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Previous Article | Next Article 
Journal of Virology, December 2000, p. 11972-11976, Vol. 74, No. 24
Department of Cancer Immunology and AIDS,
Dana-Farber Cancer Institute, Harvard Medical
School,1 Department of Immunology and
Infectious Diseases, Harvard School of Public
Health,2 and Perlmutter Laboratory,
Children's Hospital, and Department of Medicine and Pediatrics, Beth
Israel Hospital and Harvard Medical School,4
Boston, Massachusetts 02115; Pharmaceutical Discovery Research
Division, Takeda Chemical Industries, Ltd., Tsukuba, Ibaraki
300-4293, Japan3; Ethiopian Health and
Nutrition Research Institute, Addis Ababa,
Ethiopia5; and Department of Human
Retrovirology, Faculty of Medicine-Academic Medical Centre,
University of Amsterdam, Amsterdam, The
Netherlands6
Received 6 April 2000/Accepted 22 August 2000
In addition to the CCR5 and CXCR4 chemokine receptors, a subset of
primary human immunodeficiency virus type 1 (HIV-1) isolates can also
use the seven-transmembrane-domain receptor APJ as a coreceptor. A
previously identified ligand of APJ, apelin, specifically inhibited the
entry of primary T-tropic and dualtropic HIV-1 isolates from different
clades into cells expressing CD4 and APJ. Analysis of apelin analogues
demonstrated that potent and specific antiviral activity was retained
by a 13-residue, arginine-rich peptide. Antiviral potency was
influenced by the integrity of methionine 75, which contributes to
APJ-binding affinity, and by the retention of apelin residues 63 to 65. These studies demonstrate the ability of a small peptide ligand to
block the function of APJ as an HIV-1 coreceptor, identify apelin
sequences important for the inhibition, and provide new reagents for
the investigation of the significance of APJ to HIV-1 infection and pathogenesis.
Infection of humans with human
immunodeficiency virus type 1 (HIV-1) results in the depletion of host
CD4+ T lymphocytes, culminating in AIDS (3, 9, 21,
23). HIV-1 infection of target cells requires the sequential
binding of envelope glycoproteins to CD4 and a
seven-transmembrane-domain receptor (7TMR). The major 7TMRs utilized by
primary HIV-1 viruses as coreceptors are the chemokine receptors CCR5
and CXCR4 (1, 8, 11, 14, 15, 22). Macrophage-tropic
(M-tropic) or R5 viruses primarily use CCR5 and exhibit a
non-syncytium-inducing (NSI) phenotype (1, 8, 11, 14, 15);
in contrast, T-cell-line-tropic (T-tropic) or X4 viruses use CXCR4 and
exhibit a syncytium-inducing (SI) phenotype in T-cell lines
(22). Dualtropic or R5/X4 viruses can use both CCR5 and
CXCR4. R5 viruses account for most of the cases of horizontal and
vertical transmission and are recovered early in the course of disease.
In subsequent years after infection, both X4 and R5/X4 viruses are
recovered in approximately 50% of HIV-1-infected individuals (6,
10). The emergence of R5/X4 or X4 viruses is usually correlated
with rapid progression to AIDS (6, 10, 29, 39).
All primary HIV-1 strains studied to date use CCR5, CXCR4, or both
molecules as a coreceptor; however, a subset of primary HIV-1 viruses
can use other 7TMRs as alternative coreceptors. Nine alternative
coreceptors have been demonstrated to support HIV-1 infection, albeit
not as efficiently as CCR5 and CXCR4 (4, 5, 12, 13, 17, 32,
35). In certain individuals, disease progression is associated
with expansion of coreceptor usage to alternative coreceptors in vitro
(6, 10, 13, 32). However, the role of alternative
coreceptors in AIDS or other sequelae of HIV-1 infection is unknown.
Alternative coreceptors could potentially play an important role in
HIV-1 pathogenesis, depending on their level of expression and tissue
distribution, as well as how broadly and efficiently they support viral
entry. For example, the alternative coreceptor CCR3 is postulated to
play a role in central nervous system (CNS) infection in patients with
HIV-1-induced dementia. CCR3 is expressed in the microglia, which are
the major target cells of HIV-1 in the CNS, and can facilitate HIV-1
infection of these cells (26).
