Neurolo The Human Immunodeficiency Virus, Type 1: The Virus and Its Role in Neurologic Disease Joseph R. Berger, M.D. and Jay A. Levy, M .D.
In 198 1, an immunodeficiency state characterized by such illnesses as Pneumocystis carinii pneumonia1,' and chronic ulcerative genitoanal herpes simplexqn homosexual males was described. The first recognized neurologic consequences of this newly recognized illness were reported the following year.' In retrospect, perhaps, the earliest cases of this immunodeficient state had come to medical attentiorl Serologic tests performed on banked specimens, confirming the presence of antibody to human immunodeficiency virus, type 1 (HIV-I), indicate that isolated cases of the immunodeficiency state had occurred in the United States'jand Scandinavia7 as early as the middle of the 1960s. Until 1983, the etiology of this immunodeficient state, referred to as the acquired immunodeficiency syndrome (AIDS), remained uncertain.
T h e diagnosis was established on the basis of clinical criteria. T h e definition established by the Centers for Disease Control (CDC) was "a disease, at least moderately predictive of a defect of cell-mediated immunity, occurring in persons with no known cause of diminished resistance to the disease."x T h e conditions recognized to occur with AIDS included not only infectious illnesses, such as P. carinii pneumonia, severe ulcerative herpes simplex, and toxoplasmosis encephalitis, but also Bcell lymphoma^,^ and a previously rare tumor, .'' abounded with reKaposi's ~ a r c o m a . ' ~ Theories spect to the etiology of this illness. However, by 1983"-'* a retrovirus was found in patients with AlDS and, subsequently, convincingly demonstrated to be the etiologic agent. With the availability of serologic assays to demonstrate the presence of infection, the CDC definition of AIDS was mod-
Departments of Neurology and Internal Medicine, the University o f Miami School o f Medicine, Miami, Florida, and the Department o f Medicine and Cancer Research Institute, the University o f California, San Francisco, California. Supported in part by grant NS 25569 from the National Institutes of Health. Reprint requests: Dr. Berger, Department of Neurology, University of Miami School o f Medicine, 1500 NW 9th Avenue, Miami, Florida 33136.
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ified to include serologic evidence of infection, and several different staging systems were proposed. '5-16
RETROVIRUSES Retroviruses are a unique family of RNA viruses to which the causative agent of AIDS belongs. T h e name of this family of viruses is derived from the presence of RNA-dependent DNA polymerase (reverse transcriptase), an enzyme enabling these RNA viruses to produce a DNA copy of their genome, which can then be incorporated into the host genome. On occasion, the viral DNA that has been integrated into host genome can be transmitted through the germ line. T h e retroviruses are widely distributed among vertebrate animals, including horses, sheep, goats, cows, cats, and monkeys.17 Retroviruses have been divided into three major subfamilies: lentivirus (lente: slow), oncovirus (onco: tumor), and spumavirus (spuma: foam). Both lentiviruses and oncoviruses have been associated with disease in humans. Human T-lymphotropic viruses types I and I1 (HTLV-I and HTLV-11, respectively) are members of the human oncovirus subfamily. HTLV-I is the etiologic agent of adult T-cell leukemia and lymphomas. l8.Iy HTLV-I has also been linked to a progressive myelopathy referred to as HTLV-I-associated myelopathy, or ~ ~ ~ ~ has been tropical spastic p a r a p a r e s i ~ . ' HTLV-I1 associated with hairy cell le~kemia.'~It has also been linked to spinal cord disease." Although spumaviruses have not been convincingly demonstrated to cause disease in man, recent studies suggest that they are capable of inducing a demyelinating disorder of transgenic micez4 and may be linked to human neurologic disease.
VOLUME 12, NUMBER 1 MARCH 1992
gene^.'^ Significant sequence homologies exist, however, such as that between visna virus, the prototypical lentivirus, which is capable of inducing a demyelinating disorder in sheep, and HIV-1." These observations indicate that HIV belongs taxonomically in the lentivirus subfamily. All known lentiviruses, including visna, caprine arthritis encephalopathy virus, bovine visna, feline immunodeficiency virus, and simian immunodeficiency virus, are capable of causing neurologic disease.28 Other characteristics of this family of viruses are their large size, the ability to produce cytopathic changes in infected cells, and the long incubation times before the development of clinical illnesstypically, immunologic or neurologic disease.26 The HIV-1 virion, as demonstrated by electron microscopy, is an icosahedral structurezYcomprised of 72 external spikes. The dominant viral envelope proteins are gp 120 and gp4 1, and the underlying lipid bilayer contains a number of host proteins derived at the time of viral budding (Fig. I)."" Both class I and class I1 histocompatibility antigens can be found in this lipid bilayer." Four nucleocapsid proteins, p24 (p25), p17, p9, and p7, comprise the core of HIV-l.26.30 The first, p24, is the chief component of the nucleocapsid core. HIV-1 contains three transcriptive units that code for common viral structural proteins (Fig. 2). These transcriptive units are the gag, pol, and env regions. They code for three classes of polypeptides found in the majority of animal retroviruses: structural, nonenvelope polypeptides; enzymes required for viral replication; and envelope proteins. The gag region codes for the nonenvelope, core
HUMAN IMMUNODEFICIENCY VIRUS, TYPE 1
2
HIV-1, the virus that causes AIDS,'2.13has been previously referred to by other appellations, including AIDS-associated virus (ARV),14 human T-lymphotropic virus type I11 (HTLVIII),I2 lymphadenopathy-associated virus (LAV),I3 and HTLV-IIIILAV. A related virus, human immunodeficiency virus, type 2, (HIV-2), has been recognized more recently.25It is chiefly, although not exclusively, seen in Western African populations and is also capable of causing an AIDS-like illness. Although sharing a similar structure to HIV1, each subtype of lentivirus contains unique
Lipid Bilayer Figure 1. A diagram of the fundamental structure of the human immunodeficiency virus type 1. The envelope glycoproteins (gp120 and gp41) and the major viral core proteins (p25, p17, p9, and p7) are shown. The core protein p17 exists exterior to the viral nucleoid. RT: reverse transcriptase. (From Levy.26Reprinted with permission.)
