(Journal of Leukocyte Biology. 2000;68:311-317.)
© 2000
by Society for Leukocyte Biology
The level of HIV infection of macrophages is determined by interaction of viral and host cell genotypes
A. L. Cunningham,
S Li,
J Juarez,
G Lynch,
M. Alali and
H. Naif
Centre for Virus Research, The Westmead Millennium Institute, University of Sydney, and The Australian National Centre for HIV Research, Sydney, Australia
Correspondence: Anthony L. Cunningham, The Westmead Millennium Institute, P.O. Box 412, Westmead NSW 2145, Sydney, Australia. E-mail: tony_cunningham{at}wmi.usyd.edu.au
 |
ABSTRACT
|
|---|
The outcome of HIV infection in vivo and in
vitro depends on the interaction of viral and cellular genotypes.
Analysis of infection of blood monocyte-derived macrophages by primary
HIV strains shows that approximately one-third of 32 isolates was
consistently high-replicating, one-third was consistently
low-replicating, and one-third was dependent on the donor of the
macrophages (i.e., variable). HIV isolates from patients with AIDS
showed enhanced replication within macrophages and predominant use of
CCR5 for entry, although 13% did use CXCR4. Tissue isolates from brain
and CSF showed an enhanced ability to infect 1-day-old monocytes
compared with blood isolates from patients with AIDS. The ability of
primary isolates to infect neonatal or adult monocytes maturing into
macrophages or placental macrophages correlated directly with the
extent of CCR5 expression. Studies of macrophages from pairs of
identical twins and unrelated donors showed genetic control over CCR5
expression, which was independent of the CCR5
32 genotype.
Furthermore, these studies showed a marked host-cell genetic effect on
the variable primary HIV strains. Although CCR5 was essential for the
entry of most primary isolates, it was not the essential
"bottleneck" determining productivity of infection. The location of
this bottleneck in the HIV replication cycle differs according to viral
strain and host-cell donor, but it was exerted before the stage of
reverse transcription in 80–90% of cases. Such host-cell genetic
factors may affect viral load in vivo where macrophages are
the predominant target cells.
Key Words: genetics • twins • monocytes
|
INTRODUCTION
|
|---|
Human immunodeficiency virus (HIV) infection of any cell type
results in a series of viral- and host-cell protein interactions as the
virus proceeds through its replication cycle. These interactions will
differ according to host and viral genotype (Fig. 1
).
View larger version (25K):
[in this window]
[in a new window]
|
Figure 1. Effect of genetics of cell donor on HIV infection of macrophages.
"Bottlenecks" may occur at different places in different cells with
the same HIV strain. RT, Reverse transcription.
|
|
Furthermore, the process of infection, commencing with envelope
protein-CD4/chemokine-receptor interactions, also induces activation of
various cell pathways, leading to endogenous host-cell, protein-protein
interactions and secretion of cytokines or chemokines resulting in
exogenous effects, which, in turn, affect viral-cell protein
interactions. The complexity of the host-cell effects on HIV
replication makes them difficult to study unless individual viral
effects dominate, resulting in consistent interactions with the cells
of individual donors (Fig. 2
).
View larger version (28K):
[in this window]
[in a new window]
|
Figure 2. Differences in sequences of HIV proteins [1
,
2
] or macrophage [1
2
3
] proteins (A), or
differences in macrophage protein-protein interactions (B) may result
in differences in binding of HIV to macrophage proteins and thus
influence the replicative cycle.
|
|
HIV tropism for, and the level of, productive infection in T
lymphocytes and macrophages is determined by these processes.
|
BIOLOGICAL EFFECTS OF VIRAL GENOTYPES
|
|---|
The investigation of biological effects of HIV is complicated by
its ability to generate variants resulting in quasispecies in
vivo and in vitro (as "isolates") and also by
differences in composition of the quasispecies between anatomical
sites, between different infected cell types, and after isolation in
different patients’ cells [3
]. Interactions such as
coninfections, complementation, and recombination may occur.
Heterogeneity could be reduced by studying infectious molecular clones,
but such studies would need to be very comprehensive; otherwise, they
would be too selective and would not allow for the interactive effects.
Practically, very low passage isolates in pooled donor cells are best
used for biological studies, because they allow a reasonable
approximation to the blood quasispecies in vivo.
