SEMINARS IN LIVER DISEASE-VOL.
12, NO. 2, 1992
Structure and Function of the Human Immunodeficiency Virus Type 1 GEORGE N. PAVLAKIS, M.D., Ph.D.
From the Humcrn Retrovirus Section, Basic Research Program, National Cancer Institute, Frederick Cancer Research and Developmenr Center, Frederick, Maryland Reprint requests: Dr. Pavlakis, National Cancer Institute, Frederick Cancer Research and Development Center, ABL-Basic Research Program, P.O. Box BiBuilding 539 Room 121, Frederick, Maryland 21702-1201.
of the virus and its identification as the causative agent of AIDS. A large number of excellent reviews have been published on the various topics of AIDS research. Some of them dealing with virologic topics are cited
STRUCTURE OF HUMAN IMMUNODEFICIENCY VIRUS GENOME AND VIRION HIV-I belongs to the lentivirus subfamily of retroviruses. A second human lentivirus named HIV-2 has also been discovered. Found mainly in West Africa, HIV-2 spreads more slowly and may be less pathogenic than HIV-I . Several members of the lentivirus subfamily have been studied, such as simian immunodeficiency viruses (SIV), equine infectious anemia virus, visna virus, caprine arthritis-encephalitis virus, and feline immunodeficiency virus. These lentiviruses are known to be pathogenic in animals, and they are currently used to develop animal models for AIDS (see article by Lafon and Kirn in this issue of Seminars). The lentiviruses cause chronic, debilitating diseases affecting many systems; immunodeficiency is also a frequent outcome of infection. The common biologic properties of the lentiviruses are reflected to a great extent by the common organization of their genome and by their similar expression strategies. l 8 A schematic diagram of the HIV-1 genome and of the structure of a virion is shown in Figure 1. The genome contains the three characteristic retroviral genes (gag, pol, and env) encoding the structural viral components and the viral enzymes. These three genes produce precursor proteins, or "polyproteins," that are subsequently assembled into viral particles together with the viral RNA. These particles bud out of the cytoplasmic membrane and mature via the cleavage of the polyproteins by the viral protease. This cleavage produces the final morphology and infectivity of the viral particle. During the budding process, the virus envelops itself into the cytoplasmic membrane containing the embedded Env glycoproteins, which protrude out of the membrane and are used to attach the virus to new cells via the interaction of gp120 with the cellular CD4 receptor molecule. Several additional viral genes have been identified within the lentiviral genome. This is in contrast to other retroviruses, which only produce structural components
Copyright 0 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
103
Downloaded by: NYU. Copyrighted material.
Human immunodeficiency virus type 1 (HIV-I) is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV-I is a retrovirus isolated just a few years ago.'.' Due to the worldwide AIDS epidemic, a great interest in all aspects of HIV-I biology has led to significant advances in our knowledge of the virus and its mechanisms of pathogenesis. As a result, HIV-1 is among the best-studied viruses, and this knowledge has helped the development of practical clinical applications against AIDS, as well as the advancement of our understanding of basic biologic mechanisms. Many impressive scientific discoveries have resulted in advances in AIDS diagnosis and treatment in just a short period of time. Examples are the identification of the causative agent, the growth of the virus in large quantities in the laboratory,' the generation of reliable tests to detect infected individuals, and the cloning and analysis of its genetic material. Several new drugs effective against the spread of retroviruses such as zidovudine (ZDV, AZT) were discovered and approved for clinical use in record time, and additional drugs are in various stages of testing (see article by Kahn in this issue of Seminars). The attention in AIDS research is now focusing on the generation of safe and effective vaccines, on the implementation of new therapies, and on the improvement of existing therapies. In addition, new diagnostic and follow-up tests have made it possible to monitor the course of the epidemic in populations and to evaluate the course of the disease in individuals. Instrumental to these rapid developments has been the interaction among scientists in entirely different disciplines. Advances in basic biology were very important for the detection, isolation, and study of the virus, as well as for the development of diagnostics and new drugs. Today, the study of HIV and AIDS is at the forefront of medical research, and discoveries in this field are expected to find general applications in other fields. The following is a brief account of what we have learned about HIV-I over the past 8 years since the first isolation
SEMINARS IN LIVER DISEASE-VOLUME
12, NUMBER 2, 1992
tant for the in vivo characteristics of the virus, they are not essential for viral propagation in tissue culture. For example, it has been shown that SIV Nef is not essential for the replication in tissue culture, although its conservation in HIV-I, HIV-2, and SIV indicates that it may have important functions in vivo. This conclusion is supported by experimental evidence in monkeys infected with SIV, showing that Nef-defective SIV cannot replicate and cannot cause disease in injected animal^.^' Vif promotes the infectivity of viral particles, whereas Vpu increases the proportion of viral particles found extracellularly. The exact function of Vpr, which is incorporated in the virion, is not yet known.