The alternative coreceptor APJ might also play a role in HIV-1
neuropathogenesis. APJ, a homologue of the angiotensin receptor, is a
7TMR widely expressed in the brain (33, 34). APJ mRNA was
detected in glial cells, astrocytes, and neuronal subpopulations, as
well as in activated peripheral blood mononuclear cells (PBMC), the
spleen, and the thymus (7, 17, 33, 36). APJ is used efficiently by several primary R5, X4, and dualtropic (R5/X4) HIV-1 and
simian immunodeficiency viruses (7, 17, 40, 43). Some
brain-derived viruses have also been reported to use APJ as a
coreceptor (1, 38). Taken together, these observations suggest that APJ might contribute to HIV-1 pathogenesis, especially in
the development of CNS disease. In addition, its frequent use by
dualtropic HIV-1 isolates and its sequence similarity to both CCR5 and
CXCR4 raise the possibility that APJ might facilitate the adaptation of
R5 viruses to CXCR4 (7, 18).
The identification of specific inhibitors of APJ-mediated HIV-1 entry
would greatly assist efforts to understand the in vivo role of APJ. A
novel technique was employed to isolate apelin, the ligand of the human
APJ receptor, from bovine stomach tissue extracts (28, 41).
Northern and in situ hybridization analyses revealed coexpression of
human and rat apelin and APJ in the brain (30). Apelin was
also detected in a variety of tissues, including the mammary gland, and
in colostrum and breast milk (25, 30). The human and bovine
apelin cDNA encodes a preprotein consisting of 77 amino acids (Fig.
1). Amino acid sequence analysis showed that the sequence of the apelin peptide extracted from bovine stomach
tissue was encoded in the C-terminal region of the preprotein. Based on
this observation, a 36-amino-acid apelin peptide (apelin-36), which
includes most of the C-terminal portion, was predicted to comprise the
mature form. When synthesized, apelin-36, as well as some shorter
derivatives, promoted extracellular acidification in Chinese hamster
ovary (CHO) cells expressing the APJ receptor but not in parental CHO
cells, suggesting that apelin is an endogenous ligand for APJ
(41).
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Apelin, the Natural Ligand of the Orphan Seven-Transmembrane
Receptor APJ, Inhibits Human Immunodeficiency Virus Type 1 Entry
ABSTRACT
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FIG. 1.
Amino acid sequence of human preproapelin and the
synthetic apelins. The arrowhead indicates the predicted cleavage site
of a putative signal peptide. [<Glu65]apelin-13,
apelin-15, apelin-36 were synthesized using an automatic peptide
synthesizer (model 430; PE Biosystems) as described previously
(41).
The elucidation of the biologic role of CCR5 and CXCR4, as well as their role as major coreceptors of HIV-1, was aided by the identification of their natural ligands. With the discovery of apelin as the natural ligand of the HIV-1 coreceptor APJ, we can now study the biologic role of APJ, as well as its role in mediating HIV-1 infection. In the work reported here, we investigate whether apelin can inhibit the entry of primary HIV-1 viruses mediated by the APJ coreceptor. We also study the structural features of apelin analogues that contribute to anti-HIV-1 activity.
To test the anti-HIV-1 activity of apelin, we used an env-complementation assay, in which HIV-1 envelope glycoproteins expressed in trans complement a single round of replication of an env-deleted provirus expressing the chloramphenicol acetyltransferase (CAT) gene (8, 27). We generated recombinant viruses by pseudotyping HIV-1 expressing the CAT reporter gene with the envelope glycoproteins of the primary R5/X4 HIV-1 clade B isolate, 89.6. The HIV-1 isolate 89.6 was used because it was previously shown to use APJ, in addition to CCR2b, CCR3, CCR5, and CXCR4, as a coreceptor (7, 8, 14). As target cells, we used the canine thymocyte cell line, Cf2Th, which is not susceptible to HIV-1 infection unless transfected with plasmids expressing human CD4 and chemokine receptors specific for particular viral strains (8). Previously, we showed that Cf2Th cells expressing both human CD4 and human APJ allowed entry of recombinant viruses expressing envelope glycoproteins from the 89.6 strain and from several other primary HIV-1 isolates (7). Prior to infection, synthetic apelins (Fig. 1) shown previously to induce acidification of APJ-expressing cells (41) were added to CD4+ Cf2Th target cells expressing APJ. The efficiency of infection was determined by measuring the CAT activity in the target cells 3 days after infection.