In our studies of HIV infection of macrophages by primary chemokine
receptor 5 (CCR5)-utilizing HIV (R5) macrophage (M)-tropic strains,
unpassaged after initial isolation in pooled mononuclear cells, 
65%
of such strains were observed to be consistently high- or
low-replicating in any donor macrophage, but 35% replicated to a
markedly different degree in macrophages from different donors
(Tables 1
and 2
). The consistently
low-replicating isolates (extracellular p24 antigen <500 pg/ml) were
examined for the stage of restriction. In blood monocyte-derived
macrophages (MDMs), this occurred mainly prereverse transcription (low
or absent viral DNA levels <100 copies/105 cells),
presumably at viral entry/uncoating, and less frequently, post-reverse
transcription (moderate–high viral DNA, low or absent extracellular
p24 antigen) [1
, 2
].
View this table:
[in this window]
[in a new window]
|
Table 2. Classification of the Ability of R5 Primary HIV Strains to Productively Infect Macrophages from Different Donors
|
|
In a cross-sectional study of primary HIV isolates from patients at
different stages of HIV disease, these low-replicating R5 isolates were
mainly from patients at an early or asymptomatic stage without marked
depression of blood-CD4 concentrations. Most isolates from patients
with AIDS appeared to have evolved in vivo to a predominant
genotype, which was unrestricted at any stage in the replication cycle
and produced moderate-to-high levels of productive infection in
macrophages. These isolates showed greater diversity in the envelope
gene by heteroduplex mobility shift assay (HMA) than isolates from
early stages. Although there was a significant correlation between
stage of disease and this envelope-gene diversity or productivity of
macrophage infection, the correlation between the latter two showed
only a nonsignificant trend [2
]. Presumably the
"noise" of enhanced diversity in late-stage disease obscured the
specific changes in envelope and other genes responsible for enhanced
replication.
In late-stage disease, HIV isolates show broadened coreceptor usage,
mainly of CXCR4 [2
, 4
, 5
].
Higher levels than the observed 13% of isolates might be expected
because of the frequency of envelope-gene mutations, the selective
inhibition of high ß-chemokine concentrations on R5 strains, and the
reduced immune surveillance in late-stage disease and the higher
intrinsic replication rate and cytopathic effect of CXCR4-utilizng HIV
(X4) isolate for T lymphocytes in late-stage disease
[1
]. This strongly suggests that there are opposing
selective forces favoring entry of HIV into T lymphocytes and
macrophages via CCR5 at all stages of disease. Furthermore, X4
envelopes are able to induce T lymphocyte activation or apoptosis,
which would have opposing effects with an unpredictable net outcome on
X4 strain replication [6
]. In our studies, several
isolates were able to utilize CXCR4 to enter macrophages and replicate
productively also [2
]. The ability of these X4 strains
to induce apoptosis or cell signaling in macrophages needs to be
clarified.
The V3 and/or V1-V2 regions of gp120 interact with CCR5 or CXCR4 and
therefore are responsible for tropism and entry into macrophages and T
lymphocytes [7
]. As perhaps expected from isolates
obtained by mononuclear cell coculture, the strains "replicating at
low levels in macrophages" from asymptomatic patients still
replicated well in T lymphocytes. No consistent V1-V2 or V3 sequence
motifs or phylogenetic clustering were observed in the low- or
high-replicating isolates. The envelope sequences of isolates pre- and
post-passage in macrophages and T lymphocytes were also compared. The
sequences differed by several nucleotide substitutions after a single
passage in macrophages vs. T lymphocytes [1
].
Most studies of primary HIV strains have used blood isolates.
Therefore, it was interesting to determine whether there were any
biological differences between blood isolates from advanced stages of
disease, when blood CD4 lymphocytes were depleted, and tissue isolates
from brain, cerebrospinal fluid, lung, and spleen. There was little
difference between the ability of these primary blood and tissue
strains to replicate in MDM. All used CCR5 for entry. However, tissue
strains showed much greater ability to productively infect monocytes
than blood strains, similar to M-tropic laboratory-adapted strains such
as BaL, which indeed are derived from tissue (see next section). The
tissue isolates also showed greater envelope-gene diversity by HMA than
late-stage blood isolates. Because most of the tissue isolates were
derived from brain or colony-stimulating factor (CSF), these data
suggest biological differences from M-tropic strains retained within
these tissues compared with those released into blood, probably mostly
from lymph nodes, even in late-stage disease. This biological
"compartmentalization" is similar to the genetic
compartmentalization demonstrated in brain by several groups including
our own [8
].
|
HOST MACROPHAGE EFFECTS
|
|---|
Relatively few host-cell proteins have been defined that are
critical for infection with all HIV strains. These include
the binding receptor, CD4, the chemokine (co) receptors, the 
and
ß importins, and cyclin T1, which interacts with Tat
[9
10
11
]. Monocytes and macrophages express a variety of
chemokine receptors documented to allow fusion of HIV envelopes or
entry into transfected cells (such as Hos. CD4). These include
CCR2b, CCR3, CCR5, CCR8, CXCR4, BONZO/STRL33, and Bob/GPR15
[12
13
14
]. Many studies, especially those in patients who
lack CCR5 expression (CCR532 homozygotes), have demonstrated now
that only CCR5 of these potential coreceptors and, to a lesser degree,
CXCR4 are important for HIV entry into blood-derived and most tissue
macrophages. CCR3 may also be important for entry of some HIV strains
into brain microglial cells and neonatal macrophages
[15
].
