV-1 structural protein synthesis in astrocytes with only about 10% of the efficiency it displays in Rev-permissive nonglial cells (2). In addition, abnormally high levels of Rev were detected in the cytoplasm of astrocytes, suggesting that inactivation of Rev may involve cytoplasmic sequestration in these cells (2, 16). These studies indicate that diminished Rev function is a hallmark of human cultured astrocytes with a role in limiting HIV-1 production by these cells. In contrast, a recent study based in only one cell line suggested Rev function was not defective in these particular cells (24). Astrocytes are the first human cell type for which an impaired Rev-response has been demonstrated.

Apart from abnormal Rev control of HIV gene expression, post-translational mechanisms have also been proposed to contribute to restricting production of HIV structural proteins (Table 2) (11, 24, 25).

Potential for activation of HIV production in astrocytes.
In vitro studies have also shed light on the extent to which production of HIV can be activated in astrocytes. HIV production can be stimulated in infected fetal astrocytes by treatment with the cytokines tumor necrosis factor alpha (TNFalpha) and interleukin-1 beta (Il-1ß) (9). However, the initial levels of response to cytokine stimulation were not maintained following repeated exposures, despite persisting astrocyte infection (9). A two to six-fold stimulatory response was noted in the chronically HIV-1 infected astrocytoma cell line TH4-7-5 by exposure to phorbol esters, TNFalpha, Il-1ß and sodium butyrate (26, 27). It appears that these compounds, while showing a modest stimulation of HIV production, are not capable of completely rescuing HIV-production in chronically infected astrocytes.

HIV-1 Infection of Astrocytes in Human Brain Tissue
Abstract Introduction in vitro Infection in vivo Infection Conclusions References

Evidence for HIV-1 infection of astrocytes in the intact brain has accumulated from a number of studies utilizing different methodologies. Early ultrastructural examination of cases of HIV encephalitis (HIVE) revealed the presence of viral particles within the cytoplasm of astrocytes, identified by their content of intermediate filaments, as well as in multinucleated giant cells (28, 29, 30). Immunocytochemical investigation also identified HIVp17 and p24 protein in astrocytes in occasional cases of HIVE (31) as well as in other non-microglial cells. HIV nucleic acids were identified in astrocytes by in situ hybridization studies (32). Critical appraisal of these early studies led some reviewers to the view that infection of astrocytes had not been demonstrated conclusively (33). However, more recent investigation has again focused attention on the role of astrocytes and other non-microglial cells in HIV infection. Astrocytic hyperplasia is a feature of the neuropathology of HIV infection in both white and gray matter at all stages of the disease, and not just in cases of HIVE (34, 35, 36). While nearly all investigators have failed to find evidence of HIV structural protein expression in astrocytes, a number of studies employing the in situ PCR technique have shown that a proportion of astrocyte nuclei contain HIV-1 DNA both in adult and childhood cases of AIDS (37, 38, 39, 40, 41). In the studies by Nuovo et al (39) and Bagasra et al (37) this finding was confirmed by the use of reverse transcriptase (RT) in situ PCR, and other groups have confirmed the infected cells as astrocytes by double labeling for GFAP. It is of interest that in several of these studies the infected cells were more numerous in gray than in white matter and that the total number of infected cells correlated well with severity of symptoms (38, 39).

In both adult (42) and pediatric (43, 44) AIDS cases, astrocytes that express Nef protein have been identified. That these astrocytes were HIV infected was confirmed by the presence of Nef mRNA (43) or by the detection of HIV-1 DNA by in situ hybridization (44). This is consistent with the restricted HIV-1 infection seen in cultured astrocytes. Evidence for the concept of astrocytic HIV infection in vivo has been summarized by Conant et al. (45) and Kolson et al. (46), and the subject has been comprehensively reviewed by Brack-Werner (3). The mechanism of HIV entry into astrocytes in the intact brain remains unknown. The consensus view is that CD4 receptors are not expressed on macroglial cells in vivo (46). At least some astrocytes express the chemokine receptor CCR5 (47). The complex cytoarchitecture of the brain parenchyma could favor cell to cell contact transmission in vivo as observed in vitro (48). HIV-1 infection is known to upregulate expression of astrocytic adhesion molecules, namely I CAM-1 and V CAM-1 (49), which support adherence of lymphocytes and monocytes.

Abstract Introduction in vitro Infection in vivo Infection Conclusions References

Numerous studies show that HIV enters astrocytes, generating a poorly productive, persistent infection. Various aspects of the HIV-life cycle differ from other target cells for HIV, indicating unique virus-cell interactions in astrocytes. The capacity of HIV-harboring astrocytes to generate a full-blown productive infection in HIV-susceptible blood cells supports a role for astrocytes as reservoirs for HIV. Thus astrocytes may provide a sanctuary for the virus from antiviral attacks, both by their location in an immunologically privileged organ and by interfering with replicatory processes targeted by antiviral drugs. The astrocytic reservoir may constitute an important hindrance to clearance of HIV from infected individuals.

Discussion relating to HIV-1 infection of the CNS has been dominated by the concept of productive infection in microglial cells, deflecting attention away from the evidence pointing to persistent, non-productive infection in astrocytes. The extent to which these parallel infections, one overt and one more hidden, underpin the pathogenesis of HIVE is unknown. Similarly, the potential for interaction between the astrocytic and microglial cell populations has not been explored in HIVE. Studies of the role of astrocytes in pathogenesis have to date been handicapped by the limited repertoire of HIV proteins expressed by infected astrocytes. Further complications may be presented by varying susceptibilities of astrocytes to HIV infection, depending on their anatomical locations and the age of the infected individual (pediatric versus adult).

There is an urgent need to advance the study of HIV infection of astrocytes, considering the significance of these cells for the function of the CNS and their potential to fulfill both protective and detrimental roles in HIV-induced neuropathogenesis. The unique location of astrocytes at the blood-brain barrier suggests that they could protect the CNS from the effects of extensive virus production, especially during the pre-AIDS phase, by storing incoming HIV in a more or less dormant state. As breakdown of the blood-brain barrier increases the number of infiltrating HIV-susceptible cells, the astrocytic reservoir for HIV may augment HIV spread and increase of virus load in the brain. Infected astrocytes may also contribute to HIV-associated neuropathogenesis by producing cellular and/or viral neurotoxic factors. While HIV infection of astrocytes is clearly not lytic, infection-induced physiological changes may interfere with the sophisticated functions of this group of cells with deleterious consequences for neurons. For a more detailed discussion the reader is referred to (3).

Future challenges entail perceiving how and when astrocytes are infected and under which circumstances the astrocytic reservoir is activated. These studies will require refinement and expansion of in situ methods for reliable identification of infected astrocytes in the absence of virus production. Detailed analysis of cellular mechanisms associated with HIV suppression in astrocytes will increase understanding of host-cell dependent modulation of the HIV life cycle and may be exploitable for design of new antiviral strategies. Finally, understanding HIV-induced changes in properties of astrocytes may enhance development of therapeutic strategies to sustain functions of these extremely important neural cells and thus may have a more general impact for neurodegenerative diseases.

Abstract Introduction in vitro Infection in vivo Infection Conclusions References

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