Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 123
6
The Biology of HIV and
Biomedical Research Needs
Since the publication of Confronting AIDS in October 1986, there has
been appreciable progress in elucidating certain structural and functional
attributes of HIV. Early research efforts were productive in defining the
HIV genetic structure and important aspects of viral replication in vitro.
Less progress has been made in understanding the behavior of HIV in
viva and the interaction of the virus with its human host.
This chapter describes new knowledge gained from AIDS research
efforts, ways in which that knowledge may be used against HIV infection,
the difficulties of developing drugs and vaccines to combat the epidemic,
and the variety of resources needed for the task.
HIV BIOLOGY
Viral Taxonomy and Disease
Over the past 2 years, researchers have begun to appreciate more fully
the nature and diversity of HIV, especially following the discovery in
1986 and subsequent characterization of a second human retrovirus,
HIV-2. The first retrovirus found to cause AIDS, now referred to as
HIV-1, is responsible for the vast majority of AIDS cases reported to
date, and it accounts for the most prevalent and geographically dispersed
occurrences of human retroviral infection now known (IOM/NAS, 19861.
HIV-2 is most prevalent in certain regions of West Africa, where its
transmission and pathogenesis mirror those of HIV-1 (Clavel et al., 1986a,
123
OCR for page 124
124 CONFRONTING AIDS: UPDATE 1988
1987; Kanki et al., 19861; it has been linked to a growing number of cases
of immunodeficiency diseases that are clinically indistinguishable from
HIV-1-associated AIDS (Clavel et al., 1986a, 1987; Kanki et al., 1986,
19871. It is not known whether HIV-2 infection leads to AIDS at the same
rate or with the same frequency as HIV-1 infection, but it is clearly a
pathogenic retrovirus. HIV-2 is not as effectively detected as HIV-1 by
the screening tests now available.
Through morphologic and genetic analyses of HIV-1 and HIV-2, their
taxonomic assignment has been further defined as the subfamily of
retroviruses known as lentiviruses (Gonda et al., 1985; Sonigo et al., 1985;
Clavel et al., 1986b; Guyader et al., 19871. Lentiviruses are the causative
agents of a number of diseases in other mammalian species that are
characterized by persistence of infection, the effective impotence of the
host immune response to clear the infection, long incubation periods, and
protracted symptomatic phases.
Although HIV-1 was the first lentivirus to be described with profoundly
immunosuppressive properties, a growing number of retroviruses of this
type have since been discovered. Shortly after the isolation of HIV-1, a
related lentivirus, simian immunodeficiency virus, or SIV, was identified
in a variety of monkey species (Daniel et al., 1985; Kanki et al., 1985~.
HIV-2, in fact, is more closely related in its genetic structure to this
simian virus than to HIV-1 (Chakrabarti et al., 1987; Franchini et al.,
1987; Guyader et al., 1987; Hirsch et al., 19871. Recently, researchers
have identified other lentiviruses as potential agents of immunodeficiency
disease in cows (bovine immunodeficiency virus) and cats (feline immu-
nodeficiency virus) (Gonda et al., 1987; Pederson et al., 1987~. The
continued study of these simian, bovine, and feline lentiviruses may
provide valuable models of the pathogenesis and therefore potential
treatment of HIV infection in humans. In April 1988 scientists from
Gabon announced the isolation of a newly identified virus from chimpan-
zees that appears to be closely related to HIV-1 (R. Widdus, World
Health Organization, personal communication, 19881.
Using molecular cloning and nucleotide sequence analysis of multiple
isolates of HIV-1, researchers have defined an exceptionally complex
retroviral genome with characteristics not previously seen in retroviruses
(Muesing et al., 1985; Ratner et al., 1985; Sanchez-Pescador et al., 1985;
Wain-Hobson et al., 19851. Studies have shown that the HIV-1 genome
contains a number of novel genes in addition to those that encode the
usual structural and enzymatic functions required for retroviral replica-
tion. These studies have identified the protein products of HIV-l's
unusual genes, and, as they do not appear to be present in mature virus
particles, it has been postulated that these gene products have regulatory
rather than structural roles in viral replication. The importance of such
OCR for page 125
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS 125
findings lies in our improved understanding of the mechanisms of action
of the HIV regulatory genes, an understanding that could speed the
development of specific, effective means to inhibit HIV replication.
The nucleotide sequences of independent isolates of HIV-1 are also
notable for their degree of variation and the patterns of these variations
(Alizon et al.3 1986; Coffin, 1986; Starcich et al., 1986~. As discussed in
Confronting AIDS, a fuller understanding of the origin and immunologic
significance of variations in the nucleotide sequences of HIV is central to
efforts to engender protective immunity through vaccination. Work in this
area has brought improved definition of conserved and variable domains in
the envelope glycoproteins, but little is known as yet about the biological
processes that may give rise to and possibly select for sequence divergence
(Coffin, 1986; IOM/NAS, 1986~. Several independent isolates of HIV-2 have
now been molecularly cloned and sequenced, and they appear to demon-
strate a similar degree of variation (Clavel et al., 1986b; Guyader et al., 19871.
Molecular studies of the HIV-1 genome have delineated the basic struc-
ture of the genes that encode the necessary replicative functions provided by
the viral core proteins (gag), polymerase ~ poll, and surface glycoproteins
(ens). They have also defined the structure of the genetic regulatory
sequences in the retroviral long terminal repeats (LTRs). In addition to these
expected retroviral genes, the studies have shown that HIV-1 contains genes
that are without known counterparts in other retroviruses: the so-called open
reading frames, referred to as sor and 3'-orf. These open reading frames give
rise to proteins that are produced during the course of HIV infection in vitro
and in viva (Allen et al., 1985; Lee et al., 1985; Kan et al., 1986~. Recently,
Alizon and coworkers (1986) and Wong-Staal and colleagues (1987) have
demonstrated that another conserved open reading frame, R. also encodes a
protein product. Functional studies and mutagenic analyses of biologically
active molecular clones of HIV-1 have resulted in the discovery of two
additional viral genes, tat-III and art/trs (Sodroski et al., 1984; Arya et al.,
1985; Dayton et al., 1986; Feinberg et al., 1986; A. G. Fisher et al., 1986b;
Sodroski et al., 1986a).
Thus, whereas many other naturally occurring, replication-competent
retroviruses have only three genes, HIV-1 contains at least eight (Figure 21.
Of these, the tat-III and art/trs genes are known to be essential for HIV-1
replication, and the sor gene product appears to be important for efficient
viral transmission; the R and 3'-orf genes appear to be dispensable for
replication in vitro (A. G. Fisher et al., 1986a, 1987; Luciw et al., 1987;
Strebel et al., 1987~. All of the structural (gag, pot, and envy and what are
presumed to be the regulatory (tat-III, art/trs, sor, R. and 3'-oj) genes
encode proteins that are recognized by sera from infected individuals, indicating
that the proteins are produced in viva and are immunogenic (Allen et al., 1985;
Lee et al.,1985; Aldovini et al.,1986; Knight et al.,1987; Wong-Staal et al.,19871.
OCR for page 126
;
126
CD
z in
~ _
CD o
Z G
~ CL
O: ~
~ ~o
1~ <:
Z
LL ~
CD CD
CO ~
O
~ —
> cn
cn
LLI z
J
O Cr
O: 1
LL
CD
~:
~:
z
~:
LL
o
G
-
LL
CO
CL
cn
z
CC
'1
1
LL
CD
llJ
>
~:
11_—O
O C,'
Z llJ
O
X~
CD ~
~ >
O
C~
cn
z
-
o
rr
CL
llJ
~r
o
z
O
-
O ~
O
Z
Z Y
Z
LL ~
cn
Z
LL
llJ o
~o o
LLI (~)
Z
LL
· s~
e
'e
c)
· -
~ - o
m
o
C)
._
4 -
CC
S:
0 ~ ~
~ Z .O
oz 3
LL
o~
~D
._
Ct
o
o
v
. .
C)
s~
:-
o
a'
o
a,
o~
a~
.
cn
.=
h_ Ct
~ C~
r~ cc
OCR for page 127
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS 127
The genome of HIV-2 has now been molecularly cloned and studied in
detail (Guyader et al., 19871. In addition to the requisite gag, pol, ens, and
regulatory genes, HIV-2 encodes an additional centrally located open
reading frame (X) that is not found in the genome of HIV-1.