The differentiation of blood monocytes to macrophages was accompanied
by the appearance and upregulation of expression of the HIV coreceptor,
CCR5, an initial decrease and then slow increase in CD4 expression, and
coincident partial and variable downregulation of CXCR4 and CCR2b
expression [16
, 17
]. In neonatal monocytes,
CCR5 expression appeared more slowly during macrophage maturation.
However, mature, differentiated, placental macrophages expressed
negligible levels of CCR5 at the cell surface (despite expression of
moderate levels of CCR5 RNA) [18
]. The ability of R5
primary isolates to infect differentiating neonatal or adult monocytes
correlated closely with CCR5 expression and these isolates were unable
to infect placental macrophages [16
, 18
].
Conversely, at similar multiplicity of infection (MOI),
laboratory-adapted (LA) strains such as BaL were able to infect
monocytes consistently and at early stages of maturation and could even
infect placental macrophages, because they were able to utilize lower
levels of CD4 and CCR5 than primary strains. Tissue R5 isolates, but
not blood R5 isolates, even from patients with terminal AIDS were able
to infect monocytes with similar ability (see above) [18
,
19
].
However, 1-day-old monocytes demonstrated other pre- and also
post-reverse transcription (RT) blocks to infection more often than in
mature macrophages (30% vs. 10% of donors, respectively, for post-RT
blocks). With advancing maturation, monocytes become more permissive to
HIV infection at most stages of the replication cycle
[16
, 18
].
The level of surface-CCR5 expression varied between macrophages and T
lymphocytes of different donors [1
, 20
].
Studies with identical twins, compared with pairs of unrelated donors,
showed a highly significant correlation of these levels within twin
pairs only, indicating genetic control of expression (Fig. 3
). This was independent of the heterozygous state for the CCR532
deletion. Heterozygotes showed a lower median level of expression, but
the range was wide (18–32%) and overlapped with the similar wide
range of expression in those with the wild-type gene (<1–67%).
View larger version (12K):
[in this window]
[in a new window]
|
Figure 3. This scattergram shows the correlation of the proportions of 3-day-old
macrophages expressing CCR5 within unrelated donor pairs (A) and within
identical twin pairs (B). There was a significant correlation only
between identical twin pairs (r=0.81, p<0.01).
Membrane CCR5 expression by macrophages was examined by staining with
anti-CCR5 monoclonal antibody (2D7) and flow cytometry (from ref. 1
).
|
|
A series of mutations have been described in the promoter region of
CCR5 (P1–P6), and the PI mutation was associated with accelerated
progression of disease [21
]. However, no correlation
between any of these mutations and the level of CCR5 expression on CD4
lymphocyte has been demonstrated [21
, 22
].
Thus, the precise nature of genetic control over cellular CCR5
expression, whether in macrophages or T lymphocytes, remains unclear.
The role of CXCR4 as a coreceptor for entry of X4-HIV strains into
macrophages via CXCR4 is being clarified (see Collman, JLB,
this issue). Several groups, including our own, showed that primary,
but not laboratory-adapted, X4-HIV strains could infect macrophages
[2
, 23
24
25
].
These studies refine the earlier observations that primary- or
laboratory-adapted strains, which induce syncytia in T cell lines
[syncytium-inducing (or SI) isolates], are usually unable to infect
macrophages [26
]. The key question is why
laboratory-adapted X4 strains potently infect T cells but not
macrophages when both express CXCR4. Furthermore, why can many primary
but not LA X4 strains infect macrophages? The answer may be because of
the quaternary structure of CXCR4 on macrophages compared with T
lymphocytes or differences in its interactions with CD4. CXCR4 has been
shown to exist as two forms, a 55-kDa monomer and 90-kDa oligomer, in
macrophages and as a 47-kDa monomer in T lymphocytes
[27
]. Binding of CD4 is stronger to CCR5 than CXCR4
[28
, 29
]. Membrane CD4 has been shown to
exist partially as a dimer on lymphoid and monocytoid cells also. Some
cell activators, such as phorbol 12-myristate 13-acetate (PMA) enhance
dimerization [30
, 31
]. CD4 in T lymphocytes
interacts with lck, but the interacting partner(s) in macrophages are
unknown and could alter quaternary structure. Furthermore, the
importance of the quaternary structure of CD4, CCR5, and CXCR4 and
their interactions in modulating HIV entry is likely but not yet
established.
