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6 Future Research Needs In the brief period since the first descriptions of HIV and its unambig- uous identification as the cause of AIDS, a tremendous amount has been learned about the genetic structure and transmission of the virus. Much less is known, however, about how it initiates infection, how it maintains infection, and what determines the progression and diversity of the resulting illness. Research has been very effective in discovering the routes of viral transmission, enabling public health and education programs to be designed that incorporate increasingly accurate and specific information. Research has also been particularly effective in elucidating the complete genomic structure of the virus, allowing definition of many, if not all, of the virus's genes. Such insights, however impressive, are only the beginning of what promises to be a long and difficult path toward effective therapeutic interventions to minimize or eliminate the debilitating effects of HIV infection and toward limiting the spread of the virus by means of safe and effective vaccines. This chapter summarizes some of the opportunities and obstacles that will be encountered along that path. In many areas, predictions of progress are difficult to make. It is easier, however, to specify the mechanisms that will facilitate that progress. Successful development of vaccines or drugs to modify the prevalence or consequences of HIV infection will be greatly aided by a substantially improved basic under- standing of the virus, of the functioning of the healthy and impaired 177

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178 CONFRONTING AIDS human immune system, and of their interaction in the progression from infection to disease. The progress achieved to date in identifying and characterizing the causative agent of AIDS would not have been possible without the scientific and medical knowledge achieved over the years through the pursuit of basic biomedical research. In that pursuit, the investigator is rarely certain of when or if research findings will be applicable to a disease. The instance of AIDS exemplifies the value of basic research, however, in that the current understanding of AIDS is based on knowl- edge derived largely from studies carried out before AIDS was even recognized as a disease. The unusual speed with which the etiologic agent of AIDS was isolated and remarkably well characterized was heavily dependent upon 20 years of investment in molecular biology and virology. Continued support of the medical and scientific communities in their pursuit of basic knowledge related to HIV infection and AIDS will provide an essential adjunct to the necessary applied studies. These basic and applied studies can be expected to prove mutually beneficial as increased under- standing of the mechanisms and consequences of HIV infection is translated into effective interventions to limit the virus's impact. THE STRUCTURE AND REPLICATION OF HIV Retroviral Structure The molecular cloning and nucleotide analysis of a number of indepen- dent isolates of HIV have completely defined a retroviral genomic structure (see Figure 6-1) of unprecedented complexity and marked diversity (Meusing et al., 1985; Ratner et al., 1985; Sanchez-Pescador et al., 1985; Wain-Hobson et al., 19851. While HIV shares some genetic and structural elements with other known retroviruses, it possesses distinc- tive features that have not been observed previously. The replication cycles of all previously known retroviruses depend on the functions of the protein products encoded by three viral genes termed gag, pol, and env (Weiss et al., 19851. These genes specify the structural and enzymatic functions required for viral infection and transmission and are situated in a common left-to-right (5' to 3') configuration in the retroviral genome. The gag gene encodes the proteins that constitute the internal core of the virion particle. The pol gene specifies the viral enzyme known as reverse transcriptase, which is responsible for synthesizing a DNA copy of the retroviral RNA genome early after infection. The gag and pot proteins are first synthesized as a large precursor, which is then cleaved by a virus-encoded protease to give the final proteins. The ens gene codes for the surface envelope proteins of the retrovirus, which mediate the process of

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FUTURE RESEARCH NEEDS 179 sor ~-tat-3 . 3'-orf E] art -- ~ gag pol ,; ] env . - - genes for vinon proteins ~3 ~ ~ - - - genes for regulator proteins row ~ FIGURE 6-1 HIV genome. Source: Courtesy of Howard Temin, University of Wisconsin School of Medicine, Madison. virus binding to the surface membranes of host target cells. The termini of the DNA form of the retroviral genome are provided by repetitive sequences known as long terminal repeats (LTRs), which contain the essential genetic regulatory elements controlling viral expression and integration. With these three genes and the additional regulatory sequences in their LTRs, many animal retroviruses are fully competent to replicate in an appropriate host target cell. HIV, however, contains a minimum of four additional genes (see Figure 6-1), at least two of which are also function- ally required in its replication cycle. Because they have been indepen- dently described in a number of laboratories, these novel genes carry a multitude of designations. A gene known as tat-III serves a necessary function in HIV replication by controlling, in a trans-acting fashion (i.e., at a distance by means of a diffusible product), the level of expression of the other viral genes (Arya et al., 1985; Sodroski et al., 19841. The most recently discovered HIV gene, variously known as art or trs, is thought to control, in a trans-acting manner, the differential expression of viral structural and regulatory functions; it is also necessary for viral replica- tion (Feinberg et al., in press; Sodroski et al., 1986b). Two other viral genes, named sor (also known as orf-l, P', or Q) and 3'-orf (also known as orf-2, E', or F), serve unknown functions in the life-cycle of HIV, although they are known to be expressed. They are apparently not needed for replication in tissue culture cells (Allen et al., 1985; Fisher et al., 1986b; Kan et al., 1986; Lee et al., 1985; Sodroski et al., 1986a). Retroviral Replication Retroviral infection (see Figure 6-2) is initiated by the binding of a virus particle to a specific receptor molecule expressed on the surface of an