Control of Viral Gene Expression
Like all other retroviruses, HIV uses double-stranded DNA copies of
the viral genome as templates for the synthesis of viral RNA molecules.
The transcription of retroviral RNA uses the host cell's synthetic machin-
ery, but it is regulated by genetic elements resident in the viral long
terminal repeats, or LTRs. The complex behavior of HIV is thought to
include mechanisms that facilitate both the amplification and attenuation
of viral expression (production). Although there is still much to be learned
about these regulatory processes, it appears likely that they are mediated
in large part through specific nucleotide sequences in the HIV LTRs.
Studies have shown that HIV production in vitro is enhanced by a
variety of immunologic stimuli and specific cytokines (proteins produced
by host cells) (Hoxie et al., 1985; Zagury et al., 1986; Folks et al., 19871.
Whether or not increased production follows similar stimulation in viva is
unknown; if so, such stimuli (other infections, perhaps) might be impor-
tant factors mediating the pace of progression of immunocompromise and
disease following initial HIV infection. The basic mechanisms regulating
gene expression in human (and other eukaryotic) cells are only beginning
to be understood. Early studies have clearly shown, however, that the
cellular transcription apparatus may be preferentially activated to express
specific subsets of cellular genes within the context of a given cell's
differentiation program. Recently, evidence has been presented suggest-
ing that the activation of HIV production by cellular stimulation is
mediated by the activation of a host regulatory protein binding to the
genetic regulatory elements of the viral LTR, which previously had been
shown to function as transcriptional enhancer elements. Additional
studies have identified a number of other host cell proteins that bind to
specific sequences in the HIV LTR and that may also play important roles
in controlling the transcription of HIV RNA (Jones et al., 1986; Franza et
al., 1987; Garcia et al., 1987~.
Regulation and Production of HIV
As discussed in the previous section, the double-stranded DNA (pro-
viral) form of HIV residing in the nucleus of an infected cell serves as the
template for synthesizing full-length viral RNA transcripts. Some of the
transcripts remain intact and enter the cytoplasm for incorporation into
OCR for page 128
128 CONFRONTING AIDS: UPDATE aged
virus particles and transmission to other cells. Researchers also believe
that the full-length transcripts are used in the translation of HIV gag and
pol proteins, which derive from proteolytic cleavage of a large polypro-
tein precursor (IOM/NAS, 1986~. Because the reading frames of gag and
pol are adjacent but discontinuous, until recently it was unclear how the
precursor protein was produced. Now, studies have described the process,
called ribosomal frameshifting, that HIV uses to generate the precursor of
the mature gag and pol proteins (Jacks et al., 1988~. Researchers have
also recently identified a virally encoded protease responsible for the
proteolytic cleavage of the gag-pol precursor into its mature functional
constituents. The constituents include the viral core structural proteins
and the reverse transcriptase, endonuclease, and RNase H activities of
the HIV polymerase complex (Debouck et al., 19881.
The remaining HIV proteins, including the ens glycoproteins and the
regulatory proteins, are all translated from subgenomic RNA transcripts
derived by an unusually complicated pattern of RNA splicing (Muesing et
al., 19851. What is yet unknown are the mechanisms by which retroviruses
achieve an appropriate balance between sufficient unspliced RNA tran-
scripts to provide new genomic RNA molecules for additional cycles of
infection and spliced mRNAs to encode the requisite viral structural and
regulatory proteins. It appears that HIV may encode a specific, novel gene
to regulate the pattern of spliced RNAs produced in infected cells and,
consequently, the amount of virus particles produced (Feinberg et al., 19861.
HIV envelope glycoproteins play an essential role in the replication of
HIV and may be responsible for many of the cytopathic consequences of
viral infection (Lifson et al., 1986a; Sodroski et al., 1986a; Somasundaran
and Robinson, 1987; McCune et al., 1988~. The envelope protein is
translated from a spliced mRNA and synthesized as a large precursor
protein; this precursor protein is then heavily glycosylated (sugar residues
are added) to a form known as gpl60 and proteolytically cleaved into two
associated subunits, gpl20 and gp41 (IOM/NAS, 1986~. Recent work has
shown definitively that the gp120 molecule mediates viral attachment to
the cellular receptor, the host cell surface protein CD4 (Dalgleish et al.,
1984; Klatzmann et al., 1984; Maddon et al., 19861. The gp41 anchors the
envelope glycoprotein complex in the lipid bilayer of the viral membrane.
The glycosylation and proteolytic processing of the gpl60 envelope
precursor are host cell enzymatic functions (IOM/NAS, 19861. Now,
researchers also understand that glycosylation of the HIV envelope
proteir1 is necessary for receptor binding and infectivity, and may play an
additional role in masking critical envelope domains from host immuno-
logic attack (Matthews et al., 19874. Proteolytic cleavage of the envelope
precursor has been shown to be essential for the generation of infectious,
cytopathic HIV particles.
OCR for page 129
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS 129
The protein products of the HIV genes sor, R. tat-III, art/trs, and 3'-orf
(and X in the case of HIV-2) are synthesized from multiply spliced viral
mRNA transcripts. These regulatory proteins have been identified, but a
good deal of uncertainty and controversy surrounds any definition of their
exact functions. For example, early studies have demonstrated that the
tat-III and art/trs proteins play roles in HIV replication and appear to
involve genetic processes that are without known precedents in human
cells. It is likely that the R. 3'-orf, and X genes also play important roles
in the biology of HIV-1 and HIV-2, but a more thorough understanding of
these genes has been limited by the lack of in vitro assays of their
functions.
The tat-III protein greatly amplifies (or transactivates) the level of
replication of HIV-1 (Sodroski et al., 1984; Arya et al., 19851. Studies
have shown that this enhancement requires specific nucleotide sequences
(the transactivation response element, or TAR) that are contained within
the viral LTR; following transcription, these sequences are included at
the 5'-end of all viral RNA transcripts (Rosen et al., 1985; Muesing et al.,
1987~. Whether the tat-III protein directly binds to the TAR regions is not
yet known, but researchers have concluded that the TAR region assumes
a complex RNA secondary structure whose specific topology is essential
for proper functioning (Hauber and Cullen, 19881. Reportedly, the tat-III
protein enhances both the transcription and translation of HIV-1 RNA
(sullen, 1986; Feinberg et al., 1986; Peterlin et al., 1986; Rosen et al.,
1986; Wright et al., 1986; Hauber et al., 1987; Kao et al., 1987; Muesing
et al., 19871. Defining the relative importance of several proposed
mechanisms of tat-III action awaits additional experimental evaluation.
Nevertheless, although the function of the tat-III protein is still poorly
defined, it has been shown to assume a predominantly nuclear localization
in infected cells (a possible clue to its function), and important aspects of
its molecular structure are emerging (Hauber et al., 1987; Frankel et al.,
1988~.
The art/trs protein of HIV-1 also has an essential although poorly
understood function in viral replication (Feinberg et al., 1986; Sodroski et
al., 1986b; Knight et al., 19871. The art/trs gene appears to control,
directly or indirectly, the pattern of HIV-1 RNA transcripts seen in
infected cells. In the absence of art/trs expression, the smaller, multiply
spliced mRNA species that encode the viral regulation proteins predom-
inate, at the expense of the full-length and singly spliced ens transcripts
that provide viral genomes and specify translation of the HIV-1 virion
structural components (Feinberg et al., 1986; Sadaie et al., 19881. The
art/trs function may specifically affect the splicing of viral RNA and thus
permit important differential regulation of HIV expression; additional
art/trs effects on the translation of specific viral mRNAs have also been
OCR for page 130
130 CONFRONTING AIDS: UPDATE 1988
suggested. Rosen and colleagues (1988) have postulated that the art/trs
protein acts through specific, incompletely defined sequences contained
in HIV-1 RNA transcripts. Like the tat-III protein, the art/trs protein is
localized in the nucleus of HIV-1-infected cells, consistent with its
postulated role in the splicing of viral RNA.
