- Email: [email protected]
HIV virology: Implications for the pathogenesis of HIV infection
HIV virology: Implications for the pathogenesis of HIV infection Arnold B. Rabson, MD Bethesda, Maryland Infection by the human immunodeficiency virus (HIV) may result in a spectrum of disease ranging from asymptomatic seropositivity to the development ofprofound immunodeficiency. Features of the HIV life cycle may explain aspects of the pathogenesis of HIV-induced disease. The tropism of HIV for CD4+ cells of both lymphocytic and monocytic origin is of considerable importance in bringing about immune deficiency. The variability of the HIV envelope limits the ability of host-immune response to control the infection effectively. Finally, the ability of HIV to persist is latently integrated DNA in infected cells that can be reactivated by cellular signals responsible for the control of normal immune cell activation links HIV replication to normal host cell functions. This can help explain the chronic but progressive nature of the infection. (J AM ACAD DERMATOL 1990;22:1196-202.)
A tremendous amount has been learned about acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV) in the short period of time since its initial isolation 1 and proof of its role in the etiology of AIDS2, 3; however, a number ofimportant mysteries remain. Among these are issues such as the spectrum of HIV-induced disease and the concept of disease progression from a person who is infected but asymptomatic to the development of AIDS-related complex (ARC) and AIDS with the loss of CD4+ T cells. Little is known about the mechanisms by which CD4+ lymphocytes are lost, but several complex mechanisms seem to be involved. Of importance in understanding the loss of CD4+ T cells and disease progression is the concept that viral replication is intimately connected to host cellular differentiation and gene expression. What happens in the immune system of an infected individual affects how virus replicates, the degree of replication, and the spread through the body. Other important issues that are just beginning to be defined include the range of cells in the body that are infected by HIV. The critical role that infection of CD4+ lymphocytes plays in the development ofHIV disease is clear. It is becoming increasingly evident, however, that infection of cells of the monocyte/
From the Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Nationallnstltutes of HeItlth. Reprint requests: Arnold B. Rabson, MD, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
16/0/19161
1196
macrophage lineage also plays an important role. Further issues in the virology of HIV have to do with the tremendous mutability of HIV, particularly in the envelope gene, issues that have important implications for vaccine development. HIV is a member of the lentivirus family of retroviruses. These viruses induce slow, chronic, often fatal disease in their host. 4 Related to HIV-I and HIV-2, the human immunodeficiency viruses, is the family of primate lentiviruses referred to as the simian immunodeficiency viruses (SIVs). The SIVs provide an important animal model for understanding the pathogenesis of HIV disease. Although SIV is distinct from HIV-I and, in fact, is more closely related to HlV-2 than it is to HIV-I,5,6 the disease that SlV produces in infected rhesus macaques bears similarities to human AIDS.7,8 Acute infection of monkeys with SlV is associated with cutaneous manifestations that show similarities to the cutaneous manifestations of acute HIV infection. 9 Fig. 1 is a schematic representation of the life cycle of HIY. HIV is an enveloped virus that acquires a lipid envelope as it buds from the surface of an infected cell. Embedded within that lipid envelope are virally encoded glycoproteins, the envelope proteins gp160/120 and gp41. The external envelope protein, gp 120, is the protein on the surface of the virus that interacts with the CD4 molecule on a target cell. 10, 11 gp 120 is attached to the transmembrane envelope protein, gp41,12 which anchors the gp120 into the membrane and which also functions in allowing the membrane of the virus to fuse with the host cellular membrane. The gag proteins form the core within
Volume 22 Number 6, Part 2 June 1990
HIV virology 1197
Fig. 1. Schematic representation of the HIV life cycle. (Modified from Rabson AB. The molecular biology of HIV infection: clues for possible therapy. In: Levy J, ed. AIDS: pathogenesis and treatment. New York: Marcel Dekker, 1989:233. Reprinted by courtesy ofMarcel Dekker, Inc.)
which viral RNA is packaged. Shown schematically in step 1 of Fig. 1 is the binding of virion particles to the CD4 receptor on the surface of the target cell, either a CD4 + lymphocyte or other cells in the body that may express CD4. Interaction between the gp120 and the CD4 molecule mediates attachment of virus to a target cell. After attachment, there is a complex process that results in internalization of the virus. This involves fusion of the viral envelope with the lipid membrane of the cell and probably involves contributions of the gp41 molecule as well as host cellular molecules. Strategies designed to inhibit these early steps of viral replication are under evaluation both as immunoprophylactic and therapeutic approaches. These strategies include attempts to block binding of virus to receptor, such as the use of soluble CD4. 13- 16 One can also envision strategies that would block entry of virus by interfering with the fusion process; some aspects of the process by which neutralizing antibodies block HIV infection may involve steps subsequent to HIV binding. l ? After entry into the target cell, the process of reverse transcription occurs, in which a doublestranded DNA copy of viral genetic information is
generated from the viral RNA genome. This probably occurs in the context of a subviral particle with associated viral gag proteins 18 and is clearly one of the major targets for anti-HIV therapy. This is the step at which azidothymidine (AZT) and related compounds exert their antiviral effect. 19 After reverse transcription, HIV DNA enters the nucleus and, again likely in the context of a subviral particle, 18 undergoes the step of integration into the host cellular DNA. This integration step is catalyzed by a virally encoded enzyme, the integrase. 2o As a viral-specific enzyme, the integrase also represents a potential target for interference with viral replication as distinct from cellular metabolic activity. The integration process is very important in determining the next step in the viral life cycle. Once integrated into cellular DNA, this viral DNA copy is subject to the kinds of regulation of its expression that control the expression of other cellular genes. Whether integrated HIV DNA is expressed or exists in a latent form depends both on virally encoded factors and on the general transcriptional state of the cell. Furthermore, this integration process means that once virus is integrated into a cell, it is present for the life of that
Journal of the American Academy of Dermatology
1198 Rabson
o
gag
d
LTR p55
pH \
p24
, D
rev
tat
0
~
2"-----p-o-,------JhJt----e-n-v----.,RQ \p15 p7JP§ protease!
p9
RT
p64
endonuclease
p34
p51 gp160
gp120
gp41
p23--
p17-
p12-
p17 p27---
Fig. 2. The HIV DNA genome. (Modified from Rabson AB. The molecular biology of HN infection: clues for possible therapy. In: Levy J, ed. AIDS: pathogenesis and treatment. New York: Marcel Dekker, 1989:236. Reprinted by courtesy of Marcel Dekker, Inc.)