FIG. 1. Structure of the genome and the virion of HIV-1. (Reprinted with permission from Broder et aI.l9)
of the virion and viral enzymes. In HIV-I, there are six additional genes, which have been named tat, rev, nef, vif, vpr, and vpu. Two of the additional proteins produced by all lentiviruses, named Tat and Rev, are regulatory factors essential for viral expression and replication (Fig. 2). Both Tat and Rev are small, positively charged proteins that accumulate in the nucleus. They bind to specific sites on the viral mRNA, which are named TAR and RRE, respectively. This binding is necessary for the activation of virus production. The exact mechanism of function of the other identified proteins, namely, Nef, Vif, Vpr, and Vpu, is not yet known. These proteins have been named "accessory" proteins to indicate that, although they are impor-
HIV-I virions attach to cells via the Env glycoprotein, which recognizes the CD4 cell surface receptor found in T cells, monocytes, and other cell types. After binding to CD4, the virus fuses to the plasma membrane, the virus core inserts into the cell, and replication is initiated. Retroviruses contain RNA as their genetic material. After infection, this genomic RNA is converted to DNA (proviral DNA). The conversion of the viral RNA to DNA is a step characteristic of all retroviruses and is executed by the viral enzyme reverse transcriptase (RT). The proviral DNA integrates into the DNA of the cell via the function of another viral enzyme also carried in the virion, integrase. From this time onward, the proviral DNA is indistinguishable from the normal cellular genes, and it follows the same rules as the cellular genes for expression of the genetic information. This expression is achieved by the production of messenger RNA, which is transported in the cytoplasm and translated on the ribosomes into protein molecules. The structural Gag proteins are assembled into capsids that also contain viral RNA and enzymes, and the newly formed virions bud out of the cell and infect new cells. A third viral enzyme, protease, is responsible for the cleavage of the different
FIG. 2. The two positive regulators of HIV-1 expression, Tat and Rev. These viral proteins bind to specific structures on the viral RNA named TAR and RRE, respectively.
Downloaded by: NYU. Copyrighted material.
LIFE CYCLE OF HUMAN IMMUNODEFICIENCY VIRUS
STRUCTURE AND FUNCTION OF HIV-PAVLAKIS
REGULATION OF EXPRESSION A characteristic difference between HIV and other retroviruses is in the complexity of regulation of expression. HIV-1 produces two regulatory proteins, Tat and Rev (Fig. 3). Tat and Rev, and possibly additional cellular factors, interact with the viral RNA and proviral DNA in a highly complex fashion. These interactions regulate the expression of the viral genome. It is anticipated that cellular genes use similar mechanisms for the regulation of cellular gene expression. The details of the mechanism of function of Tat and Rev are under intense investigation. It is known that these factors act in concert to increase viral expression. Tat and Rev stimulate the transcription of proviral DNA to RNA, the transport of this RNA to the cytoplasm, and the efficient translation of the RNA into viral proteins. The potency and specificity of these factors for HIV-1 have triggered efforts to design drugs inhibiting their function. At least one drug with antiviral activity against Tat protein has been discovered, demonstrating the feasibility of this approach. Tat and Rev counteract negative elements in the viral genome that severely restrict virus expression. Thus, in the absence of these factors, HIV expression is not detectable. The evolution of the complexregulatory
signals is very interesting. It appears that all lentiviruses have similar controls. The Rev regulatory pathway appears to be the most conserved in the lentiviruses. The regulatory signals of HIV- I and other lentiviruses are believed to be highly relevant to their life cycle and to provide lentiviruses with their unique characteristics, among which is the generation of slow, debilitating diseases due to the chronic expression of the virus in the body.