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~ 80 CONFRONTING AIDS \ ENTRANCE ~REVERSE RCUlARIZATI INTEGRATION ~ TRANSCRIPTION ~) \ ~ N TRANSCRIPTION /& k ~ I TRANSPORT to tat ENCAPSI DAT10~ L_/ BUDDING Wit gag-pol TRANSLATION & PROCESSING . . env @) FIGURE 6-2 Life-cycle of HIV. Source: Courtesy of Howard Temin, University of Wisconsin School of Medicine, Madison. appropriate target cell (Weiss et al., 19851. After binding takes place, the retrovirus enters the cell and uncoats in the host cell's cytoplasm. The retroviral genetic information contained in its single-stranded RNA genome is then transferred to a full-length linear duplex DNA intermedi- ate by the synthetic activities of the reverse transcriptase enzyme, which accompanied it in the virion particle. This linear DNA intermediate is transported to the nucleus, where it is circularized before becoming stably integrated into the DNA of the host cell. The process of integration is thought to involve the specific interaction between retroviral sequences at the edges of the LTRs and an additional enzymatic function known as the integrase encoded by the pol gene. Once integrated into the host chromosome, the retroviral genome is termed a provirus. There it serves as a template for RNA transcription, the primary product of which is a full-length viral RNA molecule. The gag and pot products are translated from the full-length transcript, while a portion of the viral transcript undergoes RNA splicing to yield an

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FUTURE RESEARCH NEEDS i~ ~ envelope-coding mRNA from which the gag and pol sequences have been deleted. The mRNAs encoding the sor, tat-III, art, and 3'-orf proteins of HIV are derived from the genomic RNA transcript via complex splicing events (Arya et al., 1985; Muesing et al., 1985; Rabson et al., 19851. The virus's structural and regulatory proteins are then synthesized in the cytoplasm. Following secondary processing, the constituents of the virions (gag, pot, and envelope proteins) proceed to assemble in the proximity of the cellular plasma membrane into virus particles that have incorporated the full-length viral RNA genome. The retroviral membrane is derived directly from the cellular plasma membrane as the virion is released from the cell by a process known as budding. The development of specific antiviral therapies for HIV infection will depend upon identifying and interfering with critical stages of the retro- viral life-cycle. Although the replicative mechanisms of HIV have not yet been studied in great detail, many of its essential processes may be understood through analogy with other, more thoroughly analyzed exam- ples of retroviruses. It should not be assumed, however, that HIV follows a pattern of replication identical to those previously elucidated in other retroviral systems. Indeed, some significant differences have already been identified. As discussed below, these may provide additional targets for future antiviral strategies. Definition of the Structural and Functional Constituents of HIV The protein products from all seven of the genes so far identified in HIV isolates have been recognized by antibodies from persons infected with HIV. This has permitted the initial identification of these proteins and has demonstrated their expression in viva. Some of these protein products have also been expressed in bacteria, yeast, or mammalian cells in vitro. The production of large quantities of all of the virus's genes in a biologically active form will provide necessary substrates for structural and functional analyses. In addition to the study of such recombinant DNA products, it will be important to directly study the native proteins as they exist in the virion and in infected cells. Their directly determined amino acid sequences (as opposed to computer translations from the DNA sequence), and the nature and location of posttranslational modifi cations (e.g., glycosylation, phosphorylation, myristylation), should be ascertained. The nature of the proteolytic cleavages and other post- translational processing involved in the synthesis of the virus's structural or functional components may thus be established, perhaps indicating new approaches for antiviral interventions.