cell. Thus, viral DNA can persist for years in infected cells in a latent or chronic form. Expression of viral DNA involves transcription of viral RNA as either virion RNA that will be packaged into new viral genomes or as a series of spliced messenger RNAs encoding the various structural, enzymatic, and. regulatory proteins. The various regulatory proteins (described below) are vital-specific and also represent potential targets for antiviral therapy. Finally, the process of assembly and viral budding would be potential mechanisms for interference with viral replication. A particularly interesting potential target is the viral protease,21 an enzyme involved in the maturation of precursor gag and pol polypeptides. Fig. 2 shows the features of the HIV DNA genome. The long terminal repeats (LTRs) are the control elements for the viral DNA expression. The LTRs contain promoters for viral RNA transcription that are influenced both by the regulatory effects from virally encoded, transacting regulatory proteins and by cellular transcriptional factors. The
locations of the genes encoding the gag proteins, the polgene encoding the viral enzymatic activities, and the env gene are shown. Also indicated are the positions of the genes encoding the viral regulatory proteins tat, rev, and nef, as well as genes whose detailed functions are still being elucidated, such as vif, U,and R. As discussed, the first step in HIV infection is the binding of HIV to a CD4+ target cell. An increasingly large number of cell types have been shown to express CD4 and thus serve as potential targets of HIV infection. Infection of some of these different cells may account for aspects of the wide range of HIV-related syndromes. In essentially all these cell types, it has been possible to detect expression bf CD4, either at the protein or RNA levels. Thus, it appears that, for most of the clinically relevant infected cells in the body, CD4 is a critical determinant of infection. Obviously, the most dramatic effects of HIV infection can be seen in the infection of the CD4+ helper subset of T lymphocytes. In tissue culture,
Volume 22
Number 6, Part 2 June 1990
both primary T lymphocytes and CD4+ tumor cell lines are readily infectable by HIV. 1-3. 22 In tissue culture, infection of some Epstein-Barr virus-transformed CD4+ B cell lines has been demonstrated,23 although the clinical relevance of this observation in patients has not been demonstrated. Infection of cells of the monocyte/macrophage series may be extremely important in AIDS patients. In other animallentivirus infections such as visna in sheep, monocytes appear to be a critical reservoir of latent virus. 4 Although latent infection of monocytes by HIV in man has not been proved, productive HIV infection of a number of different macrophage types has been clearly demonstrated. Infected macrophages in the brain seem to play an important role in the pathogenesis of AIDS encephalopathy.24 Of particular interest to dermatologists has been the frequent identification of infectIon in Langerhans cells in the epidermis. 25 Furthermore, there appears to be depletion of these cells in AIDS patients' skin, raising the possibility that they may be killed by HIV infection. 26 Infection of the Langerhans cells may playa role in some of the cutaneous manifestations of AIDS, and depletion of these cells could potentially contribute to the progressive loss of immune competence. Infection of bone marrow precursors of the monocytic/granulocytic lineage has been demonstrated in vitr027 and could serve as a reservoir for HIV. In tissue culture and in in situ hybridization studies, some neural cells have been shown to be infected/ S' 29 and endothelial cells in the brains of patients with AIDS encephalopathy have been shown to contain virus. 29 Again, the clinical importance of these findings is not clear. Infection of intestinal epithelial cells has been shown both in viv030 and in vitr031 and may contribute to AIDSassociated gastrointestinal symptoms as well as to the epidemiologic observations regarding the role of anal intercourse as a risk factor in the spread of HIV infection. Recent studies from our laboratory (W. J. Maury, B. Potts, and A. B. Rabson, in press) have demonstrated the infectability of human placental samples, an observation that may help to explain the pathogenesis of neonatal AIDS. Thus, a large number of cell types in addition to CD4+ lymphocytes may be infected with HIV, and these other cells may help to contribute to the variety of clinical syndromes associated with HIV infection. As described, the binding of HIV to a target cell is mediated by the HIV envelope gene product,
HIV virology 1199 gp120. The envelope gene is highly variable between isolates derived from different patients32-34; less pronounced variability can be seen in isolates derived from a single patient.35 This variability has important implications. The highly conserved regions contain functionally important sites such as the domains where the cleavage between gp120 and gp41 occurs. A site shown to be involved in the binding of the gp120 to the CD4 molecule is in a moderately conserved region 36; other segments of the gp120 probably contribute to this binding as well. 37 Highly variable domains of the env gene can be identified; for example, comparison of the env genes of isolates of HIV from Zaire and the United States shows stretches of 150 to 200 amino acids over which there may be only 30% to 50% homology.34 Even within one individual over time, variability may be observed in these stretches,35 an observation that has implications for immunotherapy. This striking variability also has obvious implications for vaccine development. One region involved in the generation of antibodies that neutralize HIV infection has been identified in a highly variable domain of the envelope.38-4o Antibodies generated to peptides derived from this putative loop region will neutralize the parental virus but will not neutralize viruses bearing a different sequence in this region. In considering the molecular determinants of the pathogenesis of HIV infection, it is important to address the cellular and viral controls of HIV gene expression. The interplay between these controls determines the degree of HIV production from an infected cell, that is, whether virus persists in a latent or chronic low-level state of expression or whether high-level production of progeny virus occurs with subsequent cell death. HIV encodes proteins that affect its own gene expression. The nef protein is a negative regulator viral gene expression41 that reduces the amount of viral RNA transcription. 42 Conversely, the tat gene encodes a powerful positive regulator that can increase gene expression directed by the viral LTR hundreds of fold. 43 ,44 The tat gene product acts to increase the levels ofHIV RNA and protein in a cell, apparently through both transcriptional and posttranscriptional mechanisms. 45-49 HIV also encodes a regulator of the processing of its RNA, the rev gene. 50,51 The rev gene controls the relative amounts of unspliced genomic and gag-pol RNAs compared with the amounts of the multiply spliced RNAs for
of
Journal of the American Academy of Dermatology
1200 Rabson
the various regulatory proteins. Rev apparently acts by influencing the transport of viral RNAs containing a rev-responsive element to the cytoplasm.52, 53 By controlling the relative amounts of regulatory versus structural proteins in an infected cell, rev may affect viral latency. In addition to virally encoded regulatory genes that modulate HIV replication, cellular proteins that regulate gene transcription also influence the degree of HIV expression. These cellular factors bind to defined DNA sequences in the LTR, thus modulating promoter activity of integrated HIV genomes. Two such transcriptional factors, Spl and NF-KB, appear to be of particular importance. Three binding sites for Spl, an abundant mammalian transcriptional factor, are present 5' to the RNA start site in the HIV LTR and are required for efficient synthesis of HIV RNA.54 The HIV LTR also contains an 11 base-pair, tandomly repeated enhancer sequence that has been shown to contain binding sites for at leastthree nuclear proteins, referred to as NF-KB,55 EBP-l,56 and HIVen86AY Cellular factors that bind to and activate this enhancer sequence (and therefore activate the LTR) appear to be regulated proteins. They are not present in resting T cells but are induced when T cells are activated by phorbol esters andmitogens. Thus, HIVRNAsynthesismay be closely linked to the activation state of T cells; activated T cells contain more of the transcriptional factors that contribute to HIV gene expression. Cytokines, such as tumor necrosis factor £x, also can stimulate the production of these factors in T cells,58-6o thus' augmenting virus production from latently or chronically infected cells. 61 Thus, it is clear that multiple facets of HIV replication may contribute to the pathogenesis ofAIDS. The unique, specific interaction of the HIV gp120 with the CD4 molecule determines the spectrum of cell types that may be infected by HIV, resulting in immunodeficiency and possibly other clinical features of HIV infection. The variable nature of the HIV env proteins may limit the efficacy of the immune response to the virus, thus contributing to disease progression. Finally, the complex interactions of viral regulatory gene products and cellular transcriptional factors with the viral LTR allow for the establishment and reactivation of viral latency, with the resultant chronic progression of HIV infection and the development of AIDS.