It has been reported that the sor gene of HIV-1 is required for efficient
replication. This finding is based on studies of viruses with experimentally
induced mutations in the sor gene. The studies show that the viruses
spread poorly and only through cell-to-cell contact in in vitro lymphocyte
cultures (A. G. Fisher et al., 1987; Strebel et al., 1987~. The nature of this
handicap is not well understood, however. It is thought that the sor
protein is not incorporated in HIV virus particles.
The 3'-orf gene of HIV-1 is not needed for replication in vitro, and
recent reports have suggested that viruses that lack a functional 3'-orf
gene may, in fact, replicate more efficiently than wild-type viruses (A. G.
Fisher et al., 1986a; Luciw et al., 1987~. Whether the 3'-orf protein
specifically inhibits HIV-1 production is not yet known. It has been
suggested that the 3'-orf protein influences the expression of certain host
cellular genes.
The role of the R gene of HIV-1 has only recently begun to be
scrutinized, but preliminary results (Wong-Staal et al., 1987) indicate that
it may not be required for HIV- 1 replication in vitro. Also in need of direct
evaluation are the roles of HIV-2 regulatory genes, although these are
assumed to be analogous to those of HIV-1. The significance and function
of the distinctive X gene of HIV-2 await elucidation. Because SIV's
genetic structure is closely related to that of HIV-2, it will permit
experimental analyses of the in viva function of the unusual regulatory
genes of the immunodeficiency-inducing lentiviruses analyses that are
not possible with the human AIDS viruses (Chakrabarti et al., 1987;
Franchini et al., 1987; Hirsch et al., 1987~.
Interrupting Infection by HIV
The HIV replicative cycle presents a number of opportunities for
interruption by antiviral interventions. Since 1986 a good deal of progress
has been made; however, much of the information that emerges from
ongoing studies highlights the difficulties that must be overcome before
effective prophylactic or therapeutic interventions are feasible.
The earliest event in the establishment of HIV infection is the binding
of the virus particle through its envelope glycoprotein (gpl20) to a specific
receptor on the host cell's surface. This CD4 cell receptor is found on the
surface of certain members of the T lymphoid and macrophage-monocyte
cell lineages (IOM/NAS, 1986; Maddon et al., 1986; Sattentau and Weiss,
OCR for page 131
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS ~3 ~
19881. The range of cells that are susceptible to HIV-1 infection, both in
vitro and in viva, appears to parallel those that display the CD4 surface
receptor. HIV-2 also uses the CD4 molecule as its receptor in the
initiation of infection.
Current studies are defining the interaction between the HIV-1 gpl20
envelope protein and the CD4 receptor with increasing resolution. The
region of the gpl20 molecule that interacts with the CD4 molecule
recently has been defined; the identification of the corresponding binding
domain of CD4 is being actively pursued (Lasky et al., 19871. Potential
strategies to inhibit the gpl20-CD4 interaction, and thus HIV infection,
include vaccination to elicit antibodies that recognize and bind to the
critical receptor-binding domain of the HIV envelope and the inhibition of
cell surface binding through competition with appropriate exogenously
added fragments of the CD4 protein. Recent studies have shown the
feasibility of the latter approach by successfully inhibiting HIV infection
in vitro with a soluble form of the CD4 molecule produced through
recombinant DNA methods (Smith et al., 1987; Deen et al., 1988; R. A.
Fisher et al., 1988; Traunecker et al., 1988~. It is hoped that small
fragments of CD4 may soon be identified that will prevent HIV infection
but that will not interfere with the critical immunologic functions of the
CD4 molecule in viva. Experimental clinical trials of the soluble CD4
preparation in HIV-positive persons are expected to begin shortly;
however, this approach may be limited by the inability of such prepara-
tions to cross the blood-brain barrier and thus reach the important
reservoir of infection within the central nervous system (Ho et al., 1985;
Shaw et al., 1985; Gartner et al., 1986b; Koenig et al., 19861.
After HIV binds to the CD4 receptor, it appears to enter the host target
cell by direct fusion of the viral and cellular plasma membranes (Stein et
al., 1987; McClure et al., 19881. It is thought that this process requires a
hydrophobic domain on the HIV gp41 that assumes an active fusogenic
conformation following cleavage of the gpl60 precursor molecule (Mc-
Cune et al., 19881. One important manifestation of the cytopathic conse-
quence of HIV infection in vitro involves a specific interaction between
the HIV envelope glycoprotein complex and the CD4 molecule that
results in the fusion and subsequent death of cells that have CD4
receptors (Lifson et al., 1986a,b; Sodroski et al., 1986a). This process,
which is known as syncytia formation, may also involve the fusogenic
domain of gp41 (McCune et al., 19881. The development of approaches to
inhibit envelope-mediated membrane fusion may lead to novel ways of
preventing HIV infection and its consequences.
Once the virus is inside the host target cell, the HIV RNA genome is
copied into a double-stranded DNA form by the viral reverse transcrip-
tase. If reverse transcriptase could be inhibited, the lack of it would
OCR for page 132
132 CONFRONTING AIDS: UPDATE 1988
disrupt an essential stage of HIV replication, and this antiviral strategy is
being actively pursued (IOM/NAS, 19861. The drug zidovudine (i.e.,
AZT) acts to interrupt this stage of the infection. Zidovudine is a
nucleoside analog that, once it has been phosphorylated by host cell
kineses, is preferentially used by the HIV reverse transcriptase to
synthesize the complementary strand of retroviral DNA. Once zidovu-
dine is incorporated into the nascent DNA copy of HIV RNA, however,
DNA polymerization stops, prematurely, and the DNA strand cannot be
extended (Yarchoan and Broder, 1987~. Zidovudine effectively inhibits
HIV-1 replication in vitro, and early clinical trials have shown that it
improves survival in persons with severe manifestations of HIV-1 infec-
tion (Fischl et al., 1987; Yarchoan et al., 19871. Although the clinical
utility of zidovudine may be limited by its untoward side effects, which
include anemia and neutropenia, it provides a hopeful precedent for
future drug development efforts (Richman et al., 19871. A related chain-
terminating nucleoside analog, 2',3'-dideoxycytidine (ddC), is an even
more potent inhibitor of HIV replication in vitro and is now the subject of
clinical trials (Yarchoan and Broder, 1987~.
Another area of potential inhibition involves the processes that control
the transcription and translation of HIV RNA. Much remains to be
learned about these processes, although the requirements of the tat-III
and art/trs genes in the HIV replicative cycle are clear. Still, a much
better understanding of their functions is needed before studies can
explore the specific inhibition of their activities. Similarly, researchers
need an improved definition of the replicative role of the sor, R. X, and
3'-orf genes before they can evaluate their candidacy as targets for
antiviral interventions.
The processing and assembly of the HIV structural components offer a
range of potential points for inhibiting HIV replication. The necessary
proteolytic cleavage of the gag-pol polyprotein precursor is one possible
target, and its mechanism is currently undergoing active analysis (De-
bouck et al., 1988~. Likewise, the proteolytic processing of the envelope
polyprotein gpl60, which is necessary for HIV infectivity, is a susceptible
stage for inhibition. The glycosylation of the HIV envelope protein also
appears to be necessary for viral infectivity, and drugs that interfere with
this process have demonstrated antiviral activity in vitro (Gruters et al.,
19871. Further studies of the pathways of viral assembly and maturation
may identify additional promising antiviral targets.
Natural History of HIV Infection
Studies of HIV-infected persons have demonstrated the presence and
expression of the virus in a number of host tissues, including peripheral
OCR for page 133
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS 133
blood cells, lymph nodes, bone marrow, spleen, lung, retina, brain,
cerebrospinal fluid, semen, cervical and vaginal secretions, saliva, and
tears of infected individuals (IOM/NAS, 19864. Epidemiological analyses
provide evidence that the essentially exclusive modes of HIV transmis-
sion are sexual intercourse, blood and blood products, and perinatal
transmission (see Chapter 2~. As in the case of other lentiviruses, studies
have detected very little cell-free virus in HIV-seropositive persons.
Perhaps in keeping with the lentivirus analogy, HIV may also be spread
by virally infected cells carried in secretions rather than by cell-free virus.
The factors that determine whether an HIV-infected person will transmit
the viral infection to another individual are poorly understood (see
Chapter 21. For instance, it appears that HIV-infected persons differ in
their degree of infectiousness over time. Similarly, the factors that may
influence an individual's susceptibility to HIV infection following a given
exposure are incompletely defined.