COURSE OF THE DISEASE Primary infection by HIV-I may cause only minor symptoms, or it may be associated with an acute mononucleosis-like syndrome. At that stage, there is active virus replication and dissemination in the body. After the development of immune response, the virus levels decrease dramatically. This "silent period" may last for years. Usually, very low levels of virus are found during this period. Nonetheless, the virus continues to replicate at low levels and continues to damage the immune system. The number of CD4' cells in peripheral blood decreases gradually over the years. Finally, immunodeficiency appears, which allows the development of opportunistic infections and the formation of tumors. Detailed knowledge of the biology of HIV-I will lead to a better understanding of the complex virus-host interactions and will clarify the mechanisms of pathogenesis, which lead to the depletion of cells critical for the normal
FIG. 3. Regulation of HIV-1 gene expression by Tat and Rev. Tat protein produced by multiply spliced mRNAs is transported in the nucleus and activates HIV-1 transcription to high levels. When appropriate levels of Rev protein are produced, binding of Rev to the RRE site results in increased transport and translation of the longer viral mRNAs. This results in efficient expression of the viral structural proteins.
Downloaded by: NYU. Copyrighted material.
precursor viral proteins, a step necessary for the infectivity of the viral particles.
SEMINARS IN LIVER DISEASE-VOLUME
12, NUMBER 2, 1992
function of the immune system, such as the CD4+ lymphocytes.
ticle by Herndier and Friedman in this issue of Seminars).
DRUG THERAPIES AGAINST THE ACQUIRED IMMUNODEFICIENCY SYNDROME
VARIABILITY OF THE HUMAN IMMUNODEFICIENCY VIRUS
The identification of HIV- I and the understanding of its life cycle led to the design of rational antiviral therapies. A series of inhibitors of the unique retroviral enzyme RT were tested. These studies resulted in the identification of several drugs (ZDV, didanosine [ddI], ddC, and others) effective against HIV-I and other retroviruses. Of these, ZDV and ddI are approved drugs. ZDV has been shown to prolong the life of AIDS patients. ddI has been approved for some adult and pediatric cases. ddI and ddC may soon be used in combination with ZDV. Many other compounds acting at different stages in the viral life cycle (Fig. 4) have been tested. These now include potential drugs against the regulatory factors. Great progress has also been achieved in the management of opportunistic infections. As a result, AIDS patients live longer. Unfortunately, as the management of opportunistic infections improves, the high incidence of lymphomas and other tumors in AIDS patients is rapidly becoming one of the major causes of death (see ar-
Bindinfl
?
fl
,
A large accumulation of experimental data has demonstrated the ability of HIV-1 to mutate rapidly within the body. This is undoubtedly a major problem for the generation of both effective drug therapies and vaccines. The exceptional variability of HIV-1 within the same patient leads to a swarm of different variants (quasispecies) with different biologic properties. An understanding of the generation and role of these variants in the course of the infection is very important. The high mutation rate of HIV-1 has also been shown to lead to the rapid development of ZDV-resistant variants in the patients receiving this drug. Several investigators have tried to explain the persistence of viral replication in the presence of a vigorous response. It has been postulated that the rapid change leads to the appearance of variants that can escape both humoral and cytotoxic immune surveillance. It has also been postulated that the low immunogenicity of the Env glycoprotein may prevent the efficient development of neutralizing antibodies. Both hepatitis B virus (a hepadna virus) and hepatitis C virus (an RNA virus) are known to cause chronic active hepatitis in a substantial number of infected people. In the future, the mechanisms of HIV persistence may prove relevant to mechanisms used by other viruses, including the hepatitis viruses.