|
HOST MACROPHAGE-VIRUS INTERACTIONS
|
|---|
Infection of the same cell type from different human donors by the
same HIV isolate may not result in similar levels of replication
necessarily. Indeed, variability of replication of any given HIV strain
in T lymphocytes or macrophages from different donors has been well
known for many years [32
33
34
35
]. As mentioned above, the
best-defined, host-genetic effect is the CCR532 homozygous state,
which results in complete absence of CCR5 at the surface of T
lymphocytes and macrophages, resulting in refractoriness to infection
by R5-HIV strains [36
37
38
]. However, our twin studies
have demonstrated more subtle host-genetic effects. For example, two
HIV strains may behave in opposite ways in macrophages from two
different unrelated donors (Fig. 1) . Strain 1 may be high-replicating
in donor A’s macrophages but low-replicating in donor B’s
macrophages. The converse may occur with another HIV strain. This was
apparent when macrophages from 10 pairs of unrelated donors were
infected with primary HIV strains (variable strains; see Table 1
in Fig. 4
) [1
]. However, within eight twin pairs, the
kinetics and level of productive infection were very similar (Fig. 4)
.
The patterns in nonidentical twins were similar or dissimilar but, on
average, were intermediate in their differences between identical twins
and unrelated donors. This indicates a complex polygenic host-cell
effect on HIV replication, reflecting the many proteins involved in the
various stages of HIV replication [1
].
View larger version (16K):
[in this window]
[in a new window]
|
Figure 4. This scattergram shows the correlation between levels of HIV
replication in 3-day-old macrophages within identical twin pairs (twin
1 vs. twin 2) measured as intracellular HIV DNA by semiquantitative PCR
(a total of 24 donor macrophage HIV combinations). HIV DNA levels in
105 macrophages were classified as 0 (undetectable), + (low
copy number <102), ++ (intermediate copy number
102–103), +++ (high copy number
>103). There was a high concordance (r=0.96,
P=0.0001). (B) Correlation between levels of HIV replication
within unrelated donor pairs (URD1 vs. URD2) measured as intracellular
DNA (a total of 35 host MDM-HIV combinations). There was a very low
concordance (r=0.11, P=0.3; from ref. 1
).
|
|
The predominant stage of these host-cell genetic effects was then
dissected by quantifying the early and late products of RT (HIV DNA)
using different sets of primers and the extracellular p24 antigen
levels and comparing these with the level of CCR5 expression on these
cells. The main host-cell genetic effect was exerted prereverse
transcription in 90% of cases. However, this pre-RT restriction did
not correlate with the level of CCR5 expression on the surface of
macrophages. Indeed, CCR5 was found to be a restricting factor for HIV
entry only at a very low level (as also found with maturing monocytes;
Fig. 5
). This strongly suggests that there are other stage(s) in viral
entry or uncoating that occur prior to RT, which may act as bottlenecks
beyond binding to the chemokine receptor. Efforts are now being made to
identify these stages via a gene-screening approach [1
].
View larger version (14K):
[in this window]
[in a new window]
|
Figure 5. Correlation between the proportions of 3-day-old macrophages expressing
CCCR5 and HIV-DNA levels (measured as for Fig. 4
) in macrophages
infected with HIV for 7 days. Note that in general, there is no
correlation between CCR5 and HIV-DNA levels and that only very low
levels of CCR5 expression (<1%) affect HIV-DNA levels.
|
|
The selective effect of the various bottlenecks or critical
protein-protein interactions at the various stages pre- or post-RT is
also shown by the selective effect on the predominant strains emerging
from the infected macrophages. Interestingly, if the same strain were
used to infect the macrophages or two pairs of identical twins and two
pairs of unrelated donors, the envelope sequences of the predominant
HIV strains emerging from these macrophages were found to show less
variation within the pairs of identical twins than between the pairs of
unrelated donors. This indicated the similarity of the selective
mechanisms within the macrophages of identical twins. These effects
were surprisingly strong given the inherent biological variability of
culturing cells, indicating the importance of certain key
protein-protein interactions at critical stages in the
virus-replication cycle. It is likely that there are different
bottlenecks—i.e., different proteins at the same or different stages
exerting effects on the various HIV strains depending on the nature of
the protein-protein interactions and therefore on the sequence of
host-cell proteins and of viral proteins (Figs. 1
and 2)
. Nevertheless,
it is important to note that the predominant restrictive effects were
defined as those occurring between viral entry and RT.
