(Journal of Leukocyte Biology. 2000;68:338-344.)
© 2000
by Society for Leukocyte Biology
HIV-1 genotypes in peripheral blood monocytes
Tuofu Zhu
Department of Laboratory Medicine, University of Washington, Seattle, Washington
Correspondence: Tuofu Zhu, Department of Laboratory Medicine, University of Washington, PO Box 357110, 1959 NE Pacific Street, Seattle, WA 98195. E-mail: tzhu{at}u.washington.edu
 |
ABSTRACT
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CD4+ T cells and tissue macrophages are well defined as the
major targets for human immunodeficiency virus type 1 (HIV-1) infection
and replication, and their infection accounts for many aspects of HIV-1
pathogenesis in vivo. HIV-1 genotype and phenotype in monocytes and
their potential roles in pathogenicity in vivo remain unknown. Herein
is an overview of our initial work on HIV-1 genotype in purified
CD14+ monocytes isolated longitudinally during the course
of infection starting from the time of infection. Our data provide
evidence for HIV-1 evolution in monocytes and their role as a reservoir
of HIV-1 in vivo. A better understanding of HIV-1 in monocytes may
greatly help the development of new therapeutic strategies for HIV-1
infection.
Key Words: HIV-1 • genotype • CD14+ monocytes
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INTRODUCTION
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CD4+ T cells and tissue macrophages are the major
target cells for human immunodeficiency virus type 1 (HIV-1) infection
and replication [1
2
3
4
5
6
7
8
]. Virus replication in CD4+ T
lymphocytes accounts for the major pathogenicity in vivo. The role that
cells of monocyte-macrophage lineage play in AIDS pathogenesis is less
well understood. Monocytes in peripheral blood are rarely infected
during primary infection [9
, 10
]. In fact, HIV-1 replication is blocked
before reverse transcription and integration in freshly isolated
peripheral blood monocytes [4
]. Monocytes in culture must undergo
differentiation to monocyte-derived macrophages (MDM) to become
susceptible to productive infection with HIV-1 [11
12
13
]. It is likely
that differentiation of monocytes to macrophages in tissues such as
peripheral lymph nodes, brain, lung, and gut-associated lymphoid tissue
can result in susceptibility to infection with HIV-1 [1
2
3
4
5
6
7
8
]. Although
macrophages are susceptible to infection with HIV-1, they are
relatively resistant to its cytopathic effects [1
]. In vitro cultures
have shown that MDM are not killed by HIV-1 infection but produce virus
for as long as several weeks [4
]. In contrast, CD4+ T cells
are highly sensitive to the cytopathic effects of HIV-1. Tissue
macrophages may serve a pathogenetic role by producing virus that can
infect other target cells, although they are responsible for the
production of only a small percentage of the viral load present in the
infected host [6
7
8
]. Therefore, monocyte-macrophages have the
potential to act as a long-term reservoir for HIV-1 and disseminate the
virus to other tissues [3
4
5
6
7
8
].
Several studies suggest that cells of macrophage lineage may be
important for the pathogenesis of HIV-1 replication. The selective
transmission of monocytotropic viruses [14
15
16
17
] indicates that
macrophage tropism may facilitate establishment of the virus in the
newly infected host. The chemokine receptor CCR5 serves as the
principal co-receptor for macrophage-tropic (M-tropic) HIV-1 entry into
CD4-expressing T cells and macrophages [18
19
20
21
]. Individuals with
homozygous deletions in the CCR5 gene and peripheral blood mononuclear
cells (PBMC) of these subjects show high levels of resistance to HIV-1
infection [22
23
24
25
26
]. Although most retroviruses only infect dividing
cells [27
, 28
], several viral proteins render HIV-1 efficient infection
of nondividing macrophages [29
, 30
]. Simian immunodeficiency virus
(SIV) SM variants barely infect macrophages in vitro and are
considerably impaired in pathogenicity in vivo [31
]. After infection
with HIV-1, macrophages release several immunoregulatory and
inflammatory factors, including TNF-
, IL-1, and IL-7, which in turn
influence viral proliferation and disease associated with HIV-1
infection [32
].