n
REFERENCES
I
1
Integration
I \- n
1
DNA
Transcription
u
Expression
RNA
Translat~on
1
bly
tr a ev t ,, nef
env
I Budding, Maturation
FIG. 4. The life cycle of the human immunodeficiency virus type 1 (HIV-1). Antiviral compounds directed against specific steps of the virus life cycle are indicated in boxes. RT: reverse transcriptase; IN: integrase. (Reprinted with permission from Broder et aI.l9)
Barre-Sinoussi F, Cherman J-C, Rey F, et al: Isolation of a Tlymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220:868-871, 1983. Gallo RC, Salahuddin SZ, Popovic M , et al: Frequent detection and isolation of cytopathic retroviruses (HTLV-111) from patients with AIDS and at risk for AIDS. Science 224500503, 1984. Popovic M , Sarngadharan M , Read E, Gallo RC: Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-Ill) from patients with AIDS and pre-AIDS. Science 224:497-500, 1984. Gallo RC, Montagnier L: AIDS in 1988. Sci Am 259:40-51, 1988. Fauci AS, Fischingcr PJ: The development of an AIDS vaccine: Progress and promise. Public Health Rep 103:230-236, 1988. Fauci AS: The human immunodeficiency virus: Infectivity and mechanisms of pathogenesis. Science 239:617-622, 1988. Groopman J , Chcn ISY, Essex M, Weiss RE (eds): Human Retroviruses. New York, Alan R . Liss, 1990, pp 141-152. Pavlakis GN, Schwartz S, Benko DM, Felber BK: Structure, splicing, and regulation of expression of HIV-I: A model for the general organization of lentiviruses and other complex retroviruses. In: Kennedy R, Wong-Staal F, Koff WC (eds): Annual Review of AIDS Research. New York, Marcel Dekker 1991,41-63.
Downloaded by: NYU. Copyrighted material.
106
STRUCTURE AND FUNCTION O F HIV-PAVLAKIS Bolognesi DP: Immunobiology of the human immunodeficiency virus envelope and its relationship to vaccine strategies. Mol Biol Med 7:l-15, 1990. Vaishnav Y, Wong-Staal F: The biochemistry of AIDS. Annu Rev Biochem 60:577-630, 1991. Rosen CA, Pavlakis GN: Tat and Rev: Positive regulators of HIV gene expression. AIDS 4:499-509, 1990. Myers G , Pavlakis GN: Evolutionary potential of complex retroviruses. In Levy J (Ed): The Retroviridae. New York: Plenum Press, 1991, pp 1-37. Broder S , Mitsuya H , Yarchoan R, Pavlakis GN: Antiretroviral therapy in AIDS. Ann Intern Med 1 13:604-618, 1990. Kestler HW, Ringler DJ, Mori K, et al: Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65:651-662, 1991.
Downloaded by: NYU. Copyrighted material.
Haseltine WA, Wong-Staal F (Eds): Genetic Structure and Regulation of HIV. New York: Raven Press, 1991, pp 175192. Pavlakis GN, Felber BK: Regulation of expression of human immunodeficiency virus. New Biol 2:20-31, 1990. Greene WC: Rcgulation of HIV-I gene expression. Annu Rev lmmunol 8:453-475, 1990. Wong-Staal F, Ratner L, Shaw G , et al: Molecular biology of human T-lymphotropic retroviruses. Cancer Res 1985. Bolognesi DP (Ed): Human Retroviruses, Cancer and AIDS: Approaches to Prevention and Therapy. New York: Alan R. Liss 1988, pp 439-445. Putney SD, Rusche J , Javaherian K , et al: Structural and functional features of the HIV envelope glycoprotein and considerations for vaccine development. Biotechnology 14:81-110, 1990.