|
CONCLUSIONS
|
|---|
The capacity of primary strains to infect macrophages in
vitro was determined by the following: 1) state of maturation of
the monocytes/macrophages (The host genetic effect is more pronounced
at earlier stages of maturation, especially days 1 and 2.); 2) the
stage of HIV disease at which the primary isolate has harvested (At
later stages of disease, where there is a greater diversity of the
quasispecies within primary isolates, there is a greater ability to
produce higher levels of productive infection.); 3) viral genotype; and
4) host-cell genotype.
Overall, taking a random group of HIV isolates, the viral genotype was
dominant in two-thirds, and the host-genetic effect was prominent in
one-third of isolates; macrophages were infected after three days of
maturation. However, the importance of the genetic effect was further
enhanced when isolates were obtained from nonimmunosuppressed patients
and tested in 1-day-old monocytes [39
].
|
IMPLICATIONS
|
|---|
These data suggest that inhibitors acting at these critical stages
might be found and could contribute to new strategies for antiviral
therapy, at least in macrophages. They could be synergistic with
chemokine-receptor inhibitors. This type of work needs to be expanded
to determine whether such critical bottlenecks occur during HIV
replication in CD4 lymphocytes [34
]. Our experience so
far suggests that these will be more difficult to define.
An example of the importance of these bottlenecks is shown by the very
low expression of CCR5 on placental macrophages and the inability of
over 20 primary R5 strains to infect them. This provides one layer of
protection of the fetal circulation from maternal blood-borne HIV
infection.
These studies also suggest that genetic factors other than those
affecting immune control of HIV infection and CCR5 might have a
critical role in controlling the productivity of HIV from macrophages
and therefore influence the viral load in vivo in certain
tissues [40
]. These include the late stages of disease
in lymph nodes where CD4 lymphocytes have been depleted, but
macrophages are still plentiful, and in brain and bone marrow where
microglial cells and macrophages, respectively, are the predominant
targets for infection [40
41
42
]. Evolution (and usually
increasing diversity) of the HIV quasispecies toward enhanced tropism
and productivity in macrophages in the late stages of disease probably
contributes to enhanced total-body viral load. Exogenous factors,
including stimulatory cytokines (e.g., TNF-) and chemokines
[43
, 44
], or the products of opportunistic
infections, including lipoarabinomannan [41
,
45
] present in the late stages of HIV disease, can alter
the intracellular environment of macrophages and relieve the
bottlenecks to enhance productive HIV infection by macrophages. Foci of
such HIV-producing macrophages have been demonstrated in lymph nodes,
and macrophage-derived HIV was demonstrated in the plasma of patients
with active tuberculosis in vivo [41
,
45
]. Hence, the role of macrophage production of HIV
in vivo in the late stages of HIV disease should be more
precisely quantified in a larger patient sample.
|
ACKNOWLEDGEMENTS
|
|---|
This work was supported by the Australian National Council on AIDS
and Related Diseases. Ms. Claire Wolczak typed the manuscript.
|
REFERENCES
|
|---|
-
Naif, H. M., Li, S., Alali, M., Chang, J., Mayne, C., Sullivan, J., Cunningham, A. L. (1999) Definition of the stage of host cell genetic restriction of replication of human immunodeficiency virus type 1 in monocytes and monocyte-derived macrophages using twins J. Virol. 73,4866-4881[Abstract/Free Full Text]
-
Li, S., Juarez, J., Alali, M., Dwyer, D., Collman, R., Cunningham, A. L., Naif, H. M. (1999) Persistent CCR5 utilisation and enhanced macrophage tropism by primary blood human immunodeficiency virus type 1 isolates from advanced stages of disease and comparison to tissue-derived isolates J. Virol. 73,9741-9755[Abstract/Free Full Text]