Other aspects of HIV infection are somewhat better understood, for
example, which cells are targets of the virus in an infected human host. In
addition to the CD4 helper-inducer cell population that is progressively
depleted in the clinical development of AIDS, researchers now recognize
that cells of the macrophage-monocyte lineage are important targets in the
establishment, dissemination, and persistence of the infection (Gartner et
al., 1986a; Ho et al., 1986; Koenig et al., 19861. Because macrophages
permit HIV replication, are capable of wide-ranging migration, and are
relatively resistant to the cytopathic consequences of viral infection, they
probably play a major role in the pathogenesis of HIV-induced disease.
Studies have found infected macrophage populations within the lymphat-
ics, the central nervous system, and a variety of peripheral tissues,
frequently at sites manifesting local pathology (Koenig et al., 19861.
Interestingly, recent evidence suggests that different HIV isolates may
replicate preferentially in either CD4-positive T lymphocytes or in
macrophage populations derived from a variety of host tissues (Gartner et
al., 1986a; Koyanagi et al., 19871. It is not known whether viruses with
different cytotropisms give rise to specific clinical manifestations of HIV
infection, nor what genetic differences account for the biological diversity
of HIV isolates. Further hypotheses awaiting examination involve the
possible in viva interactions among populations of HIV in an individual or
the evolution of HIV in an infected individual, either of which might result
in altered cytotropism or enhanced virulence during the course of disease
progression.
Once HIV infection is established, it persists throughout the lifetime of
the infected person, avoiding clearance by the host immune response.
The means by which HIV is able to avoid clearance is not known.
Although HIV is found only in rare cells in the peripheral bloodstream, it
OCR for page 148
|48 CONFRONTING AIDS: UPDATE 1988
The chimpanzee is now the animal of choice when HIV is used to
challenge vaccinated animals to determine whether a vaccine provides
safe, effective protection. Tests with chimpanzees are also being used to
determine the number of different strains of HIV that must be included in
a vaccine. Nevertheless, as discussed earlier in this chapter, experiments
to date with vaccines in chimpanzees have failed to show that any vaccine
candidate confers protection against HIV infection.
The use of SIV to infect Old World primates such as rhesus macaques
results in an animal model that quickly develops an AIDS-like disease
with a subsequent high death rate. As described earlier in this chapter, the
protein products and the organization of the SIV genome generally
resemble those of HIV. The committee believes that SIV infection in
macaques and the resulting disease are the best parallels at this time to
human HIV infection and should be vigorously exploited.
Studies of AIDS pathogenesis, the development of AIDS vaccines, and
analyses of drug therapies will require tens of thousands of research
animals (Weissman, 1988~. The lack of adequate numbers of chimpanzees
and other primates for AIDS-related research is a serious problem.
Currently, there are only about 1,200 chimpanzees in biomedical research
colonies in the United States; another 80 are kept in pharmaceutical
industry colonies in the United States (Desrosiers and Letvin, 19871.
Although approximately 300 of these animals are available for breeding,
current reproductive predictions indicate an annual increase of only about
35 chimpanzees for research use.
Without significant increases in our understanding of primate reproduc-
tion and conservation, there will be inadequate numbers of these animals
available for AIDS-related research. Furthermore, the unregulated use
for medical research of chimpanzees shipped from countries in which the
animals exist in the wild could lead to their extinction. Sufficient lead time
and funding must also be provided for the production of macaques in large
numbers (Desrosiers and Letvin, 19871.
The use of chimpanzees and other primates for AIDS research and, in
particular, efforts to increase the available numbers of animals through
breeding demand national-level coordination. Present programs for the
conservation, population expansion, and optimal use of these animals
appear inadequate (Gardner and Luciw, 19871. The committee recom-
mends that plans for breeding, conserving, and otherwise expanding the
present stock of chimpanzees be examined. This expansion may require
increased funding. The committee is concerned that poorly designed
studies will waste previously unexposed chimpanzees. The assistant
secretary for health should ensure that this does not occur.
Small animals can also be used in HIV infection research and efforts to
develop animal models for AIDS. A mouse model, for example, would be
OCR for page 149
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS 149
a crucial breakthrough in AIDS research, as laboratory mice are plentiful
and well understood as research animals. In some studies, investigators
have constructed transgenic mice by introducing DNA from other orga-
nisms (humans or viruses) into the genomes of individual mice, which
then express the foreign genetic instructions. The gene encoding the CD4
molecule, the essential regulatory elements of HIV that control viral
expression, and the entire HIV genome have each been used to produce
transgenic mice. If such efforts are successful, the transgenic mouse
model could be valuable for determining which agents influence the
expression of discrete genetic regions of HIV (M. Martin, NIAID,
personal communication, 1988~.
In another model of HIV infection, researchers have transplanted all
elements of the human blood-forming and immune systems into geneti-
cally immunodeficient mice. Investigators hope this mouse strain will
prove susceptible to HIV infection and possibly to the development of
AIDS (I. Weissman, Stanford University, personal communication,
1988).
Whatever its final form, the development of a small animal model for
AIDS is of utmost importance. A completely analogous animal model of
HIV-induced human disease, especially in a small, plentiful, and well-
understood animal such as the mouse, would greatly enhance vaccine and
drug development. If efforts to develop a small animal model are carried
out under carefully regulated, safe laboratory conditions, the committee
strongly supports further work in this area.
RESOURCES
Facilities
One of the major obstacles to further advances in research on HIV and
AIDS remains the lack of adequate facilities- in particular, the shortage
of laboratories that are equipped to handle HIV safely and of centers for
housing and studying infected research animals. The paucity of such
facilities is a problem in both the public and private sectors: it was estimated
in the fall of 1987 that fewer than five pharmaceutical companies have
containment facilities suitable for work with live HIV (IOM, 19874. Even
some institutions that are generally in the forefront of research technology
are underequipped for AIDS research (Weissman, 19881.
Similar problems are apparent at the various primate centers located
throughout the United States. Despite the emergence of significant data
on simian retroviruses and AIDS, actual funding for primate research
decreased during the several years prior to 1986 (Weissman, 1988~.
Currently, five of the country's seven regional primate centers have
OCR for page 150
150 CONFRONTING AIDS: UPDATE 1988
active AIDS research programs, and the federal government has provided
additional funding to these facilities for their AIDS activities. Yet the
extent to which the centers can use these funds to further increase their
research output is limited by available laboratory space and resources. A
case in point is the small number of biological containment facilities that
are currently available in the United States for macaques inoculated with
hazardous viruses (e.g., SIV) (Desrosiers and Letvin, 19874.
In response to these needs, the federal government has authorized
additional funds to be available beginning in 1988. About $24 million has
been provided to the Division of Research Resources at the National
Institutes of Health (NIH) to support infrastructure improvements at
extramural research sites around the country and to purchase related
equipment (letter from J. B. Wyngaarden, NIH, to T. Cooper, 19881. Of
this amount, $2.8 million will be reserved for grants to the regional
primate research centers for similar uses. Congress has also appropriated
an additional $19 million to address NIH intramural facility needs. Plans
are under way to use this money for renting office and off-campus
laboratory space and for other improvements.
Yet despite these encouraging funding developments, the two congres-
sional allocations for renovations and infrastructure improvements are
only a modest beginning to the facility upgrading necessary for productive
AIDS research. More funds are needed to develop high-containment
facilities at existing labs, and money for new laboratory construction is
still a critical need. Such facilities are by no means inexpensive. Office
space for personnel is another essential underpinning of a successful
research effort. Additional funds are also needed to provide housing for
experimental animals such as large primates.
The committee recommends that the director of NIH, in consultation with
research scientists from within and without the institutes, assess the need for
and costs of new intramural and extramural facilities for AIDS research.
This information should be forwarded to Congress for evaluation and
subsequent action.
Reagent Distribution Center
To support AIDS research and provide the scientific community with
the necessary biological materials for this work, NIAID has established
the AIDS Research and Reference Reagent Program asking investigators
to contribute appropriate materials that are needed for AIDS research.