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I 82 CONFRONTING AIDS _ m0 , , Aged .' ENVELOPE ) L INTERNAL PROTEINS RNA GENOME FIGURE 6-3 Structure of the HIV virion. Source: Courtesy of Howard Temin, University of Wisconsin School of Medicine, Madison. Determination of the Structure of the HIV Virion Figure 6-3 shows a model of the structure of the HIV virion. Electron microscopic examinations of HIV particles show that it possesses an envelope with protruding spikes surrounding a central electron-dense core. The virion's spikes are formed by collections of the viral envelope glycoprotein, gpl20, which is anchored in the cell-derived plasma mem- brane through an attachment to the HIV transmembrane protein, gp41. The retroviral core is composed of collections of the gag proteins in association with the genomic RNA molecules, the reverse transcriptase, and other enzymes. Although there are generally accepted models for the structure of the interior of retrovirus virions, the models are conceptual in character and lack experimental validation (Weiss et al., 1982, 19851. Thus, the detailed structure of the potentially analogous virion of HIV is not clearly understood. Specifically, the locations and amounts of the various inter- nal proteins and the nature of their interactions are not known. Knowl- edge of these locations and interactions will be of great utility in drug design. For example, drugs that inhibit the formation of any of these complexes could block HIV replication. High-resolution structural determinations of the viral proteins, sepa- rately and in complexes, need to be performed; important candidates include the external portion of gpl20, the gpl20-gp41 complex, and the gpl20-gp41-internal protein complex. Similar structural studies have been performed with the hemagglutinin molecule of influenza virus and with the virions of rhinovirus 14 and poliovirus (Hoyle et al., 1985; Rossman et al., 1985; Wilson et al., 1981) and have provided an important foundation for understanding the interaction between infecting viruses and host cells and between viruses and neutralizing antibodies.

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FUTURE RESEARCH NEEDS I 83 Interrupting Infection by HIV The progressive stages in the life-cycle of HIV present a number of opportunities for specific interruption. Much basic knowledge must be attained, however, before a rational approach to the development of prophylactic and therapeutic measures for HIV infection and AIDS will be feasible. A critical and early event in HIV infection involves the virus's attachment, via its envelope glycoprotein, to a receptor on the surface of a susceptible cell. The primary, if not exclusive, cellular receptor for HIV appears to be provided by the CD4 molecule (Dalgleish et al., 1984; Klatzmann et al., 19841. The CD4 molecule is expressed by helper/inducer T lymphocytes and by certain types of cells of the macrophage/monocyte lineage, a distribution that parallels the target cells for HIV infection. The expression of the CD4 molecule may completely explain the tissue tropism of HIV, although further documentation of the complete repertoire of the cell types that express the molecule is necessary (see section on "Natural History of HIV Infection," below). The interaction of the HIV envelope protein with the CD4 receptor can be inhibited by antibodies directed at specific determinants on either molecule (Robert-Guroff et al., 1985; Weiss et al., 19851. The structural definition of the molecular components involved in this specific recogni- tion process will be of central importance in the development of vaccines or other prophylactic measures to prevent HIV infection. The HIV envelope protein, through its specific interaction with the CD4 molecule, plays an important role in the cytopathic effect of viral infection on T lymphocytes (Lifson et al., 1986, in press; Sodroski et al., 1986a). The specific inhibition of this interaction, if attainable, may ameliorate the immune deficiency that follows HIV infection. The HIV envelope glycoprotein is unlike the similar components of most other retroviruses, both in its large size and in the extent and pattern of its sequence variability (Coffin, 19861. The primary translation product of the HIV envelope gene is heavily glycosylated during the course of its maturation. The extensive variation that has been observed in the nucleotides (and thus in the predicted amino acid sequences) among independent isolates of HIV is of important theoretical and practical concern in understanding the processes of viral replication and in devel- oping an effective vaccine. Such variation, though striking, is not unex- pected in a virus whose genome is composed of a single strand of nucleic acid. High mutation rates may be an unavoidable consequence of the replication of such genomes. In addition, genomic variation in retroviruses can be affected by the