The heterogeneity of HIV-1 strains is studied mostly by molecular
characterization of genomic sequences. This involves sequencing
fragments amplified by the PCR or the use of the heteroduplex mobility
assay (HMA) [33
, 34
]. Genetic analyses have demonstrated the
homogeneity of envelope sequences immediately after homosexual
transmission as well as after mother–infant and parenteral
transmission [14
15
16
17
]. There are a number of reports on the genotypes
of M-tropic HIV-1 strains that are characterized by their ability to
replicate in primary macrophages but not in T cells such as MT-2 cell
line. All of these M-tropic HIV-1 strains were isolated from whole PBMC
rather than purified macrophages. This report is a review of our
unpublished work on the envelope sequences of HIV-1 in freshly purified
peripheral blood monocytes (CD14+) and the comparison with
HIV-1 sequences in CD4+ T cells.
|
HIV-1 GENOTYPES IN MONOCYTES DURING ACUTE INFECTION
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Previous studies have shown that HIV-1 sequences in newly
infected individuals are relatively homogeneous, even though the
transmitters harbor heterogeneous genotypes [14
15
16
17
, 35
]. There is also
evidence that the pressure to conserve sequences is stronger for HIV-1
envelope gp120 than for gp41, nef, and p17 of gag
during sexual transmission [14
, 16
]. In a further study of sexual
transmission, we found evidence for HIV-1 selection and
compartmentalization in both chronically infected transmitters and
newly infected individuals [36
]. These results enable us to propose a
multiple-step process for the selection of HIV-1 during sexual
transmission, that is, compartmentalization from blood to semen in the
transmitter, as well as the selection of HIV-1 in the new host, either
at the level of penetration or amplification or both. It is likely that
because of the multiple steps of selection of the virus during
transmission, HIV-1 in most of the newly infected individuals is
relatively homogeneous. Moreover, HIV-1 isolates obtained from newly
infected individuals are largely M-tropic and nonsyncytium inducing
(NSI) [14
, 37
], although those from some of the corresponding donors
are both syncytium inducing (SI) and NSI [14
, 16
, 17
, 37
]. We further
observed that a few of multiple NSI variants found in the transmitters
were detected in the newly infected recipient [36
]. Other studies have
also provided evidence that the transmitted virus was one of the
multiple NSI variants found in the corresponding transmitter [17
, 35
].
Taken together, these findings suggest that, in sexual transmission,
some, but not all, NSI virus are selected to establish new infection.
However, the so-called M-tropic HIV-1 strains were actually isolated
from PBMC and not from purified monocytes-macrophages. These viruses
were designated as M-tropic HIV-1 strains because they could replicate
in primary macrophages but not in transformed T cell lines. There is
little information about the genotypes of HIV-1 existing in
macrophages, and almost no data of HIV-1 genotypes in monocytes,
probably because of the fact that monocytes do not support HIV-1
replication [4
]. Several studies have clearly shown altered
susceptibility to HIV-1 infection depending on the state of maturation
of monocytes into macrophages [38
, 39
]. For most previous studies,
monocytes were isolated by plastic adherence only, allowing the
differentiation of monocytes into MDM in a few hours as a result of
adherence, and thus these cells became susceptible to HIV-1 infection
[39
]. Recently, we have used a 2-step strategy to isolate highly
purified monocytes from peripheral blood without adherence in vitro by
combining a negative selection assay [40
41
42
43
44
] with monoclonal
antibodies against molecules CD8, CD19, CD16, and CD3, and a positive
selection by cell-sorting with antibodies against CD14 that is
exclusively expressed on monocyte-macrophages. These freshly isolated
CD14+ monocytes, representing about 80% populations of
monocytes existing in vivo [45
], were used for DNA extraction, PCR, and
sequence analyses. Ten acutely infected patients who initiated highly
active antiretroviral therapy (HAART) within 121 days of onset of
symptoms of primary HIV-1 infection were studied. The plasma viral RNA
of all 10 subjects declined to below the detection level of 50 HIV-1
copies per milliliter of plasma within 4 months of therapy. Of them, 9
remained on HAART with undetectable levels of plasma virus for the 2–4
years of follow-up, whereas 1 patient chose to discontinue therapy
after his plasma virus had been remained undetectable for 1 year, and
his plasma virus rebounded in 2 weeks after the interruption of
therapy. None of individuals had advanced infection. Initial studies
were focused on the samples obtained at the time of acute infection,
before seroconversion and the initiation of therapy. HIV-1 in
CD14+ monocytes was genetically homogeneous near the time
of seroconversion in 8 individuals. Figure 1
is a typical example of the sequences of the first and second variable
region (V1–V2) of HIV-1 envelope gene found in CD14+
monocytes freshly isolated from a newly infected individual. Extremely
homogeneous sequences were found in this patient despite the fact that
V1–V2 regions are believed to be the most variable regions in the
HIV-1 genome. Similar homogeneity of sequences was also observed in the
V3–V5 regions of HIV-1 from this individual. However, significant
HIV-1 sequence heterogeneity was identified in CD14+
monocytes of 2 out of the 10 newly infected individuals that we studied
(Zhu et al., unpublished results). These findings, consistent with
previous observations in PBMC and plasma from us and others, suggest
that HIV-1 genotypes in CD14+ monocytes during primary
infection are homogeneous in most newly infected individuals but
heterogeneous in 
20% of patients with primary infection.