12, NO. 2, 1992
Structure and Function of the Human Immunodeficiency Virus Type 1 GEORGE N. PAVLAKIS, M.D., Ph.D.
From the Humcrn Retrovirus Section, Basic Research Program, National Cancer Institute, Frederick Cancer Research and Developmenr Center, Frederick, Maryland Reprint requests: Dr. Pavlakis, National Cancer Institute, Frederick Cancer Research and Development Center, ABL-Basic Research Program, P.O. Box BiBuilding 539 Room 121, Frederick, Maryland 21702-1201.
of the virus and its identification as the causative agent of AIDS. A large number of excellent reviews have been published on the various topics of AIDS research. Some of them dealing with virologic topics are cited
STRUCTURE OF HUMAN IMMUNODEFICIENCY VIRUS GENOME AND VIRION HIV-I belongs to the lentivirus subfamily of retroviruses. A second human lentivirus named HIV-2 has also been discovered. Found mainly in West Africa, HIV-2 spreads more slowly and may be less pathogenic than HIV-I . Several members of the lentivirus subfamily have been studied, such as simian immunodeficiency viruses (SIV), equine infectious anemia virus, visna virus, caprine arthritis-encephalitis virus, and feline immunodeficiency virus. These lentiviruses are known to be pathogenic in animals, and they are currently used to develop animal models for AIDS (see article by Lafon and Kirn in this issue of Seminars). The lentiviruses cause chronic, debilitating diseases affecting many systems; immunodeficiency is also a frequent outcome of infection. The common biologic properties of the lentiviruses are reflected to a great extent by the common organization of their genome and by their similar expression strategies. l 8 A schematic diagram of the HIV-1 genome and of the structure of a virion is shown in Figure 1. The genome contains the three characteristic retroviral genes (gag, pol, and env) encoding the structural viral components and the viral enzymes. These three genes produce precursor proteins, or "polyproteins," that are subsequently assembled into viral particles together with the viral RNA. These particles bud out of the cytoplasmic membrane and mature via the cleavage of the polyproteins by the viral protease. This cleavage produces the final morphology and infectivity of the viral particle. During the budding process, the virus envelops itself into the cytoplasmic membrane containing the embedded Env glycoproteins, which protrude out of the membrane and are used to attach the virus to new cells via the interaction of gp120 with the cellular CD4 receptor molecule. Several additional viral genes have been identified within the lentiviral genome. This is in contrast to other retroviruses, which only produce structural components
Copyright 0 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
103
Downloaded by: NYU. Copyrighted material.
Human immunodeficiency virus type 1 (HIV-I) is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV-I is a retrovirus isolated just a few years ago.'.' Due to the worldwide AIDS epidemic, a great interest in all aspects of HIV-I biology has led to significant advances in our knowledge of the virus and its mechanisms of pathogenesis. As a result, HIV-1 is among the best-studied viruses, and this knowledge has helped the development of practical clinical applications against AIDS, as well as the advancement of our understanding of basic biologic mechanisms. Many impressive scientific discoveries have resulted in advances in AIDS diagnosis and treatment in just a short period of time. Examples are the identification of the causative agent, the growth of the virus in large quantities in the laboratory,' the generation of reliable tests to detect infected individuals, and the cloning and analysis of its genetic material. Several new drugs effective against the spread of retroviruses such as zidovudine (ZDV, AZT) were discovered and approved for clinical use in record time, and additional drugs are in various stages of testing (see article by Kahn in this issue of Seminars). The attention in AIDS research is now focusing on the generation of safe and effective vaccines, on the implementation of new therapies, and on the improvement of existing therapies. In addition, new diagnostic and follow-up tests have made it possible to monitor the course of the epidemic in populations and to evaluate the course of the disease in individuals. Instrumental to these rapid developments has been the interaction among scientists in entirely different disciplines. Advances in basic biology were very important for the detection, isolation, and study of the virus, as well as for the development of diagnostics and new drugs. Today, the study of HIV and AIDS is at the forefront of medical research, and discoveries in this field are expected to find general applications in other fields. The following is a brief account of what we have learned about HIV-I over the past 8 years since the first isolation
SEMINARS IN LIVER DISEASE-VOLUME
12, NUMBER 2, 1992
tant for the in vivo characteristics of the virus, they are not essential for viral propagation in tissue culture. For example, it has been shown that SIV Nef is not essential for the replication in tissue culture, although its conservation in HIV-I, HIV-2, and SIV indicates that it may have important functions in vivo. This conclusion is supported by experimental evidence in monkeys infected with SIV, showing that Nef-defective SIV cannot replicate and cannot cause disease in injected animal^.^' Vif promotes the infectivity of viral particles, whereas Vpu increases the proportion of viral particles found extracellularly. The exact function of Vpr, which is incorporated in the virion, is not yet known.
