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OCR for page 177
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
OCR for page 178
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
OCR for page 179
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
OCR for page 180
~ 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
OCR for page 181
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
OCR for page 186
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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Representative terms from entire chapter:
confronting aids