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~ 84 CONFRONTING AIDS insertion, duplication, and deletion of genetic sequences. HIV isolates show significant sequence divergence within the env gene by these mechanisms while their other genes are considerably better conserved between different viral isolates. The variability in the ens gene is concentrated within several "hypervariable" domains, which are inter- spersed between regions that are better conserved (Coffin, 19864. The mechanisms that generate this pattern of variability and conservation of envelope sequences will be important to elucidate, as will the functions of the variable and relatively constant regions. Because all HIV isolates apparently infect cells through the binding of the envelope protein to CD4, the domain of the viral envelope protein that facilitates binding to the cell surface receptor is presumably conserved between viral isolates. Inhibiting this recognition process through immu- nization or other approaches could in principle block infection by all viral isolates. It has been postulated, however, that the variable regions mask the essential constant regions from immunologic attack. Success in developing an HIV vaccine may thus be predicated on understanding and overcoming the problems presented by the genetic mutability and varia- tion of HIV. Following attachment to its cellular receptor, HIV enters the cell by a mechanism as yet poorly defined. The virus is internalized and uncoated, most probably through the normal absorptive endocytosis pathway used by animal cells to internalize cell surface receptors that have bound their respective ligand. As with other animal viruses, a low pH-mediated structural change in the gp 120 molecule in the endocytotic vesicles probably results in the actual uncoating and entrance of the viral genome into the cytoplasm. In the case of HIV, this process may or may not involve a membrane fusion event. Increased understanding of this pro- cess may allow the derivation of drugs that inhibit these early stages of . ~ . . . ~ Injection In a v~rus-spec~nc manner. Once the retroviral particle has uncoated in the cytoplasm, the critical and characteristic process of reverse transcription of the viral RNA genome into a double-stranded DNA copy ensues. The enzyme that catalyzes this process, reverse transcriptase, provides a specific and potentially very effective target for antiviral therapy. Inhibitors of HIV's reverse transcriptase comprise a number of the candidate drugs under current clinical and laboratory evaluation (see section on "Antiviral Agents," below). The protein components and processing pathways for the synthesis of HIV's reverse transcriptase are receiving substantial analytical attention. The forces that govern the HIV genome's migration to the nucleus and subsequent circularization are not known. The virus-specific integrase encoded by the pol gene is thought to be involved in the process of retroviral integration in other retroviruses. Unlike most

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FUTURE RESEARCH NEEDS I 85 retroviruses, HIV shares with the other lentiviruses a pronounced ten- dency to accumulate unintegrated viral DNA in the course of infection in vitro and in vivo. It is thus possible that HIV does not always require integration for virus production to ensue. With the related lentivirus visna virus, dividing cells are reportedly not required for productive infection, although many other retroviruses demonstrate an obligate linkage be- tween cell division and viral integration (Haase, 19861. Whether cell division is required for HIV infection has not been established, but studies of viral production in macrophage cultures in vitro suggest that it may not be necessary (Gartner et al., 19861. The significance and origin of unintegrated HIV DNA are unclear, but they may have significant implications for understanding the cytopathic effects of the virus and for the potential of therapeutic agents to limit infection. Improved understanding of the requirements for and mecha- nisms of HIV integration, increasing availability of enzymatically active viral proteins involved in the process, and the development of cell-free systems for their assay will help in drug design and screening. Following integration into the host cell chromosome a mechanism that needs to be studied further the HIV proviral genome is transcribed into RNA by the cellular RNA polymerase. The potential host or viral factors that control the level of HIV expression are very poorly defined, but they may play a critical role in the persistence of HIV in the infected human host and the rate of immunologic compromise. It has been suggested that immunologic activation of infected T cells stimulates virus production (Hoxie et al., 1985; Zagury et al., 19861. The factors that activate provirus also need to be studied further. Subsequent to transcrip- tion, the processing of the HIV RNA transcripts also uses the host cell's machinery for capping, polyadenylation, and splicing. The tat-III gene is known to be essential for viral replication (Dayton et al., 1986; Fisher et al., 1986a), but there is much uncertainty about its precise mechanism of action. It appears to control the efficiency of translation of viral messages (Feinberg et al., in press; Rosen et al., 1986) and their stability, although effects on viral transcription have also been described. This gene operates through specific sequences contained in HIV mRNAs, and as there are no known host activities of similar character it may provide a specific target for drug attack. A second HIV gene has been described that appears to operate subsequent to the transcription of viral RNA. This gene, variously known as art (Sodroski et al., 1986b) or trs (Feinberg et al., in press), effectively modulates the specific viral mRNAs available for translation. The art (trs) product regulates the pattern of viral RNA expressed, either through differential splicing or specific message stabilization, and is essential for lIIV replication. Its exact role in the in vivo infectious process or