REFERENCES 1. Barre-Sinoussi F, Cherman JC, Rey R, et a!. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220:868-71. 2. Popovic M, Sarngadharan MG, Read E, et a!. Detection, isolation, and continuous production of cytopathic retrovi· ruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 1984;224:497-500. 3. Levy lA, Hoffman AD, Kramer SM, et al. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science 1984;225:840-2. 4. Haase AT. Pathogenesis of lentivirus infection. Nature 1986;322:130-6. 5. Franchini G, Gurgo C, Guo H-G, et al. Sequence ofsimian immunodeficiency virus and its relationship to the human immunodeficiency viruses. Nature 1987;328:539-42. 6. Chakrabati L, Guyader M, Alizon M, et al. Sequence of simian immunodeficiency virus from macaque and its relationship to other human and simian retroviruses. Nature 1987;328:543-7. 7. Daniel MD, Letvin NL, King NW, et al. Isolation ofT-cell tropic HTLV-III-like retrovirus from macaques. Science 1985;228:1201-4. 8. Letvin NL, Daniel MD, Sehgal PK, et aI. Induction of AIDS-like disease in macaque monkeys with T-cell tropic retrovirus STLV-III. Science 1985;230:71-3. 9. Ringler DJ, Hancock WW, King NW, el al. Immunophenotypic characterization of the cutaneous exanthem of SIV-infected rhesus monkeys. Am J PathoI1987;126:199207. 10. McDougal JS, Kennedy MS, Sligh JM, et al. Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110 K viral protein and the T4 molecule. Science 1986;231 :382-5. 11. Maddon Pl, Dalgleish AG, McDougal JS, et al. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 1986;47:333-48. 12. DiMarzo-Veronese F, DiVico AL, Copeland TD, et a!. Characterization of gp41 as the transmembrane protein coded by the HTLV-III/LAV envelope gene. Science 1985;229:1402-4. 13. Fisher RA, Bertonis JM, Meier W, et al. HIV infection is blocked in vitro by recombinant soluble CD4. Nature 1988;331 :76-8. 14. Hussey RE, Richardson NE, Kowalski M, et al. A soluble CD4 protein selectively inhibits HIV replication and syncytium formation. Nature 1988;331 :80-2. 15. Dean KC, McDougal JS, Inacker R, et aL A soluble form of CD4 (T4) inhibits AIDS virus infection. Nature 1988;331:82-4. 16. Traunecker A, Luke W, Karjalainen K. Soluble CD4 molecules neutralize human immunodeficiency virus type 1. Nature 1988;331:84-6. 17. Nara PL. HIV-I neutralization: evidence for rapid binding/post binding neutralization from infected humans, chimpanzees and gp120-vaccinated animals. In: Lerner RA, Ginsberg H, Chanock RM, et aI., eds. Vaccines 89. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 1989:137-44. 18. Brown PO, Bowerman B, Varmus HE, et aI. Correct integration of retroyiral DNA in vitro. Cell 1987;49:347-56. 19. Mitsuya H, Jarret RF, Matsukura M, eta!. Long-term inhibition of human T-lymphotropic virus type III/lymphad-
Volume 22 Number 6, Part 2 June 1990
20.
21.
22.
23.
24. 25. 26.
27. 28. 29.
30.
31. 32. 33.
34.
35. 36.
enopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2' 3' -dideoxynucleosides in vitro. Proc Natl Acad Sci USA 1987;84:2033-7. Lightfoote MM, Coligan JE, Folks TM, et al. Structural characterization of reverse transcriptase and endonuclease polypeptides of the acquired immunodeficiency syndrome retrovirus. J Viral 1986;60:771-5. Navia MA, Fitzgerald MND, McKeever BM, et al. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 1989;337: 615-9. Folks T, Benn S, Rabson A. et al. Characterization of a continuous T-cell line susceptible to the cytopathic effects of the acquired immunodeficiency syndrome (AIDS)associated retrovirus. Proc Natl Acad Sci USA 1985; 82:4539-43. Montagnier L, Gmest J, Chamaret S, et al. Adaptation of lymphadenopathy-associated virus to replication in EBVtransformed B Iymphoblastoid cell lines. Science 1984; 225:63-6. Koenig S, Gendelman HE, Orenstein JM, et al. Detection of AIDS vims in brain tissue from AIDS patients with encephalopathy. Science 1986;233:1089-93. Tschachler E, Groh V, Popovic M, et al. Epidermal Langerhans cells: a target for HTLV-III/LAV infection. J Invest DermatoI1987;88:233-7. Belsito DV, Sanchez MR, Baer RL, et al. Reduced Langerhans cell IgA antigen and ATPase activity in patients with the acquired immunodeficiency syndrome. N Engl J Med 1984;310:1279-82. Folks TM, Kessler SW, Orenstein JM, et al. Infection and replication of HIV-I in purified progenitor cells of normal human bone marrow. Science 1988;242:919-22. Chiodi F, Fuerstenberg S, Gidlund M, et al. Infection of brain-derived cells with human immunodeficiency vims. J Viral 1987;61:1244-7. Wiley CA, Schrier RD, Nelson JA, et al. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 1986;83:7089-93. Nelson lA, Wiley CA, Reynolds-Kohler T, et al. Human immunodeficiency virus detected in bowel epithelium of patients with gastrointestinal symptoms. Lancet 1988; 1:259-62. Adachi A, Koenig S, Gendelman HE, et al. Productive persistent infection of human colorectal cell lines with human immunodeficiency virus. J ViroI1987;61:209-13. Alizon M, Wain-Hobson S, Montagnier L, et al. Genetic variability of the AIDS virus: nucleotide sequence analysis of two isolates from African patients. Cell 1986;46:63-74. Starcich BR, Hahn BH, Shaw GM, et al. Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS. Cell 1986;45:637-48. Willey RL, Rutledge RA, Dias S, et al. Identification of conserved and divergent domains within the envelope genes of the acquired immunodeficiency syndrome retrovirus. Proc Natl Acad Sci USA 1986;83:5038-42. Hahn RH, Shaw GM, Taylor ME, et al. Genetic variation in HTLV-III/LAV over time in patients with AIDS or at risk for AIDS. Science 1986;232:1548-53. Lasky LA, Nakamura G, Smith DH, et al. Delineation of
HW Virology 1201
37. 38.
