|NeuroAIDS Vol. 1, No. 5, September 1998|
|What is known about HIV tropism in the brain?|
|J. E. Clements|
|John Hopkins University, School of Medicine, Baltimore, Maryland, United States|
|Address correspondence to: firstname.lastname@example.org|
: What is neuroAIDS?
HIV can cause infection of cells in the brain leading to a neurodegenerative disease known as the "AIDS Dementia Complex" (Johnson, 1995). The cells in the CNS most frequently infected are macrophages and microglia (Wiley et al., 1986; Kure et al., 1990a). However, other cells in the brain have been found to be infected in the brains of children and adults with AIDS-associated encephalopathy and dementia, but at a much lower frequency: these include brain microvascular endothelial cells, and astrocytes ( Kure et al., 1990a; Kure et al., 1990b; Bagasra et al., 1996).
Q: Is there a difference in HIV isolates?
HIV isolated from the CNS is most frequently macrophage-tropic, non-syncitial inducing virus that is also associated with virus transmission and early infection ( Zhu et al., 1993; McNearney et al., 1992; Roos et al., 1992; Smith et al., 1990; Popovic et al., 1988; Gartner et al., 1986). This is in contrast with T-cell tropic, syncitial inducing virus found at later times in the infection and that is frequently associated with the clinical phase of AIDS.
Q: How does HIV infect cells in the CNS?
The identification of chemokine receptors as co-receptors for HIV entry and infection raises questions about mechanisms of cell entry in the CNS ( Feng et al., 1996; Deng et al., 1996; Deng et al., 1997). The co-receptor utilization by strains of HIV-1, in part, explain the cell tropism of the virus. Macrophage-tropic strains of HIV-1 utilize the chemokine receptor CCR5 on macrophages and primary lymphocytes while strains of HIV-1 that replicate in T-cell lines utlize CXCR4 on lymphocytes but cannot use that molecule for entry of macrophages. Since mainly macrophage-tropic strains of HIV-1 are found in the CNS it is likely that this co-receptor plays an important role, however, other chemokine co-receptors are expressed in the CNS and these may provide alternative routes for HIV-1 infection.
In both the HIV-2 and SIV systems viruses have now been shown to enter and infect cells by CD4-independent pathways ( Endres et al., 1996; Clapham et al., 1992; Edinger et al., 1997). For HIV-2 this has been via CXCR4 and for SIV via CCR5. CD4-independent infection may be particularly important in the CNS where cells like the microvessel endothelial cells, astrocytes and neurons express chemokine receptors but no CD4 ( Moses et al., 1993; Mankowski et al., 1994). It has not been shown as yet whether this CD4-independent pathway is utilized by naturally occurring strains of HIV-1.
Q: Can neurovirulent, macrophage-tropic HIV selectively replicate in the CNS?
It is unclear from studying HIV isolates from the CNS whether these viruses have been selected for replication in CNS cells and specifically cause encephalopathy and dementia. There is a controversy between two theories - one is that neurovirulent HIVs are responsible for CNS disease. The other is that any macrophage-tropic isolate can replicate in the CNS and cause disease. The latter theory is difficult to reconcile with the fact that most individuals are infected with macrophage-tropic strains of HIV. Thus, if all macrophage-tropic strains of HIV could cause CNS disease, it might be expected that a higher percentage or all infected individuals would have CNS infection and disease. This is, however, not the case. Studies in the SIV model and in HIV in vitro, suggest that there are viruses that are capable of infecting CNS microvascular endothelial cells that comprise the blood brain barrier ( Edinger et al., 1997; Moses et al., 1993; Mankowski et al., 1994; Mankowski et al., 1997; Flaherty et al., 1997).These SIV isolates are neurovirulent when inoculated into macaques ( Mankowski et al., 1997; Flaherty et al., 1997). Further, SIV isolates selected for replication in microglia also replicate in CNS microvascular endothelial cells and are neurovirulent in macaques ( Strelow et al., 1998). Thus, in the SIV animal model there is experimental support for the existence of neurovirulent viruses.
In HIV it is more difficult to show a direct correlation between viruses isolated from the CNS and the development of CNS disease. However, the envelope glycoprotein of HIV isolates from the CNS have been shown to have specific amino acid changes in and around the V3 loop that may be important for cell tropism ( Powers et al., 1995).
Q: Is the CNS a significant reservoir for HIV?
HIV and SIV may enter the CNS early after infection, most likely during acute infection when there is virus in the peripheral blood and there is activation of the immune system due to the acute infection. HIV replicates in the perivascular macrophages and microglia in the brain. The perivascular macrophages remain in the CNS for relatively long periods of time (3 months) and can return to the periphery. Thus, it is possible that the CNS can provide a reservoir of virus that replicates independently of the peripheral blood.
Q: Do HIV anti-viral drugs work in the CNS?