The results in Fig. 2 show that two of
the synthetic apelins, apelin-15 and apelin-36, but not
[<Glu65]apelin-13, inhibited entry of the primary R5/X4
89.6 recombinant virus in a dose-dependent manner. Apelin-36 (50%
inhibitory concentration [IC50] = 7 µM) was a more
potent inhibitor of HIV-1 entry than apelin-15 (IC50 = 12 µM) (Fig. 2A). [<Glu65]apelin-13 did not inhibit
HIV-1 entry, even though this peptide, like apelin-15 and apelin-36, is
potent in inducing extracellular acidification in APJ-expressing CHO
cells (41). The data shown in Fig. 2A suggest that the basic
amino acid stretch (R63R64Q65) in the N-terminal end of apelin-15 is
critical for inhibiting HIV-1 entry.
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To examine the specificity of the anti-HIV-1 activity of the apelins, we tested the ability of the apelins to inhibit the infection of cells expressing other HIV-1 coreceptors such as CCR3, CCR5, and CXCR4. Both apelin-15 and apelin-36, when used at concentrations of 35 and 20 µM, respectively, dramatically inhibited the infection of APJ-expressing cells by the 89.6 HIV-1 recombinant virus (Fig. 2B). The same concentrations of apelins did not significantly inhibit the entry of the 89.6 HIV-1 recombinant virus into CD4+ Cf2Th-expressing CCR3, CCR5, or CXCR4. No infection was detected in the control Cf2Th cells expressing CD4 alone (Fig. 2B). These results suggest that apelin-15 and apelin-36 specifically inhibit HIV-1 entry that requires APJ as a coreceptor.
It is possible that the observed inhibition of HIV-1 entry by the
apelins might be strain or clade specific. To address this issue, we
examined the ability of apelin-15 and apelin-36 to inhibit other
primary HIV-1 strains and clades. We generated recombinant HIV-1
viruses containing the envelope glycoproteins of ELI (an X4, clade B
primary HIV-1 isolate), CF402.1 (an X4, clade E primary HIV-1 isolate),
and MCGP1 (an R5/X4, clade C primary HIV-1 isolate). The clade E
env clone, CF402.1, was kindly provided by Feng Gao and
Beatrice Hahn (24). MCGP1 env was cloned from a provirus isolated from the PBMC of an Ethiopian patient. Phylogenetic tree analysis of the env sequence classified MCGP1 as an HIV-1
clade C virus (unpublished data). These viruses utilize APJ, in
addition to CCR3, CXCR4, and/or CCR5 (reference 7
and unpublished data). Figure 3B shows
that apelin-15 and apelin-36 significantly abrogated APJ coreceptor
usage by all three viruses. The inhibition by both apelins is specific
for the APJ coreceptor in that usage of CCR3 by these viruses was not
significantly affected by either apelin (Fig. 3C). Although in some
experiments apelin-36 slightly inhibited the infection of
CCR3-expressing cells by viruses with the ELI envelope glycoproteins,
this effect was not consistently observed. Thus, apelin-15 and
apelin-36 specifically inhibit infection of APJ-expressing cells by a
diverse group of primary HIV-1 viruses.
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To investigate the structural requirements for the anti-HIV-1 activity
of apelin, the abilities of a group of apelin analogues to inhibit the
infection of CD4+ APJ+ cells by a recombinant
HIV-1 containing the 89.6 envelope glycoproteins were determined (Table
1). Apelin-19, which includes the
carboxy-terminal 19 residues of apelin, was as potent as apelin-36 in
this assay. Consistent with the results described above, apelin-15
exhibited weaker antiviral activity than the longer apelin variants.
However, apelin-15-(63-75)-peptide was as potent as apelin-36 and
apelin-19 in this assay. This result indicates that the simultaneous
removal of apelin residues 59 to 62 and 76 to 77 is less detrimental to the anti-HIV-1 activity than the removal of residues 59 to 62 only. The
integrity of the methionine residue at position 75 is important for
antiviral potency, as indicated by the relative potencies of
apelin-15-(63-75)-peptide, apelin-15-(63-74)-peptide, and
[Met(O)75]apelin-15-(63-74)-peptide. In the latter two
analogues, the terminal methionine at position 75 is, respectively,
deleted or oxidized.
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In a separate study, the affinity of these apelin analogues for the APJ receptor was determined. All of the analogues bound APJ at least as well as apelin-36, indicating that binding to the APJ protein is not sufficient for potent antiviral activity. In addition, no correlation was evident between the anti-HIV-1 activity of the apelin analogues and the ability to affect cyclic AMP levels in APJ-expressing cells (data not shown).