39.
40.
41.
42. 43. 44. 45.
46. 47. 48.
49. 50. 51.
52.
53.
a region of the human immunodeficiency virus type I gp120 glycoprotein critical for interaction with the CD4 receptor. Cell 1987;50:975-85. Kowalski M, Potz J, Basiripour L, et al. Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science 1987;237:1351-5. Goudsmit J, Debouck C, Meloen RH, et al. Human immunodeficiency virus type 1 neutralization epitope with conserved architecture elicits early type-specific antibodies in infected chimpanzees. Proc Natl Acad Sci USA 1988;85:4478-82. Palker TJ, Clark ME, Langlois AJ, et al. Type specific neutralization of the human immunodeficiency virus with antibodies to env-encoded synthetic peptides. Proc N atl Acad Sci USA 1988;85:1932-6. Rusche JR, Javalerian K, McDanal C, et al. Antibodies that inhibit fusion of human immunodeficiency virusinfected cells bind a 24-amino acid sequence of the viral envelope gp120. Proc Natl Acad Sci USA 1988;85:3198202. Luciw PA, Cheng-Mayer C, Levy JA. Mutational analysis of the human immunodeficiency virus: the orf-B region down regulates virus replication. Proc Natl Acad Sci USA 1987;84:1434-8. Ahmad N, Venkatesen S. Nefprotein of HIV-l is a transcriptional repressor of HIV-l LTR. Science 1988; 241:1481-5. Arya SK, Guo C, Josephs SF, Wong-Staal F. Tramactivator gene of human T-lymphotropic virus type III (HTLV-III). Science 1985;229:69-73. Sodroski l, Patarca R, Rosen C, et al. Location of the trans-activating region on the genome of human T-cell lymphotropic virus type III. Science 1985;229:74-7. Rosen CA, Sodroski JG, Goh WC, et al. Post-transcriptional regulation accounts for the trans-activation of the human T-Iymphotropic virus type III. Nature 1986; 319:555-9. Wright CM, Felber BK, Paskalis H,et al. Expression and characterization of the trans-activator of HTLV-III/LAV virus. Science 1986;243:988-92. Cullen BR.Trans-activation of human immunodeficiency virus occurs via a bimodal mechanism. Cell 1986;46:97382. Peterlin BM, Luciw PA, Barr Pl, et al. Elevated levels of mRNA can account for the trans-activation of human immunodeficiency virus. Proc Nat! Acad Sci USA 1986; 83:9734-8. Kao SoY, Caiman AF, Luciw PA, et al. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 1987;330:489-93. Sodroski lG, Goh WC, Rosen C, et al. A second post-transcriptional trans-activator gene required far HTLV-III replication. Nature 1986;321:412-7. Feinberg MB, Jarrett RF, Aldovini A, et al. HTLV-III expression and production involve complex regulation at the levels of splicing and translation af viral RNA. Cell 1986;46:807-17. Felber BK, Hadzopaulou-Cladaras M, Cladaras C, et al. Rev protein of human immunodeficiency virus type 1 affects the stability and transport of the viral mRNA. Proc Natl Acad Sci USA 1989;86:1495-9. Malim MH, Hauber J, Le SoY, et al. The HIV-1 rev trans-activator acts through a structured target sequence to
Journal of the American Academy of Dermatology
Rabson"
54. 55. 56.
57.
58.
activate nuclear export of unspliced viral mRNA. Nature 1989;338:254-7. Jones KA, Kadonaga JT, Luciw PA, et al. Activation ofthe AIDS retrovirus promoter by the cellular transcription factor, Spl. Science 1986;232:755-9. Nabel G, Baltimore D. An inducible factor activates expression of human immunodeficiency virus in T cells. Nature 1987;326:711-3. Wu G, Garcia J, Harrick D, et al. Purification of the human immunodeficiency virus type 1 enhancer and TAR bindingproteinsEBP-I and UBP-1.EMBOJ 1989;7:211729. Franza RB, Josephs SF, Gilman MZ, et al. Characterization of cellular proteins recognizing the HIV enhancer using a microscale DNA-affinity precipitation assay. Nature (London) 1987;330:391-5. Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor a:
and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor KB. Proc Nat! Acad Sci USA 1989;86:2336-40. 59. Lowenthal JW, Ballard DW, Bohnlein E, et al. Tumor necrosis factor ex induces proteins that bind specifically to KBlike enhancer elements and regulate interleukin receptor exchain gene expression in primary human T lymphocytes. Proc Natl Acad Sci USA 1989;86:2331-5. 60. Duh E, Maury W, Folks T, et al. Tumor necrosis factor ex activates human immunodeficiency virus type I through induction of nuclear factor binding to the NF-KB sites in the long terminal repeats. Proc Natl Acad Sci USA 1989; 86:5974-8. 61. Folks TM, Clouse KA, Justement J, et al. Tumor necrosis factor ex induces expression of human immunodeficiency virus in a chronically infected T cell clone. Proc Nat! Acad Sci USA 1989;86:2365-8.
The immunology of HIV infection Kathryn M. Zunich, MD, and H. Clifford Lane, MD Bethesda, Maryland A variety of immunologic abnormalities have been reported in patients with human immunodeficiency virus (HIV) infection. The most characteristic is a decrease in the number and function of CD4 helperjinducer T lymphocytes. Patients with HIV infection also have abnormalities in the number and activity of CD8 suppressor j cytotoxic T lymphocytes, defective soluble antigen recognition, polyc1onal B cell activation, and decreased cytotoxicity. The CD4 cell defect is the most critical abnormality in the immunopathogenesis of HIV disease. Understanding the relationship of this defect to the appearance of clinical problems can contribute to the management of patients with HIV infection. (J AM ACAD DERMATOL
1990;22:1202-5.)
The immune system consists of nonspecific and specific effector mechanisms, both of which play important roles in host defense against a wide variety of foreign agents. Nonspecific host resistance is mediated by phagocytic cells (monocytes, neutrophils), natural killer cells, and the complement series of proteins, while specific effector mechanisms include the B lymphocyte or antibody system and the T lymphocyte or cellular immune system. These elements of the immune system are interconnected: the CD4 (helper/inducer) T lymphocyte plays a central role in antigen recognition and immunoregulation. Virtually the entire immunologic cascade From the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Reprint requests: Kathryn M. Zunich, MD, National Institutes of Health, Building 10, Room 1\ B-] 3, Bethesda, MD 20892.