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HIV I N NEUROLOGIC DISEASE-BERGER,LEVY Transactivator of Requiredfor Reduction of InfectiousVirions
Up Regulates HIV Production
Core Protein
+
LTR
gag
4 Regulatory Sequences for HIV Replication
env
4
ProteaselReverse Transcriptasel Endonuclease
Function Unknown
4 Envelope Proteins
nef
b Down Regulationof HIV ~ e p l h i o n
proteins, which include the nucleoid shell (p24) and several smaller internal proteins. Initially, these proteins are synthesized as a 55 kd precursor and are subsequently cleaved into their final proteins. The pol region codes for reverse transcriptase, a protease, and an endonuclease. The DNA synthesized from the viral RNA by reverse transcriptase can be integrated into the host genome by the action of the endonuclease. The protease is responsible for cleaving the polyproteins coded for by the gag and pol regions into their active moieties.'"he two major envelope proteins (gp120 and gp41) are coded for by the env region. The gp120 is a large glycoprotein on the surface of the virion and gp41 is a smaller transmembrane glycoprotein. The envelope proteins are responsible for viral binding to the target cells. Four regulatory proteins have been identified with HIV-1. The tat and rev genes are believed to be responsible for the up-regulation of viral reproduction."' T h e tat gene is a transactivating regulator of RNA translation. The 14 kd product of this gene also increases transcription of DNA in HIVinfected ~ e l l s . "The ~ , ~rev ~ gene is a regulator modulating expression of the structural proteins at the level of transcription. Conversely, the nef gene is a cis-acting down-regulator of RNA tran~cription.~' The other regulatory protein is coded for by vif, which is responsible for maturation of viral proteins at the time of budding from the cell.32The action of some of the products of these regulatory genes may be through binding to the long terminal repeat (LTR) sequence of the viral genome. Other viral genes have been identified, but their functions remain unknown. Following infection, lentiviruses replicate slowly within target organs, primarily peripheral lymphoThe viruses are typically cytes and mon~cytes."~
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Figure 2. Genetic structure of the human immunodeficiency virus, type 1. The three major structural proteins (gag, pol, and env) are shown in black and the regulatory proteins (tat, rev,and nef) shown with diagonal lines. The genes that have not been fully characterized are depicted as boxes with cross-hatching.The gene products are summarized. (From Levyz6Reprinted with permission.)
harbored in a latent form, with an estimated 1 per 100 to 1 per 1000 infected cells exhibiting active viral replication."Viral replication is slowed by restricted gene expression."%Although the hypothesis is unproven, the entry of the lentivirus from blood into affected tissues such as the l i n g and brain (see later) has been suspected to result from entry of latently infected circulating cells such as the peripheral blood monocyte." A similar mechanism has been suggested for viral entry in HIV-1 infection. With respect to central nervous system (CNS) infection by HIV-1, Wiley et a1"' postulate that opportunistic infection of the CNS allows recruitment of latently infected monocytes inlo the brain with the subsequent differentiation of these infected monocytes into tissue macrophages productive of HIV-1. However, this hypothesis does not account for evidence indicating that HIV-1 is present in the CNS in the earliest stages of infection, well before significant immunosuppression occurs. Early in infection, HIV-1 can be cultured from the cerebrospinal fluid (CSF),"." and intrathecal synthesis of antibody to HIV-1 can be dem~nstrated.~" Using polymerase chain reaction, investigators have demonstrated HIV-1 nucleic acid in the brain within 15 days of infection in one recently reported case.41These observations suggest that a concomitant opportunistic infection of the CNS is not necessary for HIV-1 penetration of the blood-brain barrier.
TRANSMISSION OF HIV-1 HIV-1 has been demonstrated in varying but transamount in virtually every body fluid:' mission of HIV results chiefly through homosexual or heterosexual contact, contaminated blood or
3
blood products, or transmission from mother to fetus. The levels of virus in plasma and semen are relatively low, at 10 to 50 infectious particles per milliliter.43This value, which is substantially lower than that for hepatitis B infectious particles, explains the difference in rates of HIV-1 versus hepatitis B infection following a needlestick injury. HIV-1 in genital fluids is mostly cell-associated, with the amount of cell-free virus being quite low. Concomitant genital disease increases the presence of inflammatory cells in genital secretions and is likely to account for the increased transmission of HIV-1 that occurs in the presence of some sexually transmitted diseases. It is curious that the body fluid with the highest concentration of cell-free virus is the CSF,"j but it cannot be a source of contagion.
CONSEQUENCES OF INFECTION Even before the demonstration of the virus as the cause of AIDS, a specific pattern of immunologic defects was recognized in the illness. This pattern was characterized by a decrease in CD4 T lymphocytes (helperlinducer cells) and an inversion of the CD4lCD8 T-lymphocyte ratio to less than T h e inversion in the helper to suppressor cell ratio was recognized to be chiefly a function of a loss of the CD4+ T-lymphocyte subset.45There is an inverse correlation between the absolute number of CD4 T lymphocytes and the presence of HIV1.46,47 -Likewise, there is a direct correlation between the duration of HIV-1 infection and the degree of immunosuppression, as measured by laboratory and clinical parameter^.^^ The AIDS virus is tropic for CD4+ T-lymphocytes and can be isolated from CD4+ T-lymphocytes, monocytes, and macro phage^.^^-^^ Selective binding of HIV to the CD4 receptor on the CD4+ T lymphocyte has been demonstrated in ~ i v o This binding appears to occur as a consequence of the interaction of a 120 kd viral envelope protein and the CD4 receptor.54 In most cases, infection leads to down-modulation of the CD4 receptor on the cell surface.55 However, in culture, susceptibility to infection by HIV-1 is not universal in all CD4+ T-lymphocytes,5\nd mouse cells transfected with and expressing CD4 protein are not Conversely, cells susceptible to HIV-1 infe~tion.~' that do not express CD4 protein can be infected; this suggests that other surface moieties are important for viral infection. Both brain-derived cells and human fibroblasts, as well as other CD4 cells, can be infected in vitro with HIV-1.43 Recently, galactocerebroside on the surface of CD4 brain-de4
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rived cells has been identified as an alternative receptor'for HIV-1 .58 Tissue culture techniques and the examination of fixed specimens suggest that a wide variety of human cells may be susceptible to HIV-1 infect i ~ nIn . ~the ~ brains of infected individuals, in situ hybridization and electron microscopy reveal in. ~ ~ ~ ~ ~ fection of macrophages and glial ~ e l l s Application of these techniques has suggested that astrocytes, oligodendrocytes, and brain capillary endothelial cells may harbor low titers of HIV-1. Similar observations reveal that other cells, including crypt cells and the lamina propria of the gut and, perhaps, Langhans cells of the dermis and fetal chorionic villi, are susceptible to HIV-1 infect i ~ n . Tissue ~' cultures have established HIV-1 infection in fetal brain tissue and glioma cell lines62 as well as cells of the hematopoietic system, brain, gut, skin, and several others.26 Further study is warranted to provide unassailable evidence for some of these observations. These findings have resulted in the hypothesis that viral gp120 is responsible for attachment to the cell surface via the CD4 receptor, but entry into the cell is the consequence of fusion with the cell -membrane through the gp41 domaimZ6Entry into
.~~
Figure 3. Life cycle of HIV-1. The initial event is attachment of the virus to specific receptor on the cell surface followed by fusion of the virus to the cell membrane. The intact viral nucleoid enters the cell cytoplasm. Transcription begins with reverse transcriptase and ultimately results in viral double-stranded DNA copied from the viral RNA. Circular DNA of viral origin can enter the nucleus and integrate into the cellular chromosome using the viral endonuclease. In productive infection, the proviral DNA produces two forms of RNA: mRNA, which codes for proteins required in replication and virion RNA, which is required for the infectious virion. The virion RNA is encapsulated and then expressed from the cell by budding. (From Levyz6Reprinted with permission.)