All of the apelin derivatives used in this study have been shown to interact with the APJ protein and to promote extracellular acidification in APJ-expressing CHO cells (41). Two of the apelins, apelin-15 and apelin-36, inhibited infection of cells expressing CD4 and APJ by viruses pseudotyped with envelope glycoproteins from several different primary HIV-1 isolates. The observed inhibition is specific because infection of target cells expressing CD4 and other HIV-1 coreceptors was not significantly affected by either apelin-15 or apelin-36.
Surprisingly, a 13-residue analogue, apelin-15-(63-75)-peptide retained the potent anti-HIV-1 activity of significantly longer apelin variants, such as apelin-36. The simultaneous deletion of both the amino and the carboxyl termini of apelin contributed to this retention of potent activity. Further deletion, however, affecting residues 63 to 65 or methionine 75 resulted in significant decreases in anti-HIV-1 activity. The detrimental effects of deletion of the arginine residues at positions 63 and 64 suggest that particular arginine residues in the peptide may be important for the specific ability to block HIV-1 entry via the APJ coreceptor. It is possible that some of these arginines interact with the acidic, sulfotyrosine-containing amino-terminal segment of APJ (20). The analogous region on CCR5 has been shown to be important in HIV-1 entry (16, 19, 20).
The identification of specific APJ ligands that inhibit HIV-1 infection allows further exploration of the role of the APJ receptor in HIV-1 pathogenesis. This role is presently unclear, although the expression of APJ in the CNS raises the possibility that this protein might contribute to AIDS dementia. APJ is not expressed in microglia, the major target for HIV-1 infection in the CNS. However, APJ is expressed in astrocytes and neurons, two cell types that demonstrate apoptotic changes in autopsied brain specimens from children and adults with AIDS (37, 42). CNS injury in HIV-1-infected individuals is believed to occur through indirect mechanisms, which might include envelope glycoprotein-APJ interactions. These possibilities warrant further investigation.
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ACKNOWLEDGMENTS |
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We thank Paul Gorry and Dana Gabuzda for helpful discussion and Yvette McLaughlin for manuscript preparation. We also thank Feng Gao and Beatrice Hahn (University of Alabama) for providing the CF402.1 env clone.
M.C. is a recipient of a Ford Foundation Fellowship and is an Albert J. Ryan Fellow. This work was supported by the National Institute of Health (AI24755 and AI41851), the G. Harold and Leila Y. Mathers Foundation, the Friends 10, the late William McCarty-Cooper, and Douglas and Judi Krupp. We also thank the Ethio-Netherlands AIDS Research Programme (ENARP), which is supported by The Netherlands Ministry of Foreign Affairs and the Ethiopian Ministry of Health.
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FOOTNOTES |
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* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney St.-JFB 824, Boston, MA 02115. Phone: (617) 632-3371. Fax: (617) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu.
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), apelin-15 (
), or apelin-36
(
) at the indicated concentrations for 1 h prior to incubation
with recombinant HIV-1 containing the envelope glycoproteins of the
primary R5/X4 89.6 HIV-1 clade B isolate. The recombinant virus
containing the CAT reporter was produced by cotransfection of the
pSVIIIenv plasmid expressing the envelope glycoproteins of interest
with the pHXBH10
envCAT plasmid into 293T cells. Approximately 40,000 cpm of the reverse transcriptase (RT) activity of the recombinant virus
was used to infect the target cells. The CAT activity, calculated as a
percentage conversion of chloramphenicol to acetylated forms in target
cell lysates, is shown. All values have been normalized to a given
amount of lysate. The results shown are representative of two
independent experiments. (B) Apelin preferentially inhibits HIV-1 entry
mediated by APJ. Cf2Th-CD4 cells transfected with plasmids expressing
CCR3, CCR5, CXCR4 or APJ were mock treated (
) or 20 µM apelin-36 (
) for 1 h
prior to addition of 40,000 cpm (RT activity) of recombinant HIV-1
virus containing envelope glycoproteins of the primary R5/X4 89.6 HIV-1
clade B isolate. The CAT activity is indicated as the percent
conversion of chloramphenicol to acetylated forms for a given amount of
lysate. The figure shown is representative of two independent
experiments.