16/0/19162
1202
(neutrophil function, phagocytosis, monocyte activation, lymphokine release by T cells, natural killer cell function, and antibody secretion) can be perturbed by abnormalities of the central element, the CD4 cell. The CD4 T cell normally plays a critical role in eliciting a concerted immune response. After antigen presentation by a monocyte or macrophage, the CD4 cell calls into play various elements of the immune system to carry out their respective roles in host defense. After triggering and signaling by the CD4 cell, a variety of growth and differentiation factors are produced that have roles ranging from hematopoiesis to cytotoxicity. CD8 (suppressor/cytotoxic) T cells may be induced to kill virally infected targets or tumor cells. Natural killer cells may be further activated to carry out their nonspecific surveillance. The production of antibodies by B lymphocytes is regulated by the CD4-initiated immune
A tremendous amount has been learned about acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV) in the short period of time since its initial isolation 1 and proof of its role in the etiology of AIDS2, 3; however, a number ofimportant mysteries remain. Among these are issues such as the spectrum of HIV-induced disease and the concept of disease progression from a person who is infected but asymptomatic to the development of AIDS-related complex (ARC) and AIDS with the loss of CD4+ T cells. Little is known about the mechanisms by which CD4+ lymphocytes are lost, but several complex mechanisms seem to be involved. Of importance in understanding the loss of CD4+ T cells and disease progression is the concept that viral replication is intimately connected to host cellular differentiation and gene expression. What happens in the immune system of an infected individual affects how virus replicates, the degree of replication, and the spread through the body. Other important issues that are just beginning to be defined include the range of cells in the body that are infected by HIV. The critical role that infection of CD4+ lymphocytes plays in the development ofHIV disease is clear. It is becoming increasingly evident, however, that infection of cells of the monocyte/
From the Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Nationallnstltutes of HeItlth. Reprint requests: Arnold B. Rabson, MD, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
16/0/19161
1196
macrophage lineage also plays an important role. Further issues in the virology of HIV have to do with the tremendous mutability of HIV, particularly in the envelope gene, issues that have important implications for vaccine development. HIV is a member of the lentivirus family of retroviruses. These viruses induce slow, chronic, often fatal disease in their host. 4 Related to HIV-I and HIV-2, the human immunodeficiency viruses, is the family of primate lentiviruses referred to as the simian immunodeficiency viruses (SIVs). The SIVs provide an important animal model for understanding the pathogenesis of HIV disease. Although SIV is distinct from HIV-I and, in fact, is more closely related to HlV-2 than it is to HIV-I,5,6 the disease that SlV produces in infected rhesus macaques bears similarities to human AIDS.7,8 Acute infection of monkeys with SlV is associated with cutaneous manifestations that show similarities to the cutaneous manifestations of acute HIV infection. 9 Fig. 1 is a schematic representation of the life cycle of HIY. HIV is an enveloped virus that acquires a lipid envelope as it buds from the surface of an infected cell. Embedded within that lipid envelope are virally encoded glycoproteins, the envelope proteins gp160/120 and gp41. The external envelope protein, gp 120, is the protein on the surface of the virus that interacts with the CD4 molecule on a target cell. 10, 11 gp 120 is attached to the transmembrane envelope protein, gp41,12 which anchors the gp120 into the membrane and which also functions in allowing the membrane of the virus to fuse with the host cellular membrane. The gag proteins form the core within
Volume 22 Number 6, Part 2 June 1990
HIV virology 1197
Fig. 1. Schematic representation of the HIV life cycle. (Modified from Rabson AB. The molecular biology of HIV infection: clues for possible therapy. In: Levy J, ed. AIDS: pathogenesis and treatment. New York: Marcel Dekker, 1989:233. Reprinted by courtesy ofMarcel Dekker, Inc.)
which viral RNA is packaged. Shown schematically in step 1 of Fig. 1 is the binding of virion particles to the CD4 receptor on the surface of the target cell, either a CD4 + lymphocyte or other cells in the body that may express CD4. Interaction between the gp120 and the CD4 molecule mediates attachment of virus to a target cell. After attachment, there is a complex process that results in internalization of the virus. This involves fusion of the viral envelope with the lipid membrane of the cell and probably involves contributions of the gp41 molecule as well as host cellular molecules. Strategies designed to inhibit these early steps of viral replication are under evaluation both as immunoprophylactic and therapeutic approaches. These strategies include attempts to block binding of virus to receptor, such as the use of soluble CD4. 13- 16 One can also envision strategies that would block entry of virus by interfering with the fusion process; some aspects of the process by which neutralizing antibodies block HIV infection may involve steps subsequent to HIV binding. l ? After entry into the target cell, the process of reverse transcription occurs, in which a doublestranded DNA copy of viral genetic information is
generated from the viral RNA genome. This probably occurs in the context of a subviral particle with associated viral gag proteins 18 and is clearly one of the major targets for anti-HIV therapy. This is the step at which azidothymidine (AZT) and related compounds exert their antiviral effect. 19 After reverse transcription, HIV DNA enters the nucleus and, again likely in the context of a subviral particle, 18 undergoes the step of integration into the host cellular DNA. This integration step is catalyzed by a virally encoded enzyme, the integrase. 2o As a viral-specific enzyme, the integrase also represents a potential target for interference with viral replication as distinct from cellular metabolic activity. The integration process is very important in determining the next step in the viral life cycle. Once integrated into cellular DNA, this viral DNA copy is subject to the kinds of regulation of its expression that control the expression of other cellular genes. Whether integrated HIV DNA is expressed or exists in a latent form depends both on virally encoded factors and on the general transcriptional state of the cell. Furthermore, this integration process means that once virus is integrated into a cell, it is present for the life of that
Journal of the American Academy of Dermatology
1198 Rabson
o
gag
d
LTR p55
pH \
p24
, D
rev
tat
0
~
2"-----p-o-,------JhJt----e-n-v----.,RQ \p15 p7JP§ protease!
p9
RT
p64
endonuclease
p34
p51 gp160
gp120
gp41
p23--
p17-
p12-
p17 p27---
Fig. 2. The HIV DNA genome. (Modified from Rabson AB. The molecular biology of HN infection: clues for possible therapy. In: Levy J, ed. AIDS: pathogenesis and treatment. New York: Marcel Dekker, 1989:236. Reprinted by courtesy of Marcel Dekker, Inc.)