Reagents to be offered by the center include antisera, monoclonal
antibodies, biological response modifiers, proteins derived from HIV and
other related retroviruses, cellular proteins, bacterial and eukaryotic cell
lines, HIV-related retroviruses, and other opportunistic infectious agents
OCR for page 151
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS
151
associated with HIV infections. The committee supports this develop-
ment. Currently, however, the success of the reagent center depends
entirely on voluntary participation. The committee recommends that NIH
stipulate that all investigators receiving NIH funds must make their
AIDS-related reagents available to the distribution center, and thereby to all
qualified investigators, after publication of their research. Industry is also
urged to participate after the establishment of any patent rights. The
committee plans to review the experience of the NIAID AIDS Research
and Reference Reagent Program after it has been in operation for 1 year.
Finally, the committee supports the development by NIH, perhaps
through the reagent program, of an HIV/SIV research "starter kit" that
would enable qualified new investigators to begin research more easily. The
kit would contain sensitive cell lines, infectious virus, cloned DNAs,
specific antibodies, and initial protocols for maintaining and infecting cell
lines.
FUNDING FOR RESEARCH
Confronting AIDS recommended that federal appropriations for re-
search on AIDS and HIV infection reach at least $1 billion annually by
1990. At the present rate of increase, it appears that this goal will be met.
The 1988 NIH budget for AIDS research is $467.8 million, and the
proposed 1989 budget is $587.6 million. The 1989 budget includes an
additional $300 million (approximately) for AIDS research expenditures
by CDC, HHS's Alcohol, Drug Abuse, and Mental Health Administra-
tion, and FDA.
The committee believes that when federal research expenditures for AIDS
reach $1 billion annually, an assessment of the need for further increases
should be made. It is important to ensure that other federal research
programs are not penalized by a long-term disproportionate growth in the
AIDS budget.
REFERENCES
Abrams, D., M. Gottlieb, M. Grieco, M. Speer, and S. Bernstein, eds. 1987. AmFAR
Directory of Experimental Treatments for AIDS and ARC. Vol. 1. New York: Mary Ann
Liebert, Inc.
Aldovini, A., C. Debouck, M. B. Feinberg, M. Rosenberg, S. K. Arya, and F. Wong-Staal.
1986. Synthesis of the complete trans-activation gene product of human T-lymphotropic
virus type III in Escherichia coli: Demonstration of immunogenicity in viva and
expression in vitro. Proc. Natl. Acad. Sci. USA 83:6672-6676.
Alizon, M., S. Wain-Hobson, L. Montagnier, and P. Sonigo. 1986. Genetic variability of the
AIDS virus: Nucleotide sequence analysis of two isolates from African patients. Cell
46:63-74.
OCR for page 152
152 CONFRONTING AIDS: UPDATE 1988
Allan, J. S., J. E. Coligan, T.-H. Lee, M. F. McLane, P. J. Kanki, J. E. Groopman, and M.
Essex. 1985. A new HTLV-III/LAV encoded antigen detected by antibodies from AIDS
patients. Science 230:810-813.
Arya, S. K., C. Guo, S. F. Josephs, and F. Wong-Staal. 1985. Trans-activator gene of
human T-lymphotropic virus type III (HTLV-III). Science 229:69-73.
Chakrabarti, L., M. Guyader, M. Alizon, M. D. Daniel, R. C. Desrosiers, P. Tiollais, and
P. Sonigo. 1987. Sequence of simian immunodeficiency virus from macaques and its
relationship to other human and simian retroviruses. Nature 328:543-547.
Clavel, F., D. Guetard, F. Brun-Vezinet, S. Chamaret, M.-A. Rey, M.-O. Santos-Ferreira,
A. G. Laurent, C. Dauguet, C. Katlama, C. Ronzioux, D. Klatzmann, J.-L. Champali-
maud, and L. Montagnier. 1986a. Isolation of a new human retrovirus from West African
patients with AIDS. Science 233:343-346.
Clavel, F., M. Guyader, D. Guetard, M. Salle, L. Montagnier, and M. Alizon. 1986b.
Molecular cloning and polymorphism of the human immune deficiency virus type 2.
Nature 324:691-695.
Clavel, F., K. Mansinho, S. Chamaret, D. Guetard, V. Favier, J. Nina, M.-O. Santos-
Ferreira, J.-L. Champalimaud, and L. Montagnier. 1987. Human immunodeficiency virus
type 2 infection associated with AIDS in West Africa. N. Engl. J. Med. 316:1180-1185.
Coffin, J. M. 1986. Genetic variation in AIDS viruses. Background paper. Committee on a
National Strategy for AIDS, Washington, D.C.
Cooper, T. M. 1988. Treatment IND: Making investigational new drugs available to the
desperately ill. Address at the American Medical Association-Food and Drug Adminis-
tration Conference, Washington, D.C., February 17.
Cullen, B. R. 1986. Trans-activation of human immunodeficiency virus occurs via a bimodel
mechanism. Cell 46:973-982.
Dalgleish, A. G., P. C. L. Beverley, P. R. Clapham, D. H. Cra~vford, M. F. Greaves, and
R. A. Weiss. 1984. The CD4 (T4) antigen is an essential component of the receptor for the
AIDS retrovirus. Nature 312:763-767.
Daniel, M. D., N. L. Letvin, N. W. King, M. Kannagi, P. K. Sehgal, R. D. Hunt, P. J.
Kanki, M. Essex, and R. C. Desrosiers. 1985. Isolation of T-cell tropic HTLV-III-like
retrovirusfrommacaques.Science228:1201-1204.
Dayton, A. I., J. G. Sodroski, C. A. Rosen, W. C. Goh, and W. A. Haseltine. 1986. The
trans-activator gene of the human T cell lymphotropic virus type III is required for
replication. Cell 44:941-947.
Debouck, C., J. G. Gorniak, J. E. Strickler, T. D. Meek, B. W. Metcalf, and M. Rosenberg.
1988. Human immunodeficiency virus protease expressed in Escherichia cold exhibits
autoprocessing and specific maturation of the gag precursor. Proc. Natl. Acad. Sci. USA
84:8903-8906.
Deen, K. C., J. S. McDougal, R. Inacker, G. Folena-Wasserman, J. Arthos, J. Rosenberg,
P. J. Maddon, R. Axel, and R. W. Sweet. 1988. A soluble form of CD4 (T4) protein
inhibits AIDS virus infection. Nature 331:82-84.
Desrosiers, R. C. 1987. Simian and feline models of AIDS. Paper presented at the Institute
of Medicine Conference on the Development of Vaccines Against HIV Infection and
AIDS, Washington, D.C., December 14-15.
Desrosiers, R. C., and N. L. Letvin. 1987. Animal models for acquired immunodeficiency
syndrome. Rev. Infect. Dis. 9:438-446.
Feinberg, M. B., R. F. Jarrett, A. Aldovini, R. C. Gallo, and F. Wong-Staal. 1986.
HTLV-III expression and production involve complex regulation at the levels of splicing
and translation of viral RNA. Cell 46:807-817.
Fischl, M. A., D. D. Richman, M. H. Grieco, M. S. Gottlieb, P. A. Volberding, D. L.
Laskin, J. M. Leedom, J. E. Groopman, D. Mildvan, R. T. Schooley, G. G. Jackson,
OCR for page 153
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS 153
D. T. Durack, D. King, and the AZT Collaborative Working Group. 1987. The efficacy of
azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex:
A double-blind, placebo-controlled trial. N. Engl. J. Med. 317:185-191.
Fisher, A. G., M. B. Feinberg, S. F. Josephs, M. E. Harper, L. M. Marselle, G. Reyes,
M. A. Gonda, A. Aldovini, C. Debouk, R. C. Gallo, and F. Wong-Staal. 1986a. The
trans-activator gene of HTLV-III is essential for virus replication. Nature 320:367-371.
Fisher, A. G., L. Ratner, H. Mitsuya, L. M. Marselle, M. E. Harper, S. Broder, R. C.
Gallo, and F. Wong-Staal. 1986b. Infectious mutants of HTLV-III with changes in the 3'
region and markedly reduced cytopathic effects. Science 233:655-659.
Fisher, A. G., B. Ensoli, L. Ivanoff, M. Chamberlain, S. Petteway, L. Ratner, R. C. Gallo,
and F. Wong-Staal. 1987. The sor gene of HIV-1 is required for efficient virus transmission
in vitro. Science 237:888-893.