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identical, preliminary analysis by x-ray diffraction of the V3 loop of these isolates indicates that they are structurally identical. Indeed, even the local antibody response to HIV-1 within the CNS may be selective for the neurotropic variant of HIV- 1.70 The mechanism by which HIV-1 results in CNS dysfunction remains unanswered, although HUMAN IMMUNODEFICIENCY VIRUS, several mechanisms have been postulated. First, TYPE 1, NEUROPATHOGENESIS the virus may be neurotropic,-that is, have a proHIV-1 enters the CNS early in infection. The pensity to infect glial cells and perhaps even postulated mechanisms by which the virus invades neurons. HIV-1 infection of brain cells has been the nervous system include simple entry of circu- detected by in situ hybridization, immunocyto-~~ lating free virus, a "Trojan horse" mechanism in chemistry, and electron m i c r o ~ c o p y . ~ 'Nonprowhich the virus enters via an infected CD4+ T lym- ductive infections of human glial cell lines62,77-79 phocyte or an infected macrophage, and binding and infection and replication of HIV-1 in a neuof the virus to endothelial cells with subsequent ronal cell lines0 and human neuroblastoma cellss' passage across the blood-brain barrier through have also been demonstrated. Conceivably, the virus could directly induce brain cell dysfunction o r perivascular glial cells. Increasingly compelling evidence suggests that death as a result of the infection. Possible support a neurotropic strain of HIV- 1 exists that is distinct of this hypothesis comes from the reported loss of from peripheral blood isolates of HIV-1. Unlike neurons in HIV-infected individual^.^^ Moreover, HIV-1 isolates from the CNS, peripheral blood iso- high levels of unintegrated HIV-1 DNA, which lates of HIV-1 obtained from CD4 T lymphocytes have been associated with cell death in other retreplicate readily within CD4+ T lymphocytes and roviral systems, have been found in AIDS patients are highly cytopathic for these cells, down-modu- with dementia.s3.a4 late CD4 antigen expression on the cell surface, Second, the virus may infect CNS endothelial and are sensitive to serum neutralizing antibody.63 cells, resulting in an alteration of the blood-brain barOn the contrary, HIV-1 isolates recovered from the rier. Infection of astrocytes may disturb the mainbrain replicate in primary macrophages to a much tenance of the blood-brain barrier. Some investigreater degree than the blood isolates.63They do gators believe that other infectious agents may not down-modulate CD4, are not cytopathic for disturb the blood-brain barrier and thus permit CD4' T lymphocytes, and are not sensitive to se- HIV entry into the brain.s5 Third, viral proteins of HIV-1 may be directly rum neutralization. Even viral isolates from different sources within the CNS may differ. Koyanagi toxic for cells of the CNS. The envelope protein and colleague^,^^ for example, demonstrated that gp120 has been demonstrated to be toxic to neuviral isolates from CSF and brain from the same rons." Some regions of the envelope protein may individual exhibited distinct cellular tropisms, par- compete with neurotransmitters. For instance, a ticularly with respect to their ability to infect a pentapeptide in the threonine-rich epitope of brain glioma explant culture. HIV-1, referred to as peptide T, competes with vaEpstein and colleagues" have suggested an soactive intestinal peptide.87-s8Vasoactive intestinal evolution of peripheral blood HIV-1 into a brain- peptide has been demonstrated to prevent the specific variant. Clearly, HIV-1 undergoes evolu- killing of neurons by gp120." Another epitope of tion within the host. Shortly after the virus was dis- the envelope protein competes with neuroleukin covered, genetic heterogeneity among individual (phosphohexose isomerase) as demonstrated by isolates was d e m o n ~ t r a t e d . Extensive ~ ~ . ~ ~ genetic studies of neuronal growth in chick dorsal root differences were absent among isolates from the ganglia cultures." T h e permeability of the cell same i n d i v i d ~ a l These . ~ ~ ~ ~strain ~ variations may membrane and the electrical potential of the cell alter the pathogenicity of HIV-1. Recent studies are affected by the presence of these viral proteins. suggest that brain and blood viral isolates can be This neuronal injury resulting from HIV-1 envedistinguished by restriction enzyme sensitivity. lope protein can be blocked by anti-gp120 antibodWolinsky (Wolinsky S: Personal communication, ies, but is not blocked by anti-CD4 antibodies."' June 1991) and colleagues have posited that Lipton and colleagues" have demonstrated that a changes in the V3 loop sequences of HIV-1 are as- calcium antagonist (nimodipine) can successfully sociated with its neurotropic characteristics. Al- block the toxic effect of gp120 in brain tissue culthough the substitutions observed in the V3 loop ture. Other viral proteins, such as, the tat and nef of their brain HIV-1 isolates are not necessarily proteins, may also be neurotoxic." The former has 5
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cells that do not have the CD4 protein may be the consequence of virus-cell membrane fusion through the gp4 1. These events are highlighted in Figure 3.