FIG. 1. Structure of the genome and the virion of HIV-1. (Reprinted with permission from Broder et aI.l9)
of the virion and viral enzymes. In HIV-I, there are six additional genes, which have been named tat, rev, nef, vif, vpr, and vpu. Two of the additional proteins produced by all lentiviruses, named Tat and Rev, are regulatory factors essential for viral expression and replication (Fig. 2). Both Tat and Rev are small, positively charged proteins that accumulate in the nucleus. They bind to specific sites on the viral mRNA, which are named TAR and RRE, respectively. This binding is necessary for the activation of virus production. The exact mechanism of function of the other identified proteins, namely, Nef, Vif, Vpr, and Vpu, is not yet known. These proteins have been named "accessory" proteins to indicate that, although they are impor-
HIV-I virions attach to cells via the Env glycoprotein, which recognizes the CD4 cell surface receptor found in T cells, monocytes, and other cell types. After binding to CD4, the virus fuses to the plasma membrane, the virus core inserts into the cell, and replication is initiated. Retroviruses contain RNA as their genetic material. After infection, this genomic RNA is converted to DNA (proviral DNA). The conversion of the viral RNA to DNA is a step characteristic of all retroviruses and is executed by the viral enzyme reverse transcriptase (RT). The proviral DNA integrates into the DNA of the cell via the function of another viral enzyme also carried in the virion, integrase. From this time onward, the proviral DNA is indistinguishable from the normal cellular genes, and it follows the same rules as the cellular genes for expression of the genetic information. This expression is achieved by the production of messenger RNA, which is transported in the cytoplasm and translated on the ribosomes into protein molecules. The structural Gag proteins are assembled into capsids that also contain viral RNA and enzymes, and the newly formed virions bud out of the cell and infect new cells. A third viral enzyme, protease, is responsible for the cleavage of the different
FIG. 2. The two positive regulators of HIV-1 expression, Tat and Rev. These viral proteins bind to specific structures on the viral RNA named TAR and RRE, respectively.
Downloaded by: NYU. Copyrighted material.
LIFE CYCLE OF HUMAN IMMUNODEFICIENCY VIRUS
STRUCTURE AND FUNCTION OF HIV-PAVLAKIS
REGULATION OF EXPRESSION A characteristic difference between HIV and other retroviruses is in the complexity of regulation of expression. HIV-1 produces two regulatory proteins, Tat and Rev (Fig. 3). Tat and Rev, and possibly additional cellular factors, interact with the viral RNA and proviral DNA in a highly complex fashion. These interactions regulate the expression of the viral genome. It is anticipated that cellular genes use similar mechanisms for the regulation of cellular gene expression. The details of the mechanism of function of Tat and Rev are under intense investigation. It is known that these factors act in concert to increase viral expression. Tat and Rev stimulate the transcription of proviral DNA to RNA, the transport of this RNA to the cytoplasm, and the efficient translation of the RNA into viral proteins. The potency and specificity of these factors for HIV-1 have triggered efforts to design drugs inhibiting their function. At least one drug with antiviral activity against Tat protein has been discovered, demonstrating the feasibility of this approach. Tat and Rev counteract negative elements in the viral genome that severely restrict virus expression. Thus, in the absence of these factors, HIV expression is not detectable. The evolution of the complexregulatory
signals is very interesting. It appears that all lentiviruses have similar controls. The Rev regulatory pathway appears to be the most conserved in the lentiviruses. The regulatory signals of HIV- I and other lentiviruses are believed to be highly relevant to their life cycle and to provide lentiviruses with their unique characteristics, among which is the generation of slow, debilitating diseases due to the chronic expression of the virus in the body.