Few of the HIV anti-viral drugs penetrate into the CNS to any extent. AZT has been found to be the most effective of the anti-virals in reducing CNS related clinical signs. However, whether AZT significantly affects the level of virus replication in the CNS has been difficult to determine. There are currently a number of NIH-sponsored trials in which new drugs (specific for the CNS) are added to the best anti-retroviral regimen. Thus, it will be important to know if drug treatment reduces the virus in the CNS or whether the reduction in the development of CNS disease is due to the maintenance of the immune system.
Q: What further scientific questions need to be addressed?
There are many important questions about HIV cell tropism and the CNS. One that is particularly important for furthering our understanding of the biology of the virus is that there are few primary HIV-1 isolates from the CNS. It is important to expand the numbers of these isolates to study their biology. Further, the SIV model provides a parallel experimental system in which to test hypotheses that are not testable in humans with HIV.
Bagasra, O. et al. Cellular reserviors of HIV-1 in the central nervous system of infected individuals: identification by the continuation of in situ polymerase chain reaction and immunohistochemistry. AIDS 10, 573-585 (1996).
Clapham, P.R., McKnight, A., Weiss, R.A. Human immunodeficiency virus type 2 infection and fusion of CD4-negative human cell lines: induction and enhancement by soluble CD4. J. Virol. 66, 3531-3537 (1992). Medline
Deng, H. et al. Identification of a major co-receptor for primary isolates of HIV-1 [see comments]. Nature 381, 661-666 (1996). Medline
Deng, H., Unutmaz, D., KewalRamani, V., Littman, D. Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature 388, 296-300 (1997). Medline
Endres, M.J. et al. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell 87, 745-756 (1996). Medline
Edinger, A. et al. CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent SIV. Proc. Natl. Acad. Sci. USA In Press (1997).
Feng, Y., Broder, C.C., Kennedy, P.E., Berger, E.A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor [see comments]. Science 272, 872-877 (1996). Medline
Flaherty, M.T., Hauer, D.A., Mankowski, J.L., Zink, M.C., Clements, J.E. Molecular and biological characterization of a neurovirulent molecular clone of SIV. J. Virol. 71, 5790-5798 (1997). Medline
Gartner, S. et al. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233, 215-219 (1986). Medline
Johnson, R.T. The pathogenesis of HIV infections of the brain. Curr. Top. Microbiol. Immunol. 202, 3-10 (1995). Medline
Kure, K., Lyman, W.D., Weidenheim, K.M., Dickson, D.W. Cellular localization of an HIV-1 antigen in subacute AIDS encephalitis using an improved double-labeling immunohistochemical method. Am. J. Pathol. 136, 1085-1092 (1990). Medline
Kure, K., Weidenheim, K.M., Lyman, W.D., Dickson, D.W. Morphology and distribution of HIV-1 gp41-positive microglia in subacute AIDS encephalitis. Acta Neuropathol. 80, 393-400 (1990). Medline
Mankowski, J.L. et al. Neurovirulent simian immunodeficiency virus replicates productively in endothelial cells of the central nervous system in vivo and in vitro. J. Virol. 68, 8202-8208 (1994). Medline
Mankowski, J.L. et al. Pathogenesis of simian immunodeficiency virus encephalitis: Viral determinants of neurovirulence. J. Virol. 71, 6055-6060 (1997). Medline
McNearney, T. et al. Relationship of human immunodeficiency viurs type 1 sequence heterogeneity to stage of disease. Proc. Natl. Acad. Sci. USA 89, 10247-10251 (1992). Medline
Moses, A.V., Bloom, F.E., Pauza, C.D., Nelson, J.A. Human immunodeficiency virus infection of human brain capillary endothelial cells occurs via a CD4/galacytosylceramide -independent mechanism. Proc. Natl. Acad. Sci. (USA) 90, 10474-10478 (1993). Medline
Popovic, M., Gartner, S. Isolation of HIV-1 from monocytes but not T lymphocytes. Lancet 2, 916-910 (1987). Medline
Powers, C. et al. Distinct HIV-1 env sequences are associated with neurotropism and neurovirulence. Curr. Top. Microbiol. Immunol. 202, 89-104 (1995). Medline
Roos, M.T.J., Lange, J.M.A., deGoede, R.E.Y. Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection. J. Infect. Dis. 165, 427-432 (1992). Medline
Smith, T.W., DeGirolami, U., Henin, D., Bolgert, F., Hauw, J.-J. Human immunodeficiency virus (HIV) leukoencephalopathy and the microcirculation. J. Neuropathol. Exp. Neurol. 49, 357-370 (1990). Medline
Strelow, L.I., Watry, D.D., Fox, H.S., Nelson, J.A. Efficient infection of brain microvascular endothelial cells by an in vivo-selected neuroinvasive SIVmac variant. J. NeuroVirol. 4, 269-280 (1998). Medline
Wiley, C.A., Schrier, R.D., Nelson, J.A., Lampert, P.W., Oldstone, M.B. Cellular localization of HIV infection with the brains of AIDS patients. Proc. Natl. Acad. Sci. USA 83, 7089-7093 (1986). Medline
Zhu, T. et al. Genotypic and phenotypic characterization of HIV-1 in patients with primary infection. Science 261, 1179-1181 (1993). Medline
|Copyright Information | Site map|