Fisher, R. A., J. M. Bertonis, W. Meier, V. A. Johnson, D. S. Costopoulos, T. Liu, R.
Tizard, B. D. Walker, M. S. Hirsch, R. T. Schooley, and R. A. Flavell. 1988. HIV
infection is blocked in vitro by recombinant soluble CD4. Nature 331:76-78.
Folks, T. M., J. Justement, A. Kinter, C. A. Dinarello, and A. S. Fauci. 1987. Cytokine-
induced expression of HIV-1 in a chronically infected promonocyte cell line. Science
238:800-802.
Franchini, G., C. Gurgo, H.-G. Guo, R. C. Gallo, E. Collalti, K. A. Fargnoli, L. F. Hall, F.
Wong-Staal, and M. S. Reitz, Jr. 1987. Sequence of simian immunodeficiency virus and its
relationship to the human immunodeficiency viruses. Nature 328:539-543.
Francis, D. 1987. Current U.S. attempts at vaccine development. Paper presented at the
Institute of Medicine Conference on the Development of Vaccines Against HIV Infection
and AIDS, Washington, D.C., December 14-15.
Prankel, A. D., D. S. Bredt, and C. O. Pabo. 1988. Tat protein from human immunodefi-
ciency virus forms a metal-linked dimer. Science 240:70-73.
Franza, B. R., S. F. Josephs, M. Z. Gilman, W. Ryan, and B. Clarkson. 1987. Character-
ization of cellular proteins recognizing the HIV enhancer using a microscale DNA-affinity
precipitation assay. Nature 300:391-395.
Fultz, P. 1987a. Conspectus on primate models for AIDS. Correspondent paper. AIDS
Activities Oversight Committee, Washington, D.C.
Fultz, P. 1987b. Responses of chimpanzees to HIV immunization. Paper presented at the
Institute of Medicine Conference on the Development of Vaccines Against HIV Infection
and AIDS, Washington, D.C., December 14-15.
Garcia, J. A., F. K. Wu, R. Mitsuyasu, and R. B. Gaynor. 1987. Interactions of cellular
proteins involved in the transcriptional regulation of the human immunodeficiency virus.
EMBO J. 6:3761-3770.
Gardner, M. B., and P. Luciw. 1987. Nonhuman primate models for AIDS. Correspondent
paper. AIDS Activities Oversight Committee, Washington, D.C.
Gartner, S., P. Markovits, D. M. Markovitz, M. H. Kaplan, R. C. Gallo, and M. Popovic.
1986a. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science
233:215-219.
Gartner, S., P. Markovits, D. M. Markovitz, R. F. Betts, and M. Popovic. 1986b. Virus
isolation from and identification of HTLV-III/LAV-producing cells in brain tissue from a
patient with AIDS. J. Am. Med. Assoc. 256:2365-2371.
Gonda, M. A., F. Wong-Staal, R. C. Gallo, J. E. Clements, O. Narayan, and R. V. Gilden.
1985. Sequence homology and morphologic similarity of HTLV-III and visna virus, a
pathogenic lentivirus. Science 227:173-177.
Gonda, M. A., M. J. Braun, S. G. Carter, T. A. Kost, J. W. Bess, L. O. Arthur, and M. J.
Van Der Maaten. 1987. Characterization and molecular cloning of a bovine lentivirus
related to human immunodeficiency virus. Nature 330:388-391.
OCR for page 154
154 CONFRONTING AIDS: UPDATE 1988
Gruters, R. A., J. J. Reeves, M. Tersmette, R. E. Y. de Goede, A. Tulp, H. G. Huisman,
F. Miedema, and H. L. Ploegh. 1987. Interference with HIV-induced syncytium forma-
tion and viral infectivity by inhibitors of trimming glucosidene. Nature 330:74-77.
Guyader, M., M. Emerman, P. Sonigo, F. Clavel, L. Montagnier, and M. Alizon. 1987.
Genome organization and transactivation of the human immunodeficiency virus type 2.
Nature 326:662-669.
Haase, A. T. 1986. Pathogenesis of lentivirus infections. Nature 322: 130-136.
Hahn, B. H., G. M. Shaw, M. E. Taylor, R. R. Redfield, P. D. Markham, S. Z. Salahuddin,
F. Wong-Staal, R. C. Gallo, E. S. Parks, and W. P. Parks. 1986. Genetic variation in
HTLV-III/LAV over time in patients with AIDS or at risk for AIDS. Science
232: 1548-1553.
Halstead, S. 1987. Immuno-enhancement of disease. Paper presented at the Institute of
Medicine Conference on the Development of Vaccines Against HIV Infection and AIDS,
Washington, D.C., December 14-15.
Harper, M. E., L. M. Marselle, R. C. Gallo, and F. Wong-Staal. 1986. Detection of
lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and
peripheral blood from infected individuals by in situ hybridization. Proc. Natl. Acad. Sci.
USA 83:772-776.
Hauber, J., and B. R. Cullen. 1988. Mutational analysis of the trans-activation-responsive
region of the human immunodeficiency virus type I long terminal repeat. J. Virol.
62:673-679.
Hauber, J., A. Perkins, E. P. Heimer, and B. R. Cullen. 1987. Trans-activation of human
immunodeficiency virus gene expression is mediated by nuclear events. Proc. Natl. Acad.
Sci. USA 84:6364-6368.
Hirsch, V., N. Riedel, and J. I. Mullins. 1987. The genome organization of STLV-3 is similar
to that of the AIDS virus except for a truncated transmembrane protein. Cell 49:307-319.
Ho, D. D., T. R. Rota, R. T. Schooley, J. C. Kaplan, J. D. Allan, J. E. Groopman, L.
Resnick, D. Felsenstein, C. A. Andrews, and M. S. Hirsch. 1985. Isolation of HTLV-III
from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related
to the acquired immunodeficiency syndrome. N. Engl. J. Med. 313:1493-1497.
Ho, D. D., T. R. Rota, and M. S. Hirsch. 1986. Infection of monocyte/macrophages by
human T lymphotropic virus type III. J. Clin. Invest. 77:1712-1715.
Hoxie, J. A., B. S. Haggarty, J. L. Rackowski, N. Pillsbury, and J. A. Levy. 1985.
Persistent noncytopathic infection of normal human T lymphocytes with AIDS-associated
retrovirus. Science 229:1400-1402.
IOM (Institute of Medicine). 1987. An Agenda for AIDS Drug Development. Report of the
Conference on Promoting Drug Development Against AIDS and HIV Infection. Wash-
ington, D.C.: National Academy Press.
IOM/NAS (Institute of Medicine/National Academy of Sciences). 1986. Future research
needs. Pp. 177-259 in Confronting AIDS: Directions for Public Health, Health Care, and
Research. Washington, D.C.: National Academy Press.
Jacks, T., M. D. Power, F. R. Masiarz, P. A. Luciw, P. J. Barr, and H. E. Varmus. 1988.
Characterization of ribosomal frameshifting in HIV-1 gag-pol expression. Nature
331 :280-283.
Jones, K. A., J. T. Kadonaga, P. A. Luciw, and R. Tjian. 1986. Activation of the AIDS
retrovirus promoter by the cellular transcription factor, Spl. Science 232:755-759.
Kan, N. C., G. Franchini, F. Wong-Staal, G. C. DuBois, W. G. Robey, J. A. Lautenberger,
and T. S. Papas. 1986. Identification of HTLV-III/LAV sor gene product and detection of
antibodies in human sera. Science 231:1553-1555.
Kanki, P. J., J. Alroy, and M. Essex. 1985. Isolation of T-lymphotropic retrovirus related to
HTLV-III/LAV from wild-caught African green monkeys. Science 230:951-954.
OCR for page 155
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS 155
Kanki, P. J., F. Barin, S. M'Boup, J. S. Allen, J. L. Romet-Lemonne, R. Marlink, M. F.
McLane, T.-H. Lee, B. Arbeille, F. Denis, and M. Essex. 1986. New human T-
lymphotropic retrovirus related to simian T-lymphotropic virus type III (STLV-IIIAGM).
Science 232:238-243.