COURSE OF THE DISEASE Primary infection by HIV-I may cause only minor symptoms, or it may be associated with an acute mononucleosis-like syndrome. At that stage, there is active virus replication and dissemination in the body. After the development of immune response, the virus levels decrease dramatically. This "silent period" may last for years. Usually, very low levels of virus are found during this period. Nonetheless, the virus continues to replicate at low levels and continues to damage the immune system. The number of CD4' cells in peripheral blood decreases gradually over the years. Finally, immunodeficiency appears, which allows the development of opportunistic infections and the formation of tumors. Detailed knowledge of the biology of HIV-I will lead to a better understanding of the complex virus-host interactions and will clarify the mechanisms of pathogenesis, which lead to the depletion of cells critical for the normal
FIG. 3. Regulation of HIV-1 gene expression by Tat and Rev. Tat protein produced by multiply spliced mRNAs is transported in the nucleus and activates HIV-1 transcription to high levels. When appropriate levels of Rev protein are produced, binding of Rev to the RRE site results in increased transport and translation of the longer viral mRNAs. This results in efficient expression of the viral structural proteins.
Downloaded by: NYU. Copyrighted material.
precursor viral proteins, a step necessary for the infectivity of the viral particles.
SEMINARS IN LIVER DISEASE-VOLUME
12, NUMBER 2, 1992
function of the immune system, such as the CD4+ lymphocytes.
ticle by Herndier and Friedman in this issue of Seminars).
DRUG THERAPIES AGAINST THE ACQUIRED IMMUNODEFICIENCY SYNDROME
VARIABILITY OF THE HUMAN IMMUNODEFICIENCY VIRUS
The identification of HIV- I and the understanding of its life cycle led to the design of rational antiviral therapies. A series of inhibitors of the unique retroviral enzyme RT were tested. These studies resulted in the identification of several drugs (ZDV, didanosine [ddI], ddC, and others) effective against HIV-I and other retroviruses. Of these, ZDV and ddI are approved drugs. ZDV has been shown to prolong the life of AIDS patients. ddI has been approved for some adult and pediatric cases. ddI and ddC may soon be used in combination with ZDV. Many other compounds acting at different stages in the viral life cycle (Fig. 4) have been tested. These now include potential drugs against the regulatory factors. Great progress has also been achieved in the management of opportunistic infections. As a result, AIDS patients live longer. Unfortunately, as the management of opportunistic infections improves, the high incidence of lymphomas and other tumors in AIDS patients is rapidly becoming one of the major causes of death (see ar-
Bindinfl
?
fl
,
A large accumulation of experimental data has demonstrated the ability of HIV-1 to mutate rapidly within the body. This is undoubtedly a major problem for the generation of both effective drug therapies and vaccines. The exceptional variability of HIV-1 within the same patient leads to a swarm of different variants (quasispecies) with different biologic properties. An understanding of the generation and role of these variants in the course of the infection is very important. The high mutation rate of HIV-1 has also been shown to lead to the rapid development of ZDV-resistant variants in the patients receiving this drug. Several investigators have tried to explain the persistence of viral replication in the presence of a vigorous response. It has been postulated that the rapid change leads to the appearance of variants that can escape both humoral and cytotoxic immune surveillance. It has also been postulated that the low immunogenicity of the Env glycoprotein may prevent the efficient development of neutralizing antibodies. Both hepatitis B virus (a hepadna virus) and hepatitis C virus (an RNA virus) are known to cause chronic active hepatitis in a substantial number of infected people. In the future, the mechanisms of HIV persistence may prove relevant to mechanisms used by other viruses, including the hepatitis viruses.