VOLUME 12. NUMBER 1 MARCH 1992
been demonstrated to be neurotoxic after intraceANTIRETROVIRAL THERAPY rebral injection in an animal model. Like gp120, it can result in cellular depolarization and balloonThe development of effective therapeutic strating. Even the unintegrated DNA of HIV-1 may be egies for HIV- 1 requires a detailed knowledge of a toxic to the cell. number of viral processes, including the nature of The fourth possibility-namely, the elabo- the binding of the virus to target cells, its replicaration of toxic cellular products as a result of tive cycle, and its assembly and budding.''' BeHIV-1 infection-has become increasingly attrac- cause of the early penetration of the CNS by HIVtive. These toxic cellular products include cytokines 1 and its neurotropism, any effective antiviral released by microglia and macrophages within the agent must be able to cross the blood-brain barbrain. For instance, human recombinant tumor ne- rier. The most widely used antiretrovirals (zidovucrosis factor alpha (TNF-a) has been shown to be dine [AZT], dideoxyinosine [ddI] and 2'3'-dideoxdirectly toxic to rat" and mouseY4oligodendrocytes ycytidine [ddC]) are nucleoside analogues, which and to human glioma cell lines.95 However, no halt viral transcription by terminating DNA syncorrelation has been found between the levels of thesis through the production of incomplete proTNF-a in CSF and clinical evidence of AIDS de- viral DNA. Approximately 50% of zidovudine the blood-brain barrier.lo8T h e percent of ~ mentia or HIV-1-related CNS d e m y e l i n a t i ~ n . ~crosses Moreover, the levels of TNF-a found to be toxic ddI and ddC that crosses the blood-brain barrier are far above the quantity detected in CSF. Other appears to be substantially smaller. Zidovudine has substances elaborated by HIV-1 infected macro- been demonstrated to be effective in partially rephages are also n e u r o t o ~ i c Heyes . ~ ~ ~ et ~ ~algghave versing some of the neurologic consequences atdemonstrated that quinolinic acid levels in the tributed to HIV-1 .109~'10 Other antiretroviral strategies in development CSF of HIV-1 infected patients are elevated and correlate with degree of neurologic impairment. include blocking HIV-1 binding to target cells, Quinolinic acid is an excitotoxin, an N-methyl-D- administration of receptor analogues, prevention aspartate agonist. It is a product of tryptophan of mRNA translation, and inactivation of infected metabolism. Its c6llular origin within the CNS re- cell ribosomes. Additionally, natural substances that serve as antiviral defense mechanisms, alphamains ~ n d e t e r m i n e d . ~ ~ A fifth possibility is the induction of an interferon for example, have been used to treat autoimmune response. T h e mechanism may be AIDS."' In less than a decade, a new disease has been via hypergammaglobulinemia induced by HIV-1 or molecular m i m i c r y . " ~ u m a r et all0' demon- described, its etiology determined, and antiviral strated the presence of brain reactive antibodies therapy introduced. With increased understanding in the sera of patients with HIV-1 infection. These of the AIDS virus, an improvement in treatment is antibodies were present in higher titers in patients anticipated. Equally important is ihe development with neurologic disease. Recently, brain reactive of a safe and effective vaccine. antibodies have been demonstrated in immune complexes within the CSF (Schutzer S: Personal communication). Similarly, autoantibodies to REFERENCES peripheral nerve that may have some role in the genesis of HIV-1-related peripheral neuropathy 1. Gottlieb MS, Schroff R, Schranker HE, et al. 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rus (LAV) for helper-inducer T-lymphocytes. Science 1984;225:59-63 Dalgleish AG, Beverley PCL, Clapham PR, et al. T h e CD4 (T4) antigen is a n essential component of the receptor for the AIDS retrovirus. Nature 1984; 3 12:763-7 Klatzman D, Champagne E, Chamaret S, et al. T-lymphocyte T 4 molecule behaves as the receptor for human retrovirus LAV. Nature 1984;312:767-8 Ho DD, Rota TR, Hirsch MS. Infection of monocytel macrophages by human T-lymphotropic virus type 111. J Clin Invest 1986;77: 1712-5 Gartner S, Markovits P, Markovitz DM, et al. T h e role of mononuclear phagocytes in HTLV-IIIILAV infection. Science 1986;233:215-9 McDougal JS, Kennedy MS, Sligh JM, et al. Binding of HTLV-IIIILAV to T 4 + T cells by a complex of the 1l0k viral protein a n d the T 4 molecule. Science 1986;23 1:382-5 Hoxie JA, Alpers JD, Rackowski JL, et al. Alteration in T 4 (CD4) protein and mRNA synthesis in cells infected with HIV. Science 1986;234: 1123-7 Kikikawa R, Koyanagi Y, Harada S, Kobayanashi N, Hatanaki M, Yamamoto N. Differential susceptibility to the acquired immunodeficiency syndrome retrovirus in cloned cells of human leukemic T-cell line Molt-4. J Virol 1986;57: 1159-62 Maddon PJ, Dalgleish AG, McDougal JS, Clapham PR, Weiss RA, Axel R. T h e T 4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 1986;47:333-48 Harouse JM, Shama B, Spitalnik SL, et al. Inhibition of entry of HIV-I in neural cell lines by antibodies against galactosyl ceramide. Science 1991;253:320-3 Wiley CA, Schrier RD, Nelson JA, et al. Cellular localization of the AlDS retrovirus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 1986;83:7089-93 Koenig S, Gendelman HE, Orenstein JM, et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 1986;233: 1089-93 Castro BA, Cheng-Mayer C, Evans LA, Levy JA. HIV -heterogeneity and viral pathogenesis. AIDS 1988; 2:s17-s28 Cheng-Mayer C, Rutka JT, Rosenblum ML, et al. T h e human immunodeficiency virus (HIV) can productively infect cultured glial cells. Proc Natl Acad Sci USA 1987;84:3526-30 Cheng-Mayer C, Levy JA. Distinct biologic and serologic properties of HIV isolates from the brain. Ann Neurol 1988;23:s58-s61 Koyanagi Y, Miles S, Mitsuyasu RT, et al. Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms. Science 1987;236:819-22 Epstein LG, Kinken C, Blumberg BM, et al. HIV-I V3 domain variation in brain and spleen of children with AIDS: tissue specific evolution within host-determined quasispecies. Virology 199 1; 180:583-90 Levy JA, Kaminsky LS, Morrow WJW, et al. Infection by the retrovirus associated with the acquired immunodeficiency syndrome. Ann Intern Med 1985; 103: 694-9 Shaw GM, Hahn BH, Arya SK, et al. Molecular characterization of human T cell leukemia (lymphotropic) virus type I11 in the acquired immune deficiency syndrome. Science 1984;226: 1165-7 1 Saag MS, Hahn BJ, Gibbons J , et al. Extensive variation of human immunodeficiency virus type-1 in vivo. Nature 1988;334:440-4 Fisher AG, Ensoli B, Looney D, et al. Biologically diverse molecular variants within a single HIV-I isolate. Nature 1988;334:444-7 Sonnerborg A, Johansson B, Strannegard 0. Detection of HIV-I DNA and infectious virus in cerebrospinal fluid. AlDS Res Hum Retroviruses 1991;7:369-73