cell. Thus, viral DNA can persist for years in infected cells in a latent or chronic form. Expression of viral DNA involves transcription of viral RNA as either virion RNA that will be packaged into new viral genomes or as a series of spliced messenger RNAs encoding the various structural, enzymatic, and. regulatory proteins. The various regulatory proteins (described below) are vital-specific and also represent potential targets for antiviral therapy. Finally, the process of assembly and viral budding would be potential mechanisms for interference with viral replication. A particularly interesting potential target is the viral protease,21 an enzyme involved in the maturation of precursor gag and pol polypeptides. Fig. 2 shows the features of the HIV DNA genome. The long terminal repeats (LTRs) are the control elements for the viral DNA expression. The LTRs contain promoters for viral RNA transcription that are influenced both by the regulatory effects from virally encoded, transacting regulatory proteins and by cellular transcriptional factors. The
locations of the genes encoding the gag proteins, the polgene encoding the viral enzymatic activities, and the env gene are shown. Also indicated are the positions of the genes encoding the viral regulatory proteins tat, rev, and nef, as well as genes whose detailed functions are still being elucidated, such as vif, U,and R. As discussed, the first step in HIV infection is the binding of HIV to a CD4+ target cell. An increasingly large number of cell types have been shown to express CD4 and thus serve as potential targets of HIV infection. Infection of some of these different cells may account for aspects of the wide range of HIV-related syndromes. In essentially all these cell types, it has been possible to detect expression bf CD4, either at the protein or RNA levels. Thus, it appears that, for most of the clinically relevant infected cells in the body, CD4 is a critical determinant of infection. Obviously, the most dramatic effects of HIV infection can be seen in the infection of the CD4+ helper subset of T lymphocytes. In tissue culture,
Volume 22
Number 6, Part 2 June 1990
both primary T lymphocytes and CD4+ tumor cell lines are readily infectable by HIV. 1-3. 22 In tissue culture, infection of some Epstein-Barr virus-transformed CD4+ B cell lines has been demonstrated,23 although the clinical relevance of this observation in patients has not been demonstrated. Infection of cells of the monocyte/macrophage series may be extremely important in AIDS patients. In other animallentivirus infections such as visna in sheep, monocytes appear to be a critical reservoir of latent virus. 4 Although latent infection of monocytes by HIV in man has not been proved, productive HIV infection of a number of different macrophage types has been clearly demonstrated. Infected macrophages in the brain seem to play an important role in the pathogenesis of AIDS encephalopathy.24 Of particular interest to dermatologists has been the frequent identification of infectIon in Langerhans cells in the epidermis. 25 Furthermore, there appears to be depletion of these cells in AIDS patients' skin, raising the possibility that they may be killed by HIV infection. 26 Infection of the Langerhans cells may playa role in some of the cutaneous manifestations of AIDS, and depletion of these cells could potentially contribute to the progressive loss of immune competence. Infection of bone marrow precursors of the monocytic/granulocytic lineage has been demonstrated in vitr027 and could serve as a reservoir for HIV. In tissue culture and in in situ hybridization studies, some neural cells have been shown to be infected/ S' 29 and endothelial cells in the brains of patients with AIDS encephalopathy have been shown to contain virus. 29 Again, the clinical importance of these findings is not clear. Infection of intestinal epithelial cells has been shown both in viv030 and in vitr031 and may contribute to AIDSassociated gastrointestinal symptoms as well as to the epidemiologic observations regarding the role of anal intercourse as a risk factor in the spread of HIV infection. Recent studies from our laboratory (W. J. Maury, B. Potts, and A. B. Rabson, in press) have demonstrated the infectability of human placental samples, an observation that may help to explain the pathogenesis of neonatal AIDS. Thus, a large number of cell types in addition to CD4+ lymphocytes may be infected with HIV, and these other cells may help to contribute to the variety of clinical syndromes associated with HIV infection. As described, the binding of HIV to a target cell is mediated by the HIV envelope gene product,
HIV virology 1199 gp120. The envelope gene is highly variable between isolates derived from different patients32-34; less pronounced variability can be seen in isolates derived from a single patient.35 This variability has important implications. The highly conserved regions contain functionally important sites such as the domains where the cleavage between gp120 and gp41 occurs. A site shown to be involved in the binding of the gp120 to the CD4 molecule is in a moderately conserved region 36; other segments of the gp120 probably contribute to this binding as well. 37 Highly variable domains of the env gene can be identified; for example, comparison of the env genes of isolates of HIV from Zaire and the United States shows stretches of 150 to 200 amino acids over which there may be only 30% to 50% homology.34 Even within one individual over time, variability may be observed in these stretches,35 an observation that has implications for immunotherapy. This striking variability also has obvious implications for vaccine development. One region involved in the generation of antibodies that neutralize HIV infection has been identified in a highly variable domain of the envelope.38-4o Antibodies generated to peptides derived from this putative loop region will neutralize the parental virus but will not neutralize viruses bearing a different sequence in this region. In considering the molecular determinants of the pathogenesis of HIV infection, it is important to address the cellular and viral controls of HIV gene expression. The interplay between these controls determines the degree of HIV production from an infected cell, that is, whether virus persists in a latent or chronic low-level state of expression or whether high-level production of progeny virus occurs with subsequent cell death. HIV encodes proteins that affect its own gene expression. The nef protein is a negative regulator viral gene expression41 that reduces the amount of viral RNA transcription. 42 Conversely, the tat gene encodes a powerful positive regulator that can increase gene expression directed by the viral LTR hundreds of fold. 43 ,44 The tat gene product acts to increase the levels ofHIV RNA and protein in a cell, apparently through both transcriptional and posttranscriptional mechanisms. 45-49 HIV also encodes a regulator of the processing of its RNA, the rev gene. 50,51 The rev gene controls the relative amounts of unspliced genomic and gag-pol RNAs compared with the amounts of the multiply spliced RNAs for
of
Journal of the American Academy of Dermatology
1200 Rabson
the various regulatory proteins. Rev apparently acts by influencing the transport of viral RNAs containing a rev-responsive element to the cytoplasm.52, 53 By controlling the relative amounts of regulatory versus structural proteins in an infected cell, rev may affect viral latency. In addition to virally encoded regulatory genes that modulate HIV replication, cellular proteins that regulate gene transcription also influence the degree of HIV expression. These cellular factors bind to defined DNA sequences in the LTR, thus modulating promoter activity of integrated HIV genomes. Two such transcriptional factors, Spl and NF-KB, appear to be of particular importance. Three binding sites for Spl, an abundant mammalian transcriptional factor, are present 5' to the RNA start site in the HIV LTR and are required for efficient synthesis of HIV RNA.54 The HIV LTR also contains an 11 base-pair, tandomly repeated enhancer sequence that has been shown to contain binding sites for at leastthree nuclear proteins, referred to as NF-KB,55 EBP-l,56 and HIVen86AY Cellular factors that bind to and activate this enhancer sequence (and therefore activate the LTR) appear to be regulated proteins. They are not present in resting T cells but are induced when T cells are activated by phorbol esters andmitogens. Thus, HIVRNAsynthesismay be closely linked to the activation state of T cells; activated T cells contain more of the transcriptional factors that contribute to HIV gene expression. Cytokines, such as tumor necrosis factor £x, also can stimulate the production of these factors in T cells,58-6o thus' augmenting virus production from latently or chronically infected cells. 61 Thus, it is clear that multiple facets of HIV replication may contribute to the pathogenesis ofAIDS. The unique, specific interaction of the HIV gp120 with the CD4 molecule determines the spectrum of cell types that may be infected by HIV, resulting in immunodeficiency and possibly other clinical features of HIV infection. The variable nature of the HIV env proteins may limit the efficacy of the immune response to the virus, thus contributing to disease progression. Finally, the complex interactions of viral regulatory gene products and cellular transcriptional factors with the viral LTR allow for the establishment and reactivation of viral latency, with the resultant chronic progression of HIV infection and the development of AIDS.