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Figure 1. Deduced amino acid sequence alignment of the V1–V2 region of gp120
from CD14+ monocytes purified before seroconversion from an
individual with primary infection. The consensus sequence is indicated
at the top, with the V1 and V2 loop underlined. Dots indicate sequence
identical to the consensus sequence. Each sequence represents a
sequence from 1 clone.
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HIV-1 SEQUENCE EVOLUTION IN MONOCYTES DURING THE COURSE OF
HIV-1 INFECTION
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HIV-1 genetic evolution during the course of infection was studied
either by cross-sectional analysis of samples from individuals at
various stages of disease [34
, 46
] or longitudinal studies within some
infected individuals [34
, 47
48
49
50
]. Distinct proviral sequence variants
in PBMC compared with blood plasma and other tissues were observed
during the infection course of patients [36
, 51
52
53
54
]. It is believed
that this high level of genetic variation is the result of rapid and
mutation-prone replication of large viral populations. A large amount
of information attests to the adaptable nature of HIV-1 quasispecies
replicating in vivo. Studies of HIV-1 and SIV evolution in vivo have
shown a high ratio of nonsynonymous to synonymous site mutations (dN/dS
ratio), likely reflecting a selection for phenotypic changes [56
, 57
].
The selective forces driving such evolution may include strong and
changing immune responses [58
59
60
61
] as well as viral adaptation to
growth in different cell types [62
63
64
].
We were particularly interested in the evolution of HIV-1 in monocytes
and the comparison with variants in other cell compartments such as
resting CD4+ T cells and activated CD4+ T
cells. We have thus examined the proviral sequences in
CD14+ monocytes isolated longitudinally from the time of
infection to present. There was no evidence of sequence variation
during the 2–4 year period of study in 7 of 10 studied individuals,
whereas significant sequence variation was seen in 3 patients (2 with
continuous HAART, 1 off therapy). Figure 2
, as an example, depicts the sequence evolution of HIV-1 V3–V5 regions
during a period of 2 years within the individual who initiated HAART at
the day of seroconversion and discontinued therapy 1 year later. We
were able to obtain an early sample at 5 days before the patient was
diagnosed with HIV-1 infection with detectable HIV antibodies
(seroconversion), and another time point sample at 735 days after
seroconversion and at 300 days after the interruption of HAART. In
early infection, HIV-1 in CD14+ monocytes was homogeneous
and was the same as the strain in resting and activated
CD4+ T cells. However, 2 years later, distinct variant
populations (designated as subgroups 1–6 in Fig. 2
) were seen in
monocytes as well as in other cells. HIV-1 variants in monocytes were
neither identical to those in activated CD4+ T cells nor
resting CD4+ T cells. There were 3 viral populations
(subgroups 1–3) of sequences in monocytes, 4 populations (subgroups 2,
4–6) in activated CD4+ T cells, and only 2 in resting
CD4+ T cells. Although subgroup 2 was found in all 3 cell
compartments, distinct mutations were seen within subgroup 2 in each
cell type. More sequence populations found in activated
CD4+ T cells may reflect higher levels of viral replication
and viral turnover in activated CD4+ T cells in patients
after the interruption of therapy. In contrast, in patients receiving
continuous HAART, we observed in some individuals relatively higher
viral replication and sequence variation in CD14+ monocytes
compared with both activated and resting CD4+ T cells (Zhu
et al., unpublished results). The difference may be explained by the
finding that inhibition of viral replication by protease inhibitors,
which are often a major potent component of HAART, is much less
efficient in monocyte-macrophages than in CD4+ T cells [65
, 66
].
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Figure 2. Deduced amino acid sequence alignment of the V3–V5 region of gp120
from CD14+ monocytes, resting and activated
CD4+ T cells isolated during the course of HIV-1 infection
from 1 individual. The consensus sequence is indicated at the top with
V3, V4, and V5 loop underlined. Dots indicate sequence identical to the
consensus sequence, dashes indicate deletions, and asterisks indicate
stop codons. Clone numbers with identical sequence are shown at
right.