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I 86 CONFRONTING AIDS pathology of HIV is unknown, but because it also appears to be an essential and virus-specific activity it is an important potential candidate for antiviral therapy. As with the other viral components, the large-scale preparation and widespread availability of the tat-III and art (trs) proteins would aid in the design of inhibitors for their essential viral functions. Presently, the limiting factors are understanding their actions and developing in vitro assays for their functions. The products of the HIV genes known as sor (orf-l, P', and Q) and 3'-orf (orf-2, E', and F) may not always be essential for virus replication in cell culture (Fisher et al., 1986b; Sodroski et al., 1986c). However, the continued presence of these open reading frames in HIV in the face of the high rate of mutation of retroviruses in general, and of HIV in particular, indicates that there has been strong selection for these genes in the virus infecting the human population. (With an estimated mutation rate of 1 alteration per 10,000 nucleotides per virus replication cycle, mutations would have appeared following only a few rounds of virus replication.) The importance of these genes is also suggested by the presence of antibodies against them in the sera of many HIV-infected persons. Their preservation and serologic recognition suggest that they serve an essential role in the in vivo expression of HIV. Improved understanding of the in vivo role of these novel open reading frames of HIV is extremely important, especially if they are involved in the biological processes underlying the persistent nature or cytopathic consequences of HIV infection. Identifying their functions and develop- ing in vitro assays for their measurement will be of great value in evaluating their candidacy as effective targets for pharmacologic inhibi- tion. If their functions are only evident in infected hosts, the development of animal models will be central to progress in this area (see section on "Animal Models," below). Viral precursor proteins are translated from viral mRNAs by use of host cell ribosomes and translation factors. The gag gene is translated through the synthesis of a protein precursor, Pr55, which is subsequently proteolytically processed into ply, p24, p9, and p7. The pol gene, which encodes the HIV reverse transcriptase, integrate, and probably protease, is thought to be initially translated into a polyprotein precursor, Prl50, which is then processed into p64/53, p22, and p34, respectively. The proteolytic cleavage of the gag and pot precursor proteins may be carried out by the virally encoded protease enzyme. If so, this cleavage might be subject to specific inhibition. The derivation and production of enzymatically active p22 protease would provide a very useful substrate for drug screening and drug design. The primary translation product of the ens mRNA is a protein of

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FUTURE RESEARCH NEEDS I 87 approximately 90 kilodaltons (kd). During its transit to the cellular membrane, the envelope precursor is heavily glycosylated, which in- creases its apparent molecular weight to about 160 kd. The extent of this glycosylation of the HIV envelope protein is unprecedented among retroviruses. The observed relative conservation of glycosylation sites between divergent viral isolates suggests that glycosylation of the enve- lope protein plays an important biological role. Unlike that of many other retroviruses, the transmembrane protein (gp41) of HIV is also glycosyl- ated. Glycosylation could conceivably be an important determinant of the structure of the envelope, it could mask functionally important antigenic sites from human immune responses, or it could do both. The mature form of the viral envelope is achieved by the proteolytic cleavage of the gpl60 precursor to gpl20 and gp41. After the gpl20-gp41 complex is inserted in the plasma membrane by cellular processes, there is probably an aggregation of gpl20-gp41 molecules that excludes other cellular membrane proteins. The nature of the chemical bonds maintain- ing the stable interaction between the gpl20 and gp41 molecules should be determined as a possible specific target for drugs. Likewise, the orienta- tion of these proteins in the cell membrane and the virion particle has not been directly determined, but such information is important for drug design. HIV is formed by budding from a modified portion of the cell plasma membrane, during which the viral nucleoid assembles and organizes the gag proteins in association with copies of the genomic RNA and poly- merase components. The formation of the nucleoid involves the aggrega- tion of p24 gag molecules in a virus-specific process. There may be further protein cleavages after budding, a process referred to as maturation in the life-cycle of other retroviruses. As with other viruses the process of HIV assembly depends upon protein-protein interactions. The protein interactions in assembling virions have to be virus specific, otherwise virion production would be exceptionally inefficient or absent. As such, the process of HIV assembly may be subject to chemotherapeutic interference and hence merits further study. Interferons and related molecules have been demonstrated to inhibit the assembly and budding process in other retroviruses, including certain lentiviruses, and similar molecules may have relevance in com- bating HIV infection and spread (Narayan, 19861. Conclusions and Recommendations In the past few years the techniques of molecular biology have provided the starting materials for a detailed evaluation of the replicative pathways of HIV and for the development of therapeutic strategies to inhibit those

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