-
Wain-Hobson, S. (1992) Human immunodefiency virus type 1 quasispecies in vivo and ex vivo Curr. Top. Microbiol. Immunol. 176,181-193[Medline]
-
Connor, R. I., Sheridan, K. E., Ceradini, D., Choe, S., Landau, N. R. (1997) Change in coreceptor use correlates with disease progression in HIV-1-infected individuals J. Exp. Med. 185,621-628[Abstract/Free Full Text]
-
Scarlatti, G., Tresold, E., Bjorndal, S., Fredriksson, R., Colognesi, C., Deng, H. K., Malnati, M. S., Plebani, A., Siccardi, A. G., Littman, D. R., Fenyo, E. M. (1997) In vivo evolution of HIV-1 coreceptor usage and sensitivity to chemokine-mediated suppression Nat. Med. 3,1259-1265[Medline]
-
Glushakova, S., Yi, Y., Grivel, J. C., Singh, A., Schols, D., De Clerq, E., Collman, R. G., Margolis, L. (1999) Preferential coreceptors utilization and cytopathicity by dual-tropic HIV-1 in human lymphoid tissue ex vivo J. Clin. Invest. 104,R7-R11[Medline]
-
Hwang, S. S., Boyle, T. J., Lyerly, H. K., Cullen, B. R. (1991) Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1 Science (Wash. DC) 253,71-73[Abstract/Free Full Text]
-
Chang, J., Jozwiak, R., Wang, B., Ng, T., Ge, Y. C., Bolton, W., Dwyer, D. E., Randle, C., Osborn, R., Cunningham, A. L., Saksena, N. K. (1998) Unique HIV type 1 V3 region sequences derived from six different regions of brain: region-specific evolution within host-determined quasispecies AIDS Res. Hum. Retrovir. 14,25-30[Medline]
-
Wei, P., Garber, M. E., Fang, S. M., Fischer, W. H., Jones, K. A. (1998) A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA Cell 92,451-462[Medline]
-
Gallay, P., Stitt, V., Mundy, C., Oettinger, M., Trono, D. (1996) Role of the Karyopherin pathway in human immunodefiency virus type 1 nuclear import J. Virol. 70,1027-1032[Abstract]
-
Jenkins, Y., McEntee, M., Weis, K., Greene, W. C. (1998) Characterization of HIV-1 vpr nuclear import: analysis of signals and pathways J. Cell Biol. 143,875-885[Abstract/Free Full Text]
-
Deng, H. D., Unutmaz, D., Kewal-Armai, V. N., Littman, D. R. (1997) Expression, cloning of new receptors used by simian and human immunodeficiency viruses Nature 388,296-300[Medline]
-
Doranz, B. J., Rucker, J., Yi, Y., Smyth, R. J., Samson, M., Peiper, S. C., Parmentier, M., Collman, R. G., Doms, R. W. (1996) A dual tropic isolate that uses fusin and the beta chemokine receptors CKR-5, CKR-3 and CKR-2b as fusion cofactors Cell 85,1149-1158[Medline]
-
Liao, F., Alkhatib, G., Peden, K. W. C., Sharma, G., Berger, E. A., Farber, J. M. (1997) STRL33, a novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1 J. Exp. Med. 185,2015-2023[Abstract/Free Full Text]
-
He, J., Chen, Y., Farzan, M., Choe, H., Ohagen, A., Gartner, S., Busciglio, J., Yang, X., Hofmann, W., Neuman, W., Mackay, C. R., Sodroski, J., Gabuzda, D. (1997) CCR3 and CCR5 are coreceptors for HIV-1 infection of microglia Nature 385,645-649[Medline]
-
Naif, H. M., Li, S., Alali, M., Sloane, A., Wu, L., Kelly, M., Lynch, G., Lloyd, A., Cunningham, A. L. (1998) CCR5 expression correlates with susceptibility of maturing monocytes to human immunodeficiency virus type 1 infection J. Virol. 72,830-836[Abstract/Free Full Text]
-
Di Marzio, P., Tse, J., Landau, N. R. (1998) Chemokine receptor regulation and HIV type 1 tropism in monocyte-macrophages AIDS Res. Hum. Retrovir. 14,129-138[Medline]
-
Fear, W. R., Kesson, A. M., Naif, H. M., Lynch, G. W., Cunningham, A. L. (1998) Differential tropism and chemokine receptor expression of human immunodeficiency virus type 1 in neonatal monocytes, monocyte-derived macrophages, and placental macrophages J. Virol. 72,1334-1344[Abstract/Free Full Text]
-
Platt, E. J., Wehrly, K., Kuhnman, S. E., Chesbro, B., Kabat, D. (1998) Effects of CCR5 and CD4 cell surface concentrations on infections by macrophage-tropic isolates of human immunodeficiency virus type 1 J. Virol. 72,2855-2864[Abstract/Free Full Text]
-
Moore, J. P. (1997) Coreceptors: implications for HIV pathogenesis and therapy Science (Wash. DC) 276,51-52[Free Full Text]