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MONOCYTES AS A POTENTIAL RESERVOIR OF HIV-1
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Chronically infected macrophages could provide a reservoir of
HIV-1 that persists in patients whose CD4+ T cell viral
burdens have been drastically reduced by HAART [67
]. Our studies of
patients taking HAART suggest that HIV-1 may replicate in monocytes in
vivo and that monocytes can serve as reservoirs of HIV-1 (Zhu et al.,
unpublished results). This hypothesis is also supported by data
presented in Figure 2
. Early in infection, there was only 1 variant
population (subgroup 1) in all cell types. This initial virus was still
detected in monocytes but not in CD4+ T cells 2 years
later. We also used HMA to check if there was a trace of subgroup 1
virus in CD4+ T cells but failed to detect it. These
findings suggest that monocytes can carry HIV-1 for relatively longer
periods than CD4+ T cells. The role of CD14+
monocytes as a source of virus during HIV-1 disease has not been
considered, or as few if any productively infected cells expressing
monocyte markers have been documented. Our data suggest that monocytes,
unlike CD4+ T cells, are capable of producing HIV-1 without
necessarily succumbing to the lethal effects of productive viral
infection and, therefore, can serve as a long-term source of HIV-1.
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PATTERNS OF LINEAL SEQUENCES OF HIV-1 ENVELOPE GP120 IN MONOCYTES
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HIV-1 proviral sequences can be nonuniformly distributed
throughout the body. Distinct proviral sequence variants have been
reported in PBMC and brain tissue [62
, 68
, 69
] or cerebrospinal fluid
[52
, 53
], spleen [62
], lymph node [50
, 51
], lung [63
], and semen [36
, 70
]. Furthermore, quasispecies of HIV-1 can differ between virion RNA
and integrated proviral DNA in both blood and semen [36
].
If particular characteristics are required for replication and
production of virus in monocytes, they may be detected as signature
sequences found across various individuals as monocyte-specific. We
have not detected a monocyte-specific signature sequence of HIV-1
V3–V5 region by using a signature pattern analysis assay [71
].
However, recognition of distinctions between viruses in monocytes and
those in CD4+ T cells indicates that further analyses
should be conducted.
The NSI and SI phenotypes of HIV-1 are well predicted by variants at
positions 11 and 25 of the amino acids in the V3 loop (Fig. 3
). Amino acids with positive charge (R and K) at one or two of these
positions predict the SI and T-tropic phenotype. It is interesting that
the deduced amino acid sequences of the V3 loop of each virus in
monocytes of our patients suggested an NSI and M-tropic phenotype.
Further studies are needed to determine if SI virus is present in
CD4+ T cells of these patients at transmission, although
transmission of SI virus is rare [14
15
16
17
, 35
36
37
]. These studies may
provide evidence for a restriction of SI variants in CD14+
monocytes.
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Figure 3. Amino acid sequence comparison of the V3 region of gp120 in
CD14+ monocytes of our patients with published M-tropic and
T-tropic HIV-1 strains. All sequences were aligned with
HIV-1BAL strain that is shown at the top. Sequences derived
from purified monocytes of the patient in the present study are 1M–8M.
The other symbols are the same as in Figure 2
. Amino acids with
positive charge (R or K) at positions 11 and 25 (downward-pointing
arrow) predict SI and T-tropic phenotype, and other amino acids in
these two positions predict NSI and M-tropic phenotype.
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CONCLUSIONS
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The results of our studies indicate that CD14+
monocytes were infected at an early stage of the course of HIV-1
infection and that HIV-1 persisted in CD14+ monocytes
during the course of infection. HIV-1 in monocytes was largely
homogeneous during primary infection. The distinct viral variants found
in CD14+ monocytes compared with CD4+ T cells
in some individuals at a later stage of HIV-1 infection suggest that
HIV-1 may replicate and evolve in CD14+ monocytes
independently from CD4+ T cells. There is also evidence
that monocytes can be a potentially important reservoir of HIV-1.
Consistent with previous findings from other laboratories regarding
HIV-1 V3 genotypes, all viruses in CD14+ monocytes are
predicted to be NSI and M-tropic HIV-1 strains. Further studies would
be needed to investigate HIV-1 replication in purified
CD14+ monocytes, which may provide important information
for the role of monocytes in HIV-1 pathogenesis and for the development
of new therapeutic strategies for HIV-1 infection.
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ACKNOWLEDGEMENTS
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This work was supported by NIH grants AI41535, AI45206, AI35605,
and AI45402 and the University of Washington Center for AIDS Research
Young Investigator Award (NIH AI27757).
I thank my colleagues Yon Hwangbo Chang, Feng Feng, and David Muthui
for their work, and Lawrence Corey and James Mullins for helpful
discussions.
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