Kanki, P. J., S. M'Boup, D. Ricard, F. Barin, F. Denis, C. Boye, L. Sangare, K. Travers,
M. Albaum, R. Marlink, J.-L. Romet-Lemonne, and M. Essex. 1987. Human T-
lymphotropic virus type 4 and the human immunodeficiency virus in West Africa. Science
236:827-831.
Kao, S.-Y., A. F. Calman, P. A. Luciw, and B. M. Peterlin. 1987. Anti-termination of
transcription within the long terminal repeat of HIV-1 by tat gene product. Nature
330:489-493.
Kennedy, R. 1987. Correspondent paper (untitled). AIDS Activities Oversight Committee,
Washington, D.C.
Klatzmann, D., E. Champagne, S. Chamaret, J. Gruest, D. Guetard, T. Hercend, J.-C.
Gluckman, and L. Montagnier. 1984. T-lymphocyte T4 molecule behaves as the receptor
for human retrovirus LAV. Nature 312:767-768.
Knight, D. M., F. A. Flomerfelt, and J. Ghrayeb. 1987. Expression of the art/trs protein of
HIV and study of its role in viral envelope synthesis. Science 236:837-840.
Koenig, S., H. E. Gendelman, J. M. Orenstein, M. C. Dal Canto, G. H. Pezeshkpour, M.
Yungbluth, F. Janotta, A. Aksamit, M. A. Martin, and A. S. Fauci. 1986. Detection of
AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy.
Science 233:1089-1093.
Koyanagi, Y., S. Miles, R. T. Mitsuyasu, J. E. Merrill, H. V. Vinters, and I. S. Y. Chen.
1987. Dual infection of the central nervous system by AIDS viruses with distinct cellular
tropisms. Science 236:819-822.
Lasky, L. A., G. Nakamura, D. H. Smith, C. Fennie, C. Shimasaki, E. Patzer, P. Berman,
T. Gregory, and D. J. Capon. 1987. Delineation of a region of the human immunodefi-
ciency virus type 1 gpl20 glycoprotein critical for interaction with the CD4 receptor. Cell
50:975-985.
Laurence, J., A. Saunders, and J. Kulkosky. 1987. Characterization and clinical association
of antibody inhibitory to HIV reverse transcriptase activity. Science 235:1501-1504.
Lee, T. H., J. E. Coligan, J. S. Allan, M. F. McLane, J. E. Groopman, and M. Essex. 1985.
A new HTLV-III/LAV protein encoded by a gene found in cytopathic retroviruses.
Science 236:1546-1549.
Letvin, N. L., M. D. Daniel, P. K. Sehgal, J. M. Yetz, K. R. Solomon, M. Kannagh, D. K.
Schmidt, D. P. Silva, L. Montagnier, and R. C. Desrosiers. 1987. Infection of baboons
with human immunodeficiency virus-2 (HIV-2). J. Infect. Dis. 156:406-407.
Lifson, J. D., G. R. Reyes, M. S. McGrath, B. S. Stein, and E. G. Engleman. 1986a. AIDS
retrovirus induced cytopathology: Giant cell formation and involvement of CD4 antigen.
Science 232:1123-1127.
Lifson, J. D., M. B. Feinberg, G. R. Reyes, L. Rabin, B. Banapour, S. Chakrabarti, B.
Moss, F. Wong-Staal, K. S. Steimer, and E. G. Engleman. 1986b. Induction of
CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein. Nature
323:725-728.
Luciw, P. A., C. Cheng-Mayer, and J. A. Levy. 1987. Mutational analysis of the human
immunodeficiency virus: The orf-B region down-regulates virus replication. Proc. Natl.
Acad. Sci. USA 84:1434-1438.
Lyerly, H. K., T. J. Matthews, A. J. Langlois, D. P. Bolgonesi, and K. J. Weinhold. 1987.
Human T-cell lymphotropic virus IIIB glycoprotein (gpl20) bound to CD4 determinants on
normal lymphocytes and expressed by infected cells serves as target for immune attack.
Proc. Natl. Acad. Sci. USA 84:4601-4605.
OCR for page 156
156 CONFRONTING AIDS: UPDATE 1988
Maddon, P. J., A. G. Dalgleish, J. S. McDougal, P. R. Clapham, R. A. Weiss, and R. Axel.
1986. The T4 gene encodes the AIDS virus receptor and is expressed in the immune
system and the brain. Cell 47:333-348.
Matthews, T. J., K. J. Weinhold, H. K. Lyerly, A. J. Langlois, H. Wigzell, and D. P.
Bolognesi. 1987. Interaction between the human T-cell lymphotropic virus type IIIB
envelope glycoprotein gpl20 and the surface antigen CD4: Role of carbohydrate in binding
and cell fusion. Proc. Natl. Acad. Sci. USA 84:5424-5428.
McClure, M. O., M. Marsh, and R. A. Weiss. 1988. Human immunodeficiency virus infection
of CD4-bearing cells occurs by a pH-independent mechanism. EMBO J. 7:513-518.
McCune, J. M., L. B. Rabin, M. B. Feinberg, M. Lieberman, J. C. Kosek, G. R. Reyes, and
I. L. Weissman. 1988. Endoproteolytic cleavage of gpl60 is required for the activation of
human immunodeficiency virus. Cell 53:55-67.
McDougal, J. S. 1987. The immune response to HIV. Correspondent paper. AIDS Activities
Oversight Committee, Washington, D.C.
Moreine, B. 1987. Adjuvants and presentation of antigens. Paper presented at the Institute
of Medicine Conference on the Development of Vaccines Against HIV Infection and
AIDS, Washington, D.C., December 14-15.
Muesing, M. A., D. H. Smith, C. D. Cabradilla, C. V. Benton, L. A. Lasky, and D. J.
Capon. 1985. Nucleic acid structure and expression of the human AIDS/lymphadeno-
pathy retrovirus. Nature 313 :450-458.
Muesing, M. A., D. H. Smith, and D. J. Capon. 1987. Regulation of mRNA accumulation
by a human immunodeficiency virus trans-activator protein. Cell 48:691-701.
Nara, P. 1988. Introductory remarks at the Public Health Service Workshop on AIDS
Vaccines, Bethesda, Maryland, April 25.
Pederson, N. C., E. W. Ho, M. L. Brown, and J. K. Yamamoto. 1987. Isolation of a
T-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome.
Science 235:790-793.
Peterlin, B. M., P. A. Luciw, P. J. Barr, and M. D. Walker. 1986. Elevated levels of mRNA
can account for the trans-activation of human immunodeficiency virus. Proc. Natl. Acad.
Sci. USA 83:9734-9738.
Plata, F., B. Autran, L. P. Martins, S. Wain-Hobson, M. Raphael, C. Mayaud, M. Denis,
J.-M. Guillon, and P. Debre. 1987. AIDS virus-specific cytotoxic T lymphocytes in lung
disorders. Nature 328:348-351.
Ratner, L., W. Haseltine, R. Patarca, K. J. Livak, B. Starcich, S. F. Josephs, E. R. Doran,
J. Antoni Rafalski, E. A. Whitehorn, K. Baumeister, L. Ivanoff, S. R. Petteway, M. L.
Pearson, J. A. Lautenberger, T. S. Papas, J. Ghrayeb, N. T. Chang, R. C. Gallo, and F.
Wong-Staal. 1985. Complete nucleotide sequence of the AIDS virus, HTLV-III. Nature
313:277-284.
Richman, D. D., M. A. Fischl, M. H. Grieco, M. S. Gottlieb, P. A. Volberding, O. L.
Laskin, J. M. Leedom, J. E. Groopman, D. Mildvan, M. S. Hirsch, G. G. Jackson, D. T.
Durack, S. Nusinoff-Lehrman, and the AZT Collaborative Working Group. 1987. The
toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related
complex: A double-blind, placebo-controlled trial. N. Engl. J. Med. 317:192-197.
Robert-Guroff, M., M. Brown, and R. C. Gallo. 1985. HTLV-III-neutralizing antibodies in
patients with AIDS and AIDS-related complex. Nature 316:72-74.
Rosen, C. A., J. G. Sodroski, and W. A. Haseltine. 1985. The location of cis-acting
regulatory sequences in the human T cell lymphotropic virus type III (HTLV-III/LAV)
long terminal repeat. Cell 41:813-823.
Rosen, C. A., J. G. Sodroski, W. C. Goh, A. I. Dayton, J. Lippke, and W. A. Haseltine.