n
REFERENCES
I
1
Integration
I \- n
1
DNA
Transcription
u
Expression
RNA
Translat~on
1
bly
tr a ev t ,, nef
env
I Budding, Maturation
FIG. 4. The life cycle of the human immunodeficiency virus type 1 (HIV-1). Antiviral compounds directed against specific steps of the virus life cycle are indicated in boxes. RT: reverse transcriptase; IN: integrase. (Reprinted with permission from Broder et aI.l9)
Barre-Sinoussi F, Cherman J-C, Rey F, et al: Isolation of a Tlymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220:868-871, 1983. Gallo RC, Salahuddin SZ, Popovic M , et al: Frequent detection and isolation of cytopathic retroviruses (HTLV-111) from patients with AIDS and at risk for AIDS. Science 224500503, 1984. Popovic M , Sarngadharan M , Read E, Gallo RC: Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-Ill) from patients with AIDS and pre-AIDS. Science 224:497-500, 1984. Gallo RC, Montagnier L: AIDS in 1988. Sci Am 259:40-51, 1988. Fauci AS, Fischingcr PJ: The development of an AIDS vaccine: Progress and promise. Public Health Rep 103:230-236, 1988. Fauci AS: The human immunodeficiency virus: Infectivity and mechanisms of pathogenesis. Science 239:617-622, 1988. Groopman J , Chcn ISY, Essex M, Weiss RE (eds): Human Retroviruses. New York, Alan R . Liss, 1990, pp 141-152. Pavlakis GN, Schwartz S, Benko DM, Felber BK: Structure, splicing, and regulation of expression of HIV-I: A model for the general organization of lentiviruses and other complex retroviruses. In: Kennedy R, Wong-Staal F, Koff WC (eds): Annual Review of AIDS Research. New York, Marcel Dekker 1991,41-63.
Downloaded by: NYU. Copyrighted material.
106
STRUCTURE AND FUNCTION O F HIV-PAVLAKIS Bolognesi DP: Immunobiology of the human immunodeficiency virus envelope and its relationship to vaccine strategies. Mol Biol Med 7:l-15, 1990. Vaishnav Y, Wong-Staal F: The biochemistry of AIDS. Annu Rev Biochem 60:577-630, 1991. Rosen CA, Pavlakis GN: Tat and Rev: Positive regulators of HIV gene expression. AIDS 4:499-509, 1990. Myers G , Pavlakis GN: Evolutionary potential of complex retroviruses. In Levy J (Ed): The Retroviridae. New York: Plenum Press, 1991, pp 1-37. Broder S , Mitsuya H , Yarchoan R, Pavlakis GN: Antiretroviral therapy in AIDS. Ann Intern Med 1 13:604-618, 1990. Kestler HW, Ringler DJ, Mori K, et al: Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65:651-662, 1991.
Downloaded by: NYU. Copyrighted material.
Haseltine WA, Wong-Staal F (Eds): Genetic Structure and Regulation of HIV. New York: Raven Press, 1991, pp 175192. Pavlakis GN, Felber BK: Regulation of expression of human immunodeficiency virus. New Biol 2:20-31, 1990. Greene WC: Rcgulation of HIV-I gene expression. Annu Rev lmmunol 8:453-475, 1990. Wong-Staal F, Ratner L, Shaw G , et al: Molecular biology of human T-lymphotropic retroviruses. Cancer Res 1985. Bolognesi DP (Ed): Human Retroviruses, Cancer and AIDS: Approaches to Prevention and Therapy. New York: Alan R. Liss 1988, pp 439-445. Putney SD, Rusche J , Javaherian K , et al: Structural and functional features of the HIV envelope glycoprotein and considerations for vaccine development. Biotechnology 14:81-110, 1990.