-
Martin, M. P., Dean, M., Smith, M. W., Winkler, C., Gerrard, B., Michael, N. L., Lee, B., Doms, R. W., Margolick, J., Buchbinder, S., Goedert, J. J., O’Brien, T. R., Hilgartner, M. W., Vlahov, D., O’Brien, S. J., Carrington, M. (1998) Genetic acceleration of AIDS progression by a promoter variant of CCR5 Science (Wash. DC) 282,1907-1911[Abstract/Free Full Text]
-
Liu, R., Zhao, X., Gurney, T. A., Landau, N. R. (1998) Functional analysis of the proximal CCR5 promoter AIDS Res. Hum. Retrovir. 14,1509-1519[Medline]
-
Yi, Y., Rana, S., Tyrner, J. D., Gaddis, N., Collman, R. G. (1998) CXCR4 is expressed by primary macrophages and supports CCR5-independent infection by dual-tropic but not T-tropic isolates of human immunodeficiency virus type 1 J. Virol. 72,772-777[Abstract/Free Full Text]
-
Verani, A., Pesenti, E., Polo, S., Tresoldi, E., Scarlatti, G., Lusso, P., Siccardi, A. G., Vercelli, D. (1998) CXCR4 is a functional coreceptor for infection of human macrophages by CXCR4-dependent primary HIV-1 isolates J. Immunol. 161,2084-2088[Abstract/Free Full Text]
-
Simmons, G., Reeves, J. D., McKnight, A., Dejucq, N., Hibitts, S., Power, C. A., Aarons, E., Schols, D., De Clercq, E., Proudfoot, A. E., Clapham, P. R. (1998) CXCR4 as a functional coreceptor for human immunodeficiency virus type 1 infection of primary macrophages J. Virol. 72,8453-8457[Abstract/Free Full Text]
-
Schuitemaker, H., Koot, M., Kootstra, K. N. A., Dercksen, M. W., de Goede, R. E. Y., van Steenwijk, R. P., Lange, T. M. A., Eeftink Schattenkerk, T. K. M., Miedema, F., Tersmette, M. (1992) Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell tropic virus populations J. Virol. 66,1354-1360[Abstract/Free Full Text]
-
Lapham, C. K., Zaitseva, M. B., Lee, S., Romanstseva, T., Golding, H. (1999) Fusion of monocytes and macrophages with HIV-1 correlates with biochemical properties of CXCR4 and CCR5 Nat. Med. 5,590
-
Xiao, X., Wu, L., Stantchev, T. S., Feng, Y. R., Ugolini, S., Chen, H., Shen, Z., Riley, J. L., Broder, C. C., Sattentau, Q. J., Dimitrov, D. S. (1999) Constitutive cell surface association between CD4 and CCR5 Proc. Natl. Acad. Sci. USA 96,7496-7501[Abstract/Free Full Text]
-
Dimitrov, D. S., Norwood, D., Stantchev, T. S., Feng, Y., Xiao, X., Broder, C. C. (1999) A mechanism of resistance to HIV-1 entry: inefficient interactions of CXCR4 with CD4 and gp120 in macrophages Virology 259,1-6[Medline]
-
Lynch, G., Dearden, M., Sloane, A. J., Humphrey Smith, I., Cunningham, A. L. (1996) Analysis of recombinant and native CD4 by single and two dimensional gel electrophoresis Electrophoresis 17,227-234[Medline]
-
Lynch, G., Sloane, A. J., Raso, V., Lai, A., Cunningham, A. L. (1999) Direct evidence for native CD4 oligomers in lymphoid and monocytoid cells Eur. J. Immunol. 29,2590-2602[Medline]
-
Chang, J., Li, S., Naif, H., Cunningham, A. L. (1994) The magnitude of HIV replication in monocytes and macrophages is influenced by environmental conditions, viral strain and host cells J. Leukoc. Biol. 56,230-235[Abstract]
-
Evans, L. A., McHugh, T. M., Stites, D. P., Levy, J. A. (1987) Differential ability of human immunodeficiency virus isolates to productively infect human cells J. Immunol. 138,3415-3418[Abstract]
-
Collman, R. G., Yi, Y., Liu, Q-H., Freedman, B. D. (2000) Chemokine signaling and HIV-1 fusion mediated by macrophage CXCR4: implications for target cell tropism J. Leukoc. Biol. 68,000-000
-
Williams, L. M., Cloyd, M. W. (1992) Polymorphic human genes determines differential susceptibility of CD4 lymphocytes to infection by certain HIV-1 isolates Virology 184,723-728
-
Spira, A. I., Ho, D. D. (1995) Effect of different donor cells on human immunodeficiency virus type 1 replication and selection in vitro J. Virol. 69,422-429[Abstract]
-
Paxton, W. A., Martin, S. R., Tse, D., O’Brien, T. R., Skurnick, J., Van Devanter, N. L., Padian, N., Braun, J. F., Kotler, D. P., Wolinsky, S. M., Koup, R. A. (1996) Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure Nat. Med. 2,412-417[Medline]