REFERENCES 1. Barre-Sinoussi F, Cherman JC, Rey R, et a!. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220:868-71. 2. Popovic M, Sarngadharan MG, Read E, et a!. Detection, isolation, and continuous production of cytopathic retrovi· ruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 1984;224:497-500. 3. Levy lA, Hoffman AD, Kramer SM, et al. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science 1984;225:840-2. 4. Haase AT. Pathogenesis of lentivirus infection. Nature 1986;322:130-6. 5. Franchini G, Gurgo C, Guo H-G, et al. Sequence ofsimian immunodeficiency virus and its relationship to the human immunodeficiency viruses. Nature 1987;328:539-42. 6. Chakrabati L, Guyader M, Alizon M, et al. Sequence of simian immunodeficiency virus from macaque and its relationship to other human and simian retroviruses. Nature 1987;328:543-7. 7. Daniel MD, Letvin NL, King NW, et al. Isolation ofT-cell tropic HTLV-III-like retrovirus from macaques. Science 1985;228:1201-4. 8. Letvin NL, Daniel MD, Sehgal PK, et aI. Induction of AIDS-like disease in macaque monkeys with T-cell tropic retrovirus STLV-III. Science 1985;230:71-3. 9. Ringler DJ, Hancock WW, King NW, el al. Immunophenotypic characterization of the cutaneous exanthem of SIV-infected rhesus monkeys. Am J PathoI1987;126:199207. 10. McDougal JS, Kennedy MS, Sligh JM, et al. Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110 K viral protein and the T4 molecule. Science 1986;231 :382-5. 11. Maddon Pl, Dalgleish AG, McDougal JS, et al. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 1986;47:333-48. 12. DiMarzo-Veronese F, DiVico AL, Copeland TD, et a!. Characterization of gp41 as the transmembrane protein coded by the HTLV-III/LAV envelope gene. Science 1985;229:1402-4. 13. Fisher RA, Bertonis JM, Meier W, et al. HIV infection is blocked in vitro by recombinant soluble CD4. Nature 1988;331 :76-8. 14. Hussey RE, Richardson NE, Kowalski M, et al. A soluble CD4 protein selectively inhibits HIV replication and syncytium formation. Nature 1988;331 :80-2. 15. Dean KC, McDougal JS, Inacker R, et aL A soluble form of CD4 (T4) inhibits AIDS virus infection. Nature 1988;331:82-4. 16. Traunecker A, Luke W, Karjalainen K. Soluble CD4 molecules neutralize human immunodeficiency virus type 1. Nature 1988;331:84-6. 17. Nara PL. HIV-I neutralization: evidence for rapid binding/post binding neutralization from infected humans, chimpanzees and gp120-vaccinated animals. In: Lerner RA, Ginsberg H, Chanock RM, et aI., eds. Vaccines 89. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 1989:137-44. 18. Brown PO, Bowerman B, Varmus HE, et aI. Correct integration of retroyiral DNA in vitro. Cell 1987;49:347-56. 19. Mitsuya H, Jarret RF, Matsukura M, eta!. Long-term inhibition of human T-lymphotropic virus type III/lymphad-
Volume 22 Number 6, Part 2 June 1990
20.
21.
22.
23.
24. 25. 26.
27. 28. 29.
30.
31. 32. 33.
34.
35. 36.
enopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2' 3' -dideoxynucleosides in vitro. Proc Natl Acad Sci USA 1987;84:2033-7. Lightfoote MM, Coligan JE, Folks TM, et al. Structural characterization of reverse transcriptase and endonuclease polypeptides of the acquired immunodeficiency syndrome retrovirus. J Viral 1986;60:771-5. Navia MA, Fitzgerald MND, McKeever BM, et al. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 1989;337: 615-9. Folks T, Benn S, Rabson A. et al. Characterization of a continuous T-cell line susceptible to the cytopathic effects of the acquired immunodeficiency syndrome (AIDS)associated retrovirus. Proc Natl Acad Sci USA 1985; 82:4539-43. Montagnier L, Gmest J, Chamaret S, et al. Adaptation of lymphadenopathy-associated virus to replication in EBVtransformed B Iymphoblastoid cell lines. Science 1984; 225:63-6. Koenig S, Gendelman HE, Orenstein JM, et al. Detection of AIDS vims in brain tissue from AIDS patients with encephalopathy. Science 1986;233:1089-93. Tschachler E, Groh V, Popovic M, et al. Epidermal Langerhans cells: a target for HTLV-III/LAV infection. J Invest DermatoI1987;88:233-7. Belsito DV, Sanchez MR, Baer RL, et al. Reduced Langerhans cell IgA antigen and ATPase activity in patients with the acquired immunodeficiency syndrome. N Engl J Med 1984;310:1279-82. Folks TM, Kessler SW, Orenstein JM, et al. Infection and replication of HIV-I in purified progenitor cells of normal human bone marrow. Science 1988;242:919-22. Chiodi F, Fuerstenberg S, Gidlund M, et al. Infection of brain-derived cells with human immunodeficiency vims. J Viral 1987;61:1244-7. Wiley CA, Schrier RD, Nelson JA, et al. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 1986;83:7089-93. Nelson lA, Wiley CA, Reynolds-Kohler T, et al. Human immunodeficiency virus detected in bowel epithelium of patients with gastrointestinal symptoms. Lancet 1988; 1:259-62. Adachi A, Koenig S, Gendelman HE, et al. Productive persistent infection of human colorectal cell lines with human immunodeficiency virus. J ViroI1987;61:209-13. Alizon M, Wain-Hobson S, Montagnier L, et al. Genetic variability of the AIDS virus: nucleotide sequence analysis of two isolates from African patients. Cell 1986;46:63-74. Starcich BR, Hahn BH, Shaw GM, et al. Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS. Cell 1986;45:637-48. Willey RL, Rutledge RA, Dias S, et al. Identification of conserved and divergent domains within the envelope genes of the acquired immunodeficiency syndrome retrovirus. Proc Natl Acad Sci USA 1986;83:5038-42. Hahn RH, Shaw GM, Taylor ME, et al. Genetic variation in HTLV-III/LAV over time in patients with AIDS or at risk for AIDS. Science 1986;232:1548-53. Lasky LA, Nakamura G, Smith DH, et al. Delineation of
HW Virology 1201
37. 38.
39.
40.
41.
42. 43. 44. 45.
46. 47. 48.
49. 50. 51.
52.