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71. Gyorkey F, Melnick JL, Gyorkey P. HIV in brain biopsies of patients with AIDS and progressive encephalopathy. J Infect Dis 1987;155:870-6 72. Pumarola-Sune T, Navia BA, Cordon-Cardo C, et al. HIV antigen in the brains of patients with AIDS dementia complex. Ann Neurol 1987;2 1 :490-6 73. Sharer LR, Epstein LC, Cho ES, Petito C. Pathological features of AIDS encephalopathy in children: evidence of LAVIHIV infection of brain. Hum Pathol 1986;17:271-84 74. Shaw GM, Harper ME, Hahn BW, et al. HTLV-111 infection in brains of children and adults with AIDS encephalopathy. Science 1985;227: 177-82 75. Stoler MH, Eskin TA, Benn S, et al. Human T-cell lymphotropic virus type 111 infection of the CNS. JAMA 1986;256:2360-4 76. Vazeux R, Brousse N, Jarry A, et al. AIDS subacute encephalitis, identification of HIV-infected cells. Am J Pathol 1987; 126:403-10 77. Dewhurst S, Bresser J, Stevenson M, et al. Persistent productive infection of human glial cells by HIV and by infectious clones of HIV. J Virol 1987;61:3774-82 78. Weber J , Clapham P, McKeating J, et al. Infection of brain cells by diverse human immunodeficiency virus isolates: role of CD4 as receptor. J Gen Virol 1989; 70:2653-60 79. Wigdahl B, Guyton R, Sarin PS. Human immunodeficiency virus infection of the developing human nervous system. Virology 1987; 159:440-5 80. Li XL, Moudgil T, Vinters HV, Ho DD. CD4-independent, productive infection of a neuronal cell line by HIV type 1. J Virol 1990;64:1383-7 81. Shapshak P, Sun NCJ, Resnick L, et al. HIV-1 propagates in human neuroblastoma cells. J Acquir Immune Defic Syndr 1991;4:228-37 82. Ketzler S, Weis S, Haug H, Budka H. Loss of neurons in the frontal cortex in AIDS brains. Acta Neuropathol (Berl) 1990;80:92-4 83. Pang S, Koyanagi Y, Miles S, et al. High levels of unintegrated HIV-I DNA in brain tissue of AIDS dementia patients. Nature 1990;343:85-9 84. Keshet E, Temin HM. Cell killing by spleen necrosis virus DNA. J Virol 1979;31:376-88 85. Fontana A, Fiierz W, Wekerle H. Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature 1984;307:273-6 86. Brenneman DE, Westbrook GL, Fitzgerald SP, et al. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 1988;335:639-42 87. Pert CB, Hill JM, Ruff MR, et al. Octapeptides deduced from the neuropeptide receptor-like pattern of antigen T 4 in brain potently inhibit human immunodeficiency virus receptor binding and T cell infectivity. Proc Natl Acad Sci USA 1986;23:9254-8 88. Pert CB, Smith CC, Ruff MR, Hill JM. AIDS and its dementia as a neuropeptide disorder: role of VIP receptor blockade by human immunodeficiency virus envelope. Ann Neurol 1988;23:s71-3 89. Lee MR, Ho DD, Gurney ME. Functional interaction and partial homology between human immunodeficiency virus and interleukin. Science 1987;237: 1047-5 1 90. Kaiser PK, Offerman JT, Lipton SA. Neuronal injury due to HIV-1 envelope protein is blocked by antigp120 antibodies but not by anti-CD4 antibodies. Neurology 1990;40: 1757-61 9 1. Lipton SA. Calcium channel antagonists and human immunodeficiency virus coat protein-mediated neuronal injury. Ann Neurol 1991;30: 110-4 92. Sabatier JM, Vives E, Mabrouk K, et al. Evidence for neurotoxic activity of tat from human immunodeficiency virus type 1. J Virol 1991;65:961-7 93. Robbins, DS, Shirazi Y, Drysdale BE, et al. Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. J Immunol 1987;139:2593-7
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94. Selmaj KW, Raine CS. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 1988;23:339-46 95. Rutka JT, Giblin JR, Berens ME, et al. The effects of human recombinant tumor necrosis factor on gliomaderived cell lines: cellular proliferation, cytotoxicity, morphological and radioreceptor studies. Int J Cancer 1988;4 1:573-82 96. Grimaldi LME, Marino GV, Franciotta DM, et al. Elevated alpha-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with central nervous system involvement. Ann Neurol 1991;29:21-5 97. Giulian D, Vaca K, Noonan CA. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science 1990;250: 1593-6 98. Pulliam L, Herndier BG, Tang NM, McGrath MS. Human immunodeficiency virus infected macrophages produce soluble factors that cause histological and neurochemical alteration in cultured human brains. J Clin Invest 1991;87:503-12 99. Heyes MP, Brew BJ, Martin A, et al. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann Neurol 199 1;29:202-9 100. Oldstone MBA. Molecular mimicry and autoimmune disease. Cell 1987;50:819-20 101. Kumar M, Resnick L, Loewenstein D, et al. Brain reactive antibodies and the AIDS dementia complex. J Acquir Immune Defic Syndr 1989;2:469-71 102. Kiprov D, Pfaeffl W, Parry G, et al. Antibody-mediated peripheral neuropathies associated with ARC and AIDS: successful treatment with plasmapheresis. J Clin Apheresis 1988;4:3-7 103. Yamada M, Zurbriggen A, Oldstone MBA, Fuhinami
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RS. Common immunologic determinant between human immunodeficiency virus type 1 gp41 and astrocytes. J Virol 1991;65:1370-6 Wiley CA, Nelson JA. Role of human immunodeficiency virus and cytomegalovirus in AIDS encephalitis. Am J Pathol 1988; 133:73-81 Tada H, Rappaport J, Lashgari M, et al. Trans-activation of the JC virus late promoter by the tat protein of type 1 human immunodeficiency virus in glial cells. Proc Natl Acad Sci USA 1990;87:3479-83 Kieburtz KD, Giang DW, Schiffer RB, Vakil N. Abnormal vitamin B12 metabolism in human immunodeficiency virus infection: association with neurological dysfunction. Arch Neurol 1991;48:3 12-4 Yarchoan R, Mitsuya H, Broder S. Clinical and basic advances in the antiretroviral therapy of human immunodeficiency virus infection. Am J Med 1989;87: 191200 Klecker LW, Collins JM, Yarchoan R, et al. Plasma and cerebrospinal fluid pharmacokinetics of 3'-azido3'deoxythymidine: a novel pytimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther 1987;41:407-12 Yarchoan R, Berg G, Browers P, et al. Response of human immunodeficiency virus-associated neurological disease to 3'-azido-3'-deoxythymidine. Lancet 1987; 1:132-5 Pizzo PA, Eddy J, Falloon J , et al. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med 1988;319:889-96 De Clercq E. Basic approaches to anti-retroviral treatment. J AIDS 1991;4:207-18
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HIV IN NEUROLOGIC DISEASE-BERGER, LEVY
In 198 1, an immunodeficiency state characterized by such illnesses as Pneumocystis carinii pneumonia1,' and chronic ulcerative genitoanal herpes simplexqn homosexual males was described. The first recognized neurologic consequences of this newly recognized illness were reported the following year.' In retrospect, perhaps, the earliest cases of this immunodeficient state had come to medical attentiorl Serologic tests performed on banked specimens, confirming the presence of antibody to human immunodeficiency virus, type 1 (HIV-I), indicate that isolated cases of the immunodeficiency state had occurred in the United States'jand Scandinavia7 as early as the middle of the 1960s. Until 1983, the etiology of this immunodeficient state, referred to as the acquired immunodeficiency syndrome (AIDS), remained uncertain.
T h e diagnosis was established on the basis of clinical criteria. T h e definition established by the Centers for Disease Control (CDC) was "a disease, at least moderately predictive of a defect of cell-mediated immunity, occurring in persons with no known cause of diminished resistance to the disease."x T h e conditions recognized to occur with AIDS included not only infectious illnesses, such as P. carinii pneumonia, severe ulcerative herpes simplex, and toxoplasmosis encephalitis, but also Bcell lymphoma^,^ and a previously rare tumor, .'' abounded with reKaposi's ~ a r c o m a . ' ~ Theories spect to the etiology of this illness. However, by 1983"-'* a retrovirus was found in patients with AlDS and, subsequently, convincingly demonstrated to be the etiologic agent. With the availability of serologic assays to demonstrate the presence of infection, the CDC definition of AIDS was mod-
Departments of Neurology and Internal Medicine, the University o f Miami School o f Medicine, Miami, Florida, and the Department o f Medicine and Cancer Research Institute, the University o f California, San Francisco, California. Supported in part by grant NS 25569 from the National Institutes of Health. Reprint requests: Dr. Berger, Department of Neurology, University of Miami School o f Medicine, 1500 NW 9th Avenue, Miami, Florida 33136.