-
Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., MacDonald, M. E., Stuhlmann, H., Koup, R. A., Landau, N. R. (1996) Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection Cell 86,367-377[Medline]
-
Rana, S., Besson, G., Cook, D. G., Rucker, J., Smyth, R. J., Yi, Y., Turner, J. D., Guo, H-H., Du, J-G., Peiper, S. C., Lavi, E., Samson, M., Libert, F., Liesnard, C., Vassart, G., Doms, R. W., Parmentier, M., Collman, R. (1997) Role of CCR5 in infection of primary macrophages and lymphocytes by macrophage-tropic strains of HIV: resistance to patient-derived and prototype isolates resulting from the CCR5 mutation J. Virol. 71,3219-3227[Abstract]
-
Chang, J., Naif, H. M., Li, S., Sullivan, J. S., Randle, C. M., Cunningham, A. L. (1996) Twin studies demonstrate a host cell genetic effect on productive human immunodeficiency virus infection of human monocytes and macrophages in vitro J. Virol. 70,7792-7803[Abstract]
-
Mellors, J. W., Kingsley, L. A., Rinaldo, C. R., Jr, Todd, J. A., Hoo, B. S., Kokka, R. P., Gupta, P. (1995) Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion Ann. Intern. Med. 122,573-579[Abstract/Free Full Text]
-
Orenstein, J. M., Fox, C., Wahl, S. M. (1997) Macrophages as a source of HIV during opportunistic infections Science (Wash. DC) 276,1857-1860[Abstract/Free Full Text]
-
Gartner, S. (2000) HIV infection and dementia Science (Wash. DC) 287,602-604[Free Full Text]
-
Fauci, A. S., Pantaleo, G., Stanley, S., Weissman, D. (1996) Immunopathogenic mechanisms of HIV infection Ann. Intern. Med. 124,654-663[Abstract/Free Full Text]
-
Kelly, M. D., Naif, H. M., Adams, S. L., Cunningham, A. L., Lloyd, A. R. (1998) Cutting edge: dichotomous effects of ß-chemokines on HIV replication in monocytes and monocyte-derived macrophages J. Immunol. 160,3091-3095[Abstract/Free Full Text]
-
Lawn, S. D., Roberts, B. D., Griffin, G. E., Folks, T. M., Butera, S. T. (2000) Cellular compartments of human immunodeficiency virus type 1 replication in vivo: determination by presence of virion-associated host proteins and impact of opportunistic infection J. Virol. 74,139-145[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
M. M. Goodenow, S. L. Rose, D. L. Tuttle, and J. W. Sleasman
HIV-1 fitness and macrophages
J. Leukoc. Biol.,
November 1, 2003;
74(5):
657 - 666.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Tang, B. Shelton, N. J. Makhatadze, Y. Zhang, M. Schaen, L. G. Louie, J. J. Goedert, E. C. Seaberg, J. B. Margolick, J. Mellors, et al.
Distribution of Chemokine Receptor CCR2 and CCR5 Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression
J. Virol.,
January 15, 2002;
76(2):
662 - 672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. H. Wang, Y. K. Donaldson, R. P. Brettle, J. E. Bell, and P. Simmonds
Identification of Shared Populations of Human Immunodeficiency Virus Type 1 Infecting Microglia and Tissue Macrophages outside the Central Nervous System
J. Virol.,
December 1, 2001;
75(23):
11686 - 11699.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. R. Gorry, G. Bristol, J. A. Zack, K. Ritola, R. Swanstrom, C. J. Birch, J. E. Bell, N. Bannert, K. Crawford, H. Wang, et al.
Macrophage Tropism of Human Immunodeficiency Virus Type 1 Isolates from Brain and Lymphoid Tissues Predicts Neurotropism Independent of Coreceptor Specificity
J. Virol.,
November 1, 2001;
75(21):
10073 - 10089.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Hein, J.-P. Martin, and R. Dorries
In Vitro Activation of Feline Immunodeficiency Virus in Ramified Microglial Cells from Asymptomatically Infected Cats
J. Virol.,
September 1, 2001;
75(17):
8090 - 8095.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. J. Montaner, C.-F. Perno, and S. Crowe
Macrophage infection by HIV-1: focus on viral reservoirs and pathogenesis
J. Leukoc. Biol.,
September 1, 2000;
68(3):
301 - 302.
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