1986. Post-transcriptional regulation accounts for the trans-activation of the human
T-lymphotropic virus type III. Nature 319:555-559.
OCR for page 157
BIOLOGY OF HIV AND BIOMEDICAL RESEARCH NEEDS 157
Rosen, C. A., E. Terwilliger, A. Dayton, J. G. Sodroski, and W. A. Haseltine. 1988
Intragenic cis-acting art gene-responsive sequences of the human immunodeficiency
virus. Proc. Natl. Acad. Sci. USA 85:2071-2075.
Sadaie, M. R., T. Benter, and F. Wong-Staal. 1988. Site-directed mutagenesis of two
trans-regulatory genes (tat-III, trs) of HIV-1. Science 239:910-913.
Salk, J. 1987. Prospects for the control of AIDS by immunizing seropositive individuals.
Nature 327:473-476.
Sanchez-Pescador, R., M. D. Power, P. J. Barr, K. S. Steimer, M. M. Stempien, S. L.
Brown-Shimer, W. W. Gee, A. Renard, A. Randolph, J. A. Levy, D. Dina, and P. A.
Luciw. 1985. Nucleotide sequence and expression of an AIDS-associated retrovirus
(ARV-2). Science 227:484-492.
Sattentau, Q. J., and R. A. Weiss. 1988. The CD4 antigen: Physiological ligand and HIV
receptor. Cell 52:631-633.
Seligmann, M., A. J. Pinching, F. S. Rosen, J. L. Fahey, R. K. Khaitov, D. Klatzmann, S.
Koenig, N. Luo, J. Ngu, G. Rietmuller, and T. J. Spiral 1987. Immunology of human
immunodeficiency virus infection and the acquired immunodeficiency syndrome. Ann.
Intern. Med. 107:234-242.
Shaw, G. M., M. E. Harper, B. H. Hahn, L. G. Epstein, D. C. Gajdusek, R. W. Price, B. A.
Navia, C. K. Petito, C. J. O'Hara, J. E. Groopman, E.-S. Cho, J. M. Oleske, F.
Wong-Staal, and R. C. Gallo. 1985. HTLV-III infection in brains of children and adults
with AIDS encephalopathy. Science 227:177-182.
Shearer, G. 1987. Immune responses to HIV. Correspondent paper. AIDS Activities
Oversight Committee, Washington, D.C.
Smith, D. H., R. A. Byrn, S. A. Marsters, T. Gregory, J. E. Groopman, and D. J. Capon.
1987. Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen.
Science 238:1704-1707.
Sodroski, J. G., C. A. Rosen, and W. A. Haseltine. 1984. Trans-acting transcriptional
activation of the long terminal repeat of human T lymphotropic viruses in infected cells.
Science 225:381-385.
Sodroski, J., W. C. Goh, C. Rosen, K. Campbell, and W. A. Haseltine. 1986a. Role of
HTLV-III/LAV envelope in syncytium formation and cytopathicity. Nature 322:470-474.
Sodroski, J. G., W. C. Goh, C. Rosen, A. Dayton, E. Terwilliger, and W. Haseltine. 1986b.
A second post-transcriptional trans-activator gene required for HTLV-III replication.
Nature 321:412-417.
Somasundaran, M., and H. L. Robinson. 1987. A major mechanism of human immunode-
ficiency virus-induced cell killing does not involve cell fusion. J. Virol. 61:3114-3119.
Sonigo, P., M. Alizon, K. Staskus, D. Klatzmann, S. Cole, O. Danos, E. Retzel, P. Tiollais,
A. Haase, and S. Wain-Hobson. 1985. Nucleotide sequence of the visna lentivirus:
Relationship to the AIDS virus. Cell 42:369-382.
Starcich, B. R., B. H. Hahn, G. M. Shaw, P. D. McNeeley, S. Modrow, H. Wolf, E. S.
Parks, W. P. Parks, S. F. Josephs, R. C. Gallo, and F. Wong-Staal. 1986. Identification
and characterization of conserved and variable regions in the envelope gene of HTLV-
III/LAV, the retrovirus of AIDS. Cell 45:637-648.
Stein, B. S., S. D. Gowda, J. D. Lifson, R. C. Penhallow, K. G. Bensch, and E. G.
Engleman. 1987. pH-Independent HIV entry into CD4-positive T cells via virus envelope
fusion to the plasma membrane. Cell 49:659-668.
Strebel, K., D. Daugherty, K. Clouse, D. Cohen, T. Folks, and M. A. Martin. 1987. The
HIV "A" (sor) gene product is essential for virus infectivity. Nature 328:728-730.
Stricker, R. B., T. M. McHugh, D. J. Moody, W. J. W. Morrow, D. P. Stites, M. A.
Shuman, and J. A. Levy. 1987. An AIDS-related cytotoxic autoantibody reacts with a
specific antigen on stimulated CD4+ T cells. Nature 327:710-713.
OCR for page 158
158 CONFRONTING AIDS: UPDATE 1988
Traunecker, A., W. Luke, and K. Karjalainen. 1988. Soluble CD4 molecules neutralize
human immunodeficiency virus type 1. Nature 331:84-86.
Wain-Hobson, S., P. Sonigo, O. Danos, S. Cole, and M. Alizon. 1985. Nucleotide sequence
of the AIDS virus, LAV. Cell 40:9-17.
Walker, B. D., S. Chakrabarti, B. Moss, T. J. Paradis, T. Flynn, A. G. Durno, R. S.
Blumberg, J. C. Kaplan, M. S. Hirsch, and R. T. Schooley. 1987. HIV-specific cytotoxic
T lymphocytes in seropositive individuals. Nature 328:345-348.
Walker, B. D., C. Flexner, T. J. Paradis, T. C. Fuller, M. S. Hirsch, R. T. Schooley, and
B. Moss. 1988. HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in
infected individuals. Science 240:64-66.
Weber, J. N., P. R. Clapham, R. A. Weiss, D. Parker, C. Roberts, J. Duncan, I. Weller, C.
Came, R. S. Tedder, A. J. Pinching, and R. Cheingsong-Popov. 1987. Human immuno-
deficiency virus infection in two cohorts of homosexual men: Neutralizing sera and
association of anti-gag antibody with prognosis. Lancet 1:119-122.
Weiss, R. A., P. R. Clapham, R. Cheingsong-Popov, A. G. Dalgleish, C. A. Came, I. V. D.
Weller, and R. S. Tedder. 1985. Neutralization of human T-lymphotropic virus type III by
sera of AIDS and AIDS-risk patients. Nature 316:69-72.
Weissman, I. L. 1988. AIDS research funding. Report presented to the President's
Commission on the Human Immunodeficiency Virus Epidemic, New York, February 18.
Wong-Staal, F., P. K. Chanda, and J. Ghrayeb. 1987. Human immunodeficiency virus: The
eighth gene. AIDS Res. Hum. Retrovir. 3:33-39.
Wright, C. M., B. K. Felber, H. Paskalis, and G. N. Pavlakis. 1986. Expression and
characterization of the trans-activator of HTLV-III/LAV virus. Science 234:988-992.
Yarchoan, K., and S. Broder. 1987. Development of antiretroviral therapy for the acquired
immunodeficiency syndrome and related disorders: A progress report. N. Engl. J. Med.
316:557-564.
Yarchoan, K., G. Berg, P. Brouwers, M. A. Fischl, A. R. Spitzer, A. Wichman, J. Grafman,
R. V. Thomas, B. Safai, A. Brunetti, C. F. Perno, P. J. Schmidt, S. M. Larson, C. E.
Myers, and S. Broder. 1987. Response of human-immunodeficiency-virus-associated
neurological disease to 3'-azido-3'-deoxythyminine. Lancet 1:132-135.
Young, F. E. 1987. Treatment use of experimental drugs. Address to the Council on Health
Care Technology, Institute of Medicine, Washington, D.C., March 20.
Zagury, D., J. Bernard, R. Leonard, R. Cheynier, M. Feldman, P. S. Sarin, and R. C. Gallo.
1986. Long-term cultures of HTLV-III-infected cells: A model of cytopathology of T-cell
depletion in AIDS. Science 231:850-853.
Representative terms from entire chapter:
immunodeficiency virus