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March 1992
Volume 12, Number 1
ified to include serologic evidence of infection, and several different staging systems were proposed. '5-16
RETROVIRUSES Retroviruses are a unique family of RNA viruses to which the causative agent of AIDS belongs. T h e name of this family of viruses is derived from the presence of RNA-dependent DNA polymerase (reverse transcriptase), an enzyme enabling these RNA viruses to produce a DNA copy of their genome, which can then be incorporated into the host genome. On occasion, the viral DNA that has been integrated into host genome can be transmitted through the germ line. T h e retroviruses are widely distributed among vertebrate animals, including horses, sheep, goats, cows, cats, and monkeys.17 Retroviruses have been divided into three major subfamilies: lentivirus (lente: slow), oncovirus (onco: tumor), and spumavirus (spuma: foam). Both lentiviruses and oncoviruses have been associated with disease in humans. Human T-lymphotropic viruses types I and I1 (HTLV-I and HTLV-11, respectively) are members of the human oncovirus subfamily. HTLV-I is the etiologic agent of adult T-cell leukemia and lymphomas. l8.Iy HTLV-I has also been linked to a progressive myelopathy referred to as HTLV-I-associated myelopathy, or ~ ~ ~ ~ has been tropical spastic p a r a p a r e s i ~ . ' HTLV-I1 associated with hairy cell le~kemia.'~It has also been linked to spinal cord disease." Although spumaviruses have not been convincingly demonstrated to cause disease in man, recent studies suggest that they are capable of inducing a demyelinating disorder of transgenic micez4 and may be linked to human neurologic disease.
VOLUME 12, NUMBER 1 MARCH 1992
gene^.'^ Significant sequence homologies exist, however, such as that between visna virus, the prototypical lentivirus, which is capable of inducing a demyelinating disorder in sheep, and HIV-1." These observations indicate that HIV belongs taxonomically in the lentivirus subfamily. All known lentiviruses, including visna, caprine arthritis encephalopathy virus, bovine visna, feline immunodeficiency virus, and simian immunodeficiency virus, are capable of causing neurologic disease.28 Other characteristics of this family of viruses are their large size, the ability to produce cytopathic changes in infected cells, and the long incubation times before the development of clinical illnesstypically, immunologic or neurologic disease.26 The HIV-1 virion, as demonstrated by electron microscopy, is an icosahedral structurezYcomprised of 72 external spikes. The dominant viral envelope proteins are gp 120 and gp4 1, and the underlying lipid bilayer contains a number of host proteins derived at the time of viral budding (Fig. I)."" Both class I and class I1 histocompatibility antigens can be found in this lipid bilayer." Four nucleocapsid proteins, p24 (p25), p17, p9, and p7, comprise the core of HIV-l.26.30 The first, p24, is the chief component of the nucleocapsid core. HIV-1 contains three transcriptive units that code for common viral structural proteins (Fig. 2). These transcriptive units are the gag, pol, and env regions. They code for three classes of polypeptides found in the majority of animal retroviruses: structural, nonenvelope polypeptides; enzymes required for viral replication; and envelope proteins. The gag region codes for the nonenvelope, core
HUMAN IMMUNODEFICIENCY VIRUS, TYPE 1
2
HIV-1, the virus that causes AIDS,'2.13has been previously referred to by other appellations, including AIDS-associated virus (ARV),14 human T-lymphotropic virus type I11 (HTLVIII),I2 lymphadenopathy-associated virus (LAV),I3 and HTLV-IIIILAV. A related virus, human immunodeficiency virus, type 2, (HIV-2), has been recognized more recently.25It is chiefly, although not exclusively, seen in Western African populations and is also capable of causing an AIDS-like illness. Although sharing a similar structure to HIV1, each subtype of lentivirus contains unique
Lipid Bilayer Figure 1. A diagram of the fundamental structure of the human immunodeficiency virus type 1. The envelope glycoproteins (gp120 and gp41) and the major viral core proteins (p25, p17, p9, and p7) are shown. The core protein p17 exists exterior to the viral nucleoid. RT: reverse transcriptase. (From Levy.26Reprinted with permission.)
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HIV I N NEUROLOGIC DISEASE-BERGER,LEVY Transactivator of Requiredfor Reduction of InfectiousVirions
Up Regulates HIV Production
Core Protein
+
LTR
gag
4 Regulatory Sequences for HIV Replication
env
4
ProteaselReverse Transcriptasel Endonuclease
Function Unknown
4 Envelope Proteins
nef
b Down Regulationof HIV ~ e p l h i o n
proteins, which include the nucleoid shell (p24) and several smaller internal proteins. Initially, these proteins are synthesized as a 55 kd precursor and are subsequently cleaved into their final proteins. The pol region codes for reverse transcriptase, a protease, and an endonuclease. The DNA synthesized from the viral RNA by reverse transcriptase can be integrated into the host genome by the action of the endonuclease. The protease is responsible for cleaving the polyproteins coded for by the gag and pol regions into their active moieties.'"he two major envelope proteins (gp120 and gp41) are coded for by the env region. The gp120 is a large glycoprotein on the surface of the virion and gp41 is a smaller transmembrane glycoprotein. The envelope proteins are responsible for viral binding to the target cells. Four regulatory proteins have been identified with HIV-1. The tat and rev genes are believed to be responsible for the up-regulation of viral reproduction."' T h e tat gene is a transactivating regulator of RNA translation. The 14 kd product of this gene also increases transcription of DNA in HIVinfected ~ e l l s . "The ~ , ~rev ~ gene is a regulator modulating expression of the structural proteins at the level of transcription. Conversely, the nef gene is a cis-acting down-regulator of RNA tran~cription.~' The other regulatory protein is coded for by vif, which is responsible for maturation of viral proteins at the time of budding from the cell.32The action of some of the products of these regulatory genes may be through binding to the long terminal repeat (LTR) sequence of the viral genome. Other viral genes have been identified, but their functions remain unknown. Following infection, lentiviruses replicate slowly within target organs, primarily peripheral lymphoThe viruses are typically cytes and mon~cytes."~
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Figure 2. Genetic structure of the human immunodeficiency virus, type 1. The three major structural proteins (gag, pol, and env) are shown in black and the regulatory proteins (tat, rev,and nef) shown with diagonal lines. The genes that have not been fully characterized are depicted as boxes with cross-hatching.The gene products are summarized. (From Levyz6Reprinted with permission.)