53.
a region of the human immunodeficiency virus type I gp120 glycoprotein critical for interaction with the CD4 receptor. Cell 1987;50:975-85. Kowalski M, Potz J, Basiripour L, et al. Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science 1987;237:1351-5. Goudsmit J, Debouck C, Meloen RH, et al. Human immunodeficiency virus type 1 neutralization epitope with conserved architecture elicits early type-specific antibodies in infected chimpanzees. Proc Natl Acad Sci USA 1988;85:4478-82. Palker TJ, Clark ME, Langlois AJ, et al. Type specific neutralization of the human immunodeficiency virus with antibodies to env-encoded synthetic peptides. Proc N atl Acad Sci USA 1988;85:1932-6. Rusche JR, Javalerian K, McDanal C, et al. Antibodies that inhibit fusion of human immunodeficiency virusinfected cells bind a 24-amino acid sequence of the viral envelope gp120. Proc Natl Acad Sci USA 1988;85:3198202. Luciw PA, Cheng-Mayer C, Levy JA. Mutational analysis of the human immunodeficiency virus: the orf-B region down regulates virus replication. Proc Natl Acad Sci USA 1987;84:1434-8. Ahmad N, Venkatesen S. Nefprotein of HIV-l is a transcriptional repressor of HIV-l LTR. Science 1988; 241:1481-5. Arya SK, Guo C, Josephs SF, Wong-Staal F. Tramactivator gene of human T-lymphotropic virus type III (HTLV-III). Science 1985;229:69-73. Sodroski l, Patarca R, Rosen C, et al. Location of the trans-activating region on the genome of human T-cell lymphotropic virus type III. Science 1985;229:74-7. Rosen CA, Sodroski JG, Goh WC, et al. Post-transcriptional regulation accounts for the trans-activation of the human T-Iymphotropic virus type III. Nature 1986; 319:555-9. Wright CM, Felber BK, Paskalis H,et al. Expression and characterization of the trans-activator of HTLV-III/LAV virus. Science 1986;243:988-92. Cullen BR.Trans-activation of human immunodeficiency virus occurs via a bimodal mechanism. Cell 1986;46:97382. Peterlin BM, Luciw PA, Barr Pl, et al. Elevated levels of mRNA can account for the trans-activation of human immunodeficiency virus. Proc Nat! Acad Sci USA 1986; 83:9734-8. Kao SoY, Caiman AF, Luciw PA, et al. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 1987;330:489-93. Sodroski lG, Goh WC, Rosen C, et al. A second post-transcriptional trans-activator gene required far HTLV-III replication. Nature 1986;321:412-7. Feinberg MB, Jarrett RF, Aldovini A, et al. HTLV-III expression and production involve complex regulation at the levels of splicing and translation af viral RNA. Cell 1986;46:807-17. Felber BK, Hadzopaulou-Cladaras M, Cladaras C, et al. Rev protein of human immunodeficiency virus type 1 affects the stability and transport of the viral mRNA. Proc Natl Acad Sci USA 1989;86:1495-9. Malim MH, Hauber J, Le SoY, et al. The HIV-1 rev trans-activator acts through a structured target sequence to
Journal of the American Academy of Dermatology
Rabson"
54. 55. 56.
57.
58.
activate nuclear export of unspliced viral mRNA. Nature 1989;338:254-7. Jones KA, Kadonaga JT, Luciw PA, et al. Activation ofthe AIDS retrovirus promoter by the cellular transcription factor, Spl. Science 1986;232:755-9. Nabel G, Baltimore D. An inducible factor activates expression of human immunodeficiency virus in T cells. Nature 1987;326:711-3. Wu G, Garcia J, Harrick D, et al. Purification of the human immunodeficiency virus type 1 enhancer and TAR bindingproteinsEBP-I and UBP-1.EMBOJ 1989;7:211729. Franza RB, Josephs SF, Gilman MZ, et al. Characterization of cellular proteins recognizing the HIV enhancer using a microscale DNA-affinity precipitation assay. Nature (London) 1987;330:391-5. Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor a:
and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor KB. Proc Nat! Acad Sci USA 1989;86:2336-40. 59. Lowenthal JW, Ballard DW, Bohnlein E, et al. Tumor necrosis factor ex induces proteins that bind specifically to KBlike enhancer elements and regulate interleukin receptor exchain gene expression in primary human T lymphocytes. Proc Natl Acad Sci USA 1989;86:2331-5. 60. Duh E, Maury W, Folks T, et al. Tumor necrosis factor ex activates human immunodeficiency virus type I through induction of nuclear factor binding to the NF-KB sites in the long terminal repeats. Proc Natl Acad Sci USA 1989; 86:5974-8. 61. Folks TM, Clouse KA, Justement J, et al. Tumor necrosis factor ex induces expression of human immunodeficiency virus in a chronically infected T cell clone. Proc Nat! Acad Sci USA 1989;86:2365-8.
The immunology of HIV infection Kathryn M. Zunich, MD, and H. Clifford Lane, MD Bethesda, Maryland A variety of immunologic abnormalities have been reported in patients with human immunodeficiency virus (HIV) infection. The most characteristic is a decrease in the number and function of CD4 helperjinducer T lymphocytes. Patients with HIV infection also have abnormalities in the number and activity of CD8 suppressor j cytotoxic T lymphocytes, defective soluble antigen recognition, polyc1onal B cell activation, and decreased cytotoxicity. The CD4 cell defect is the most critical abnormality in the immunopathogenesis of HIV disease. Understanding the relationship of this defect to the appearance of clinical problems can contribute to the management of patients with HIV infection. (J AM ACAD DERMATOL
1990;22:1202-5.)
The immune system consists of nonspecific and specific effector mechanisms, both of which play important roles in host defense against a wide variety of foreign agents. Nonspecific host resistance is mediated by phagocytic cells (monocytes, neutrophils), natural killer cells, and the complement series of proteins, while specific effector mechanisms include the B lymphocyte or antibody system and the T lymphocyte or cellular immune system. These elements of the immune system are interconnected: the CD4 (helper/inducer) T lymphocyte plays a central role in antigen recognition and immunoregulation. Virtually the entire immunologic cascade From the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Reprint requests: Kathryn M. Zunich, MD, National Institutes of Health, Building 10, Room 1\ B-] 3, Bethesda, MD 20892.
16/0/19162
1202
(neutrophil function, phagocytosis, monocyte activation, lymphokine release by T cells, natural killer cell function, and antibody secretion) can be perturbed by abnormalities of the central element, the CD4 cell. The CD4 T cell normally plays a critical role in eliciting a concerted immune response. After antigen presentation by a monocyte or macrophage, the CD4 cell calls into play various elements of the immune system to carry out their respective roles in host defense. After triggering and signaling by the CD4 cell, a variety of growth and differentiation factors are produced that have roles ranging from hematopoiesis to cytotoxicity. CD8 (suppressor/cytotoxic) T cells may be induced to kill virally infected targets or tumor cells. Natural killer cells may be further activated to carry out their nonspecific surveillance. The production of antibodies by B lymphocytes is regulated by the CD4-initiated immune