harbored in a latent form, with an estimated 1 per 100 to 1 per 1000 infected cells exhibiting active viral replication."Viral replication is slowed by restricted gene expression."%Although the hypothesis is unproven, the entry of the lentivirus from blood into affected tissues such as the l i n g and brain (see later) has been suspected to result from entry of latently infected circulating cells such as the peripheral blood monocyte." A similar mechanism has been suggested for viral entry in HIV-1 infection. With respect to central nervous system (CNS) infection by HIV-1, Wiley et a1"' postulate that opportunistic infection of the CNS allows recruitment of latently infected monocytes inlo the brain with the subsequent differentiation of these infected monocytes into tissue macrophages productive of HIV-1. However, this hypothesis does not account for evidence indicating that HIV-1 is present in the CNS in the earliest stages of infection, well before significant immunosuppression occurs. Early in infection, HIV-1 can be cultured from the cerebrospinal fluid (CSF),"." and intrathecal synthesis of antibody to HIV-1 can be dem~nstrated.~" Using polymerase chain reaction, investigators have demonstrated HIV-1 nucleic acid in the brain within 15 days of infection in one recently reported case.41These observations suggest that a concomitant opportunistic infection of the CNS is not necessary for HIV-1 penetration of the blood-brain barrier.
TRANSMISSION OF HIV-1 HIV-1 has been demonstrated in varying but transamount in virtually every body fluid:' mission of HIV results chiefly through homosexual or heterosexual contact, contaminated blood or
3
blood products, or transmission from mother to fetus. The levels of virus in plasma and semen are relatively low, at 10 to 50 infectious particles per milliliter.43This value, which is substantially lower than that for hepatitis B infectious particles, explains the difference in rates of HIV-1 versus hepatitis B infection following a needlestick injury. HIV-1 in genital fluids is mostly cell-associated, with the amount of cell-free virus being quite low. Concomitant genital disease increases the presence of inflammatory cells in genital secretions and is likely to account for the increased transmission of HIV-1 that occurs in the presence of some sexually transmitted diseases. It is curious that the body fluid with the highest concentration of cell-free virus is the CSF,"j but it cannot be a source of contagion.
CONSEQUENCES OF INFECTION Even before the demonstration of the virus as the cause of AIDS, a specific pattern of immunologic defects was recognized in the illness. This pattern was characterized by a decrease in CD4 T lymphocytes (helperlinducer cells) and an inversion of the CD4lCD8 T-lymphocyte ratio to less than T h e inversion in the helper to suppressor cell ratio was recognized to be chiefly a function of a loss of the CD4+ T-lymphocyte subset.45There is an inverse correlation between the absolute number of CD4 T lymphocytes and the presence of HIV1.46,47 -Likewise, there is a direct correlation between the duration of HIV-1 infection and the degree of immunosuppression, as measured by laboratory and clinical parameter^.^^ The AIDS virus is tropic for CD4+ T-lymphocytes and can be isolated from CD4+ T-lymphocytes, monocytes, and macro phage^.^^-^^ Selective binding of HIV to the CD4 receptor on the CD4+ T lymphocyte has been demonstrated in ~ i v o This binding appears to occur as a consequence of the interaction of a 120 kd viral envelope protein and the CD4 receptor.54 In most cases, infection leads to down-modulation of the CD4 receptor on the cell surface.55 However, in culture, susceptibility to infection by HIV-1 is not universal in all CD4+ T-lymphocytes,5\nd mouse cells transfected with and expressing CD4 protein are not Conversely, cells susceptible to HIV-1 infe~tion.~' that do not express CD4 protein can be infected; this suggests that other surface moieties are important for viral infection. Both brain-derived cells and human fibroblasts, as well as other CD4 cells, can be infected in vitro with HIV-1.43 Recently, galactocerebroside on the surface of CD4 brain-de4
VOLUME 12, NUMBER 1 MARCH 1992
rived cells has been identified as an alternative receptor'for HIV-1 .58 Tissue culture techniques and the examination of fixed specimens suggest that a wide variety of human cells may be susceptible to HIV-1 infect i ~ nIn . ~the ~ brains of infected individuals, in situ hybridization and electron microscopy reveal in. ~ ~ ~ ~ ~ fection of macrophages and glial ~ e l l s Application of these techniques has suggested that astrocytes, oligodendrocytes, and brain capillary endothelial cells may harbor low titers of HIV-1. Similar observations reveal that other cells, including crypt cells and the lamina propria of the gut and, perhaps, Langhans cells of the dermis and fetal chorionic villi, are susceptible to HIV-1 infect i ~ n . Tissue ~' cultures have established HIV-1 infection in fetal brain tissue and glioma cell lines62 as well as cells of the hematopoietic system, brain, gut, skin, and several others.26 Further study is warranted to provide unassailable evidence for some of these observations. These findings have resulted in the hypothesis that viral gp120 is responsible for attachment to the cell surface via the CD4 receptor, but entry into the cell is the consequence of fusion with the cell -membrane through the gp41 domaimZ6Entry into
.~~
Figure 3. Life cycle of HIV-1. The initial event is attachment of the virus to specific receptor on the cell surface followed by fusion of the virus to the cell membrane. The intact viral nucleoid enters the cell cytoplasm. Transcription begins with reverse transcriptase and ultimately results in viral double-stranded DNA copied from the viral RNA. Circular DNA of viral origin can enter the nucleus and integrate into the cellular chromosome using the viral endonuclease. In productive infection, the proviral DNA produces two forms of RNA: mRNA, which codes for proteins required in replication and virion RNA, which is required for the infectious virion. The virion RNA is encapsulated and then expressed from the cell by budding. (From Levyz6Reprinted with permission.)
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HIV IN NEUROLOGIC DISEASE-BERGER,LEVY
identical, preliminary analysis by x-ray diffraction of the V3 loop of these isolates indicates that they are structurally identical. Indeed, even the local antibody response to HIV-1 within the CNS may be selective for the neurotropic variant of HIV- 1.70 The mechanism by which HIV-1 results in CNS dysfunction remains unanswered, although HUMAN IMMUNODEFICIENCY VIRUS, several mechanisms have been postulated. First, TYPE 1, NEUROPATHOGENESIS the virus may be neurotropic,-that is, have a proHIV-1 enters the CNS early in infection. The pensity to infect glial cells and perhaps even postulated mechanisms by which the virus invades neurons. HIV-1 infection of brain cells has been the nervous system include simple entry of circu- detected by in situ hybridization, immunocyto-~~ lating free virus, a "Trojan horse" mechanism in chemistry, and electron m i c r o ~ c o p y . ~ 'Nonprowhich the virus enters via an infected CD4+ T lym- ductive infections of human glial cell lines62,77-79 phocyte or an infected macrophage, and binding and infection and replication of HIV-1 in a neuof the virus to endothelial cells with subsequent ronal cell lines0 and human neuroblastoma cellss' passage across the blood-brain barrier through have also been demonstrated. Conceivably, the virus could directly induce brain cell dysfunction o r perivascular glial cells. Increasingly compelling evidence suggests that death as a result of the infection. Possible support a neurotropic strain of HIV- 1 exists that is distinct of this hypothesis comes from the reported loss of from peripheral blood isolates of HIV-1. Unlike neurons in HIV-infected individual^.^^ Moreover, HIV-1 isolates from the CNS, peripheral blood iso- high levels of unintegrated HIV-1 DNA, which lates of HIV-1 obtained from CD4 T lymphocytes have been associated with cell death in other retreplicate readily within CD4+ T lymphocytes and roviral systems, have been found in AIDS patients are highly cytopathic for these cells, down-modu- with dementia.s3.a4 late CD4 antigen expression on the cell surface, Second, the virus may infect CNS endothelial and are sensitive to serum neutralizing antibody.63 cells, resulting in an alteration of the blood-brain barOn the contrary, HIV-1 isolates recovered from the rier. Infection of astrocytes may disturb the mainbrain replicate in primary macrophages to a much tenance of the blood-brain barrier. Some investigreater degree than the blood isolates.63They do gators believe that other infectious agents may not down-modulate CD4, are not cytopathic for disturb the blood-brain barrier and thus permit CD4' T lymphocytes, and are not sensitive to se- HIV entry into the brain.s5 Third, viral proteins of HIV-1 may be directly rum neutralization. Even viral isolates from different sources within the CNS may differ. Koyanagi toxic for cells of the CNS. The envelope protein and colleague^,^^ for example, demonstrated that gp120 has been demonstrated to be toxic to neuviral isolates from CSF and brain from the same rons." Some regions of the envelope protein may individual exhibited distinct cellular tropisms, par- compete with neurotransmitters. For instance, a ticularly with respect to their ability to infect a pentapeptide in the threonine-rich epitope of brain glioma explant culture. HIV-1, referred to as peptide T, competes with vaEpstein and colleagues" have suggested an soactive intestinal peptide.87-s8Vasoactive intestinal evolution of peripheral blood HIV-1 into a brain- peptide has been demonstrated to prevent the specific variant. Clearly, HIV-1 undergoes evolu- killing of neurons by gp120." Another epitope of tion within the host. Shortly after the virus was dis- the envelope protein competes with neuroleukin covered, genetic heterogeneity among individual (phosphohexose isomerase) as demonstrated by isolates was d e m o n ~ t r a t e d . Extensive ~ ~ . ~ ~ genetic studies of neuronal growth in chick dorsal root differences were absent among isolates from the ganglia cultures." T h e permeability of the cell same i n d i v i d ~ a l These . ~ ~ ~ ~strain ~ variations may membrane and the electrical potential of the cell alter the pathogenicity of HIV-1. Recent studies are affected by the presence of these viral proteins. suggest that brain and blood viral isolates can be This neuronal injury resulting from HIV-1 envedistinguished by restriction enzyme sensitivity. lope protein can be blocked by anti-gp120 antibodWolinsky (Wolinsky S: Personal communication, ies, but is not blocked by anti-CD4 antibodies."' June 1991) and colleagues have posited that Lipton and colleagues" have demonstrated that a changes in the V3 loop sequences of HIV-1 are as- calcium antagonist (nimodipine) can successfully sociated with its neurotropic characteristics. Al- block the toxic effect of gp120 in brain tissue culthough the substitutions observed in the V3 loop ture. Other viral proteins, such as, the tat and nef of their brain HIV-1 isolates are not necessarily proteins, may also be neurotoxic." The former has 5
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cells that do not have the CD4 protein may be the consequence of virus-cell membrane fusion through the gp4 1. These events are highlighted in Figure 3.
VOLUME 12. NUMBER 1 MARCH 1992
been demonstrated to be neurotoxic after intraceANTIRETROVIRAL THERAPY rebral injection in an animal model. Like gp120, it can result in cellular depolarization and balloonThe development of effective therapeutic strating. Even the unintegrated DNA of HIV-1 may be egies for HIV- 1 requires a detailed knowledge of a toxic to the cell. number of viral processes, including the nature of The fourth possibility-namely, the elabo- the binding of the virus to target cells, its replicaration of toxic cellular products as a result of tive cycle, and its assembly and budding.''' BeHIV-1 infection-has become increasingly attrac- cause of the early penetration of the CNS by HIVtive. These toxic cellular products include cytokines 1 and its neurotropism, any effective antiviral released by microglia and macrophages within the agent must be able to cross the blood-brain barbrain. For instance, human recombinant tumor ne- rier. The most widely used antiretrovirals (zidovucrosis factor alpha (TNF-a) has been shown to be dine [AZT], dideoxyinosine [ddI] and 2'3'-dideoxdirectly toxic to rat" and mouseY4oligodendrocytes ycytidine [ddC]) are nucleoside analogues, which and to human glioma cell lines.95 However, no halt viral transcription by terminating DNA syncorrelation has been found between the levels of thesis through the production of incomplete proTNF-a in CSF and clinical evidence of AIDS de- viral DNA. Approximately 50% of zidovudine the blood-brain barrier.lo8T h e percent of ~ mentia or HIV-1-related CNS d e m y e l i n a t i ~ n . ~crosses Moreover, the levels of TNF-a found to be toxic ddI and ddC that crosses the blood-brain barrier are far above the quantity detected in CSF. Other appears to be substantially smaller. Zidovudine has substances elaborated by HIV-1 infected macro- been demonstrated to be effective in partially rephages are also n e u r o t o ~ i c Heyes . ~ ~ ~ et ~ ~algghave versing some of the neurologic consequences atdemonstrated that quinolinic acid levels in the tributed to HIV-1 .109~'10 Other antiretroviral strategies in development CSF of HIV-1 infected patients are elevated and correlate with degree of neurologic impairment. include blocking HIV-1 binding to target cells, Quinolinic acid is an excitotoxin, an N-methyl-D- administration of receptor analogues, prevention aspartate agonist. It is a product of tryptophan of mRNA translation, and inactivation of infected metabolism. Its c6llular origin within the CNS re- cell ribosomes. Additionally, natural substances that serve as antiviral defense mechanisms, alphamains ~ n d e t e r m i n e d . ~ ~ A fifth possibility is the induction of an interferon for example, have been used to treat autoimmune response. T h e mechanism may be AIDS."' In less than a decade, a new disease has been via hypergammaglobulinemia induced by HIV-1 or molecular m i m i c r y . " ~ u m a r et all0' demon- described, its etiology determined, and antiviral strated the presence of brain reactive antibodies therapy introduced. With increased understanding in the sera of patients with HIV-1 infection. These of the AIDS virus, an improvement in treatment is antibodies were present in higher titers in patients anticipated. Equally important is ihe development with neurologic disease. Recently, brain reactive of a safe and effective vaccine. antibodies have been demonstrated in immune complexes within the CSF (Schutzer S: Personal communication). Similarly, autoantibodies to REFERENCES peripheral nerve that may have some role in the genesis of HIV-1-related peripheral neuropathy 1. Gottlieb MS, Schroff R, Schranker HE, et al. 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