(Journal of Leukocyte Biology. 2000;68:345-350.)
© 2000
by Society for Leukocyte Biology
HIV-1 can be recovered from a variety of cells including peripheral blood monocytes of patients receiving highly active antiretroviral therapy: a further obstacle to eradication
Suzanne M. Crowe and
Secondo Sonza
AIDS Pathogenesis Research Unit, Macfarlane Burnet Centre for Medical Research, Melbourne, Victoria, Australia
Correspondence: Prof. Suzanne M. Crowe, Macfarlane Burnet Centre for Medical Research, Yarra Bend Road, Fairfield, Victoria 3078, Australia. E-mail: tolli{at}burnet.edu.au
 |
ABSTRACT
|
|---|
During highly active antiretroviral therapy (HAART), HIV-1 can still
persist in circulating, resting CD4+ T lymphocytes, lymph
node mononuclear cells, and seminal cells of patients despite sustained
suppression of plasma viremia to undetectable levels. Sanctuary sites
where antiretroviral drug penetration is not optimal may allow local
HIV-1 infection of cells within and passing through these tissues.
Factors such as imperfect drug adherence due to complicated drug
regimens may also result in tissue compartments with suboptimal drug
concentrations allowing viral replication. We have examined blood
monocytes from HIV-1-infected subjects being effectively treated with
HAART to determine virus carriage in these cells. Monocytes were
purified from peripheral blood of patients with plasma HIV-1 RNA below
50 copies/mL and who had maintained levels of plasma RNA below
detection for 3 months or more. Replication-competent virus could be
recovered from the majority of monocyte populations by co-culture with
CD8-depleted, PHA-activated, peripheral blood mononuclear cells.
Sequencing of the reverse transcriptase and protease genes of the
recovered viruses did not reveal resistance to both reverse
transcriptase and protease inhibitors. Continued new infection of this
transitory, circulating population of cells even during prolonged,
effective HAART most likely reflects ongoing, low-level HIV-1
replication within cellular reservoirs and sanctuary sites in the
body.
Key Words: reservoirs • macrophages • lymphocytes • persistence
|
INTRODUCTION
|
|---|
Since the introduction of highly active antiretroviral therapy
(HAART, a treatment regimen comprising a combination of at least three
antiretroviral drugs and usually including a member of the protease
inhibitor class), there has been a significant decline in the morbidity
and mortality of patients with human immunodeficiency virus (HIV-1)
infection. This has resulted from the control of viral replication
(measured as suppression of plasma HIV RNA to less than 50 copies/mL),
allowing at least partial reconstitution of the immune system.
The availability of HAART has also provided a useful tool for the
mathematical modeling of the kinetics of plasma HIV-1 decay and CD4 T
cell recovery. Treatment with HAART has been shown in early modeling
studies to initially reduce plasma viral load by 100- to 1000-fold
within the first few weeks of therapy (phase I), suggesting that most
of the circulating HIV-1 within plasma is produced by short-lived,
productively infected cells (half-lives estimated to be about 1 day). A
slower phase II decline in viral load reflects the decay of long-lived
infected cell populations (half-lives estimated to be 1–4 weeks). An
alternate hypothesis for this slower phase of plasma virus decay
suggests that the clearance of lymphocytes and macrophages is
essentially similar, and that a decline in antigen-driven immune
responses (particularly effector cells) is responsible for the slower
phase of viral decay [1
]. The early modeling studies
allowed a prediction of eradication of HIV-1 from infected individuals
with 2.3 to 3.1 years of continuous HAART [2
,
3
]. However, despite sustained viral suppression for
prolonged periods of time, eradication of HIV-1 from such patients has
not been achieved.
A number of factors have been identified that make eradication of HIV-1
by HAART more difficult. These include the difficulties of adhering to
complex antiretroviral regimens of drugs with often low margins for
pharmacokinetic deviation, the identification of cellular reservoirs
that survive despite HAART, and the potential existence of sanctuary
sites within the body where antiretroviral drug levels are not optimal.
In a recent review, the authors suggested that attention should be
focused on why potent drug regimens fail to completely suppress HIV-1
and propose that pharmacokinetics, cellular concentrations of drugs,
and patient adherence may be of greater importance than drug
penetration into anatomical sanctuaries [4
].
|
CELLULAR RESERVOIRS VERSUS ANATOMICAL SANCTUARY SITES
|
|---|
HIV-1 may be inaccessible to HAART as a result of infection within
certain cell types or in certain tissues. There are often significant
differences in viral load detected in plasma and cerebrospinal fluid
[5
], or between plasma and semen [6
,
7
], suggesting that there is compartmentalization of
HIV-1 replication in vivo. Sanctuary sites (those anatomic
sites that are either inaccessible to HAART or where drug
concentrations may be lower than those in plasma as a result of
tissue-blood endothelial barriers) such as brain, testes, and retina
[8
9
10
] may harbor cells containing HIV-1, allowing
local viral replication. Certain cells containing proviral HIV-1 DNA
have a very slow turnover, such as resting CD4 lymphocytes and tissue
macrophage populations, especially microglia. Once infected the latter
cells represent a stable viral reservoir, as microglial turnover is
virtually non-existent [11
], and given their location,
may escape the effects of HAART.
Replication-competent HIV-1 has been isolated from seminal cells (which
comprise spermatozoa, germ cell precursors, epithelial cells,
macrophages, and T cells) of patients on HAART with no detectable HIV
RNA in plasma, suggesting that the genital tract may be a reservoir of
HIV in infected men [10
]. Whether cervical or vaginal
secretions provide a viral reservoir in infected women receiving HAART
is not known.
Within the brain, microglia, which express both CCR5 and CCR3, can be
infected with HIV-1 and have a relatively long half-life
[11
]. Other long-lived cells such as bone marrow-derived
dendritic cells within the choroid plexus can also be infected with
HIV-1 and serve as a cellular reservoir [12
].
Discrepancies between plasma and cerebrospinal fluid (CSF) HIV RNA
levels, together with the observation that infection within the central
nervous system (CNS) results in an increase in CSF viral load
[13
], suggests local production of HIV-1
[5
].
|
LYMPHOCYTES AS A VIRAL RESERVOIR
|
|---|
Several years ago three groups identified long-lived latently
infected resting CD4-expressing memory (CD45RO+) T cells as
a latent reservoir of HIV-1 in patients who had received prolonged
courses of HAART with sustained viral load suppression
[14
15
16
]. Infectious virus was able to be recovered from
these cells through the use of different techniques. There being no
evidence of mutations conferring drug resistance, these observations
were not considered to be due to drug failure, but rather to
persistence of long-lived and latently infected T cell populations.
This reservoir is established early in the course of HIV infection, as
efforts to eradicate HIV-1 by commencing HAART soon after infection
have failed. These cells have been isolated from patients who commenced
HAART within 10 days of development of symptoms of acute HIV infection
[17
]. The cellular population is estimated only to be in
the range of 105 cells per infected individual. However,
initial optimism for eradication of HIV-1 with HAART has been dampened
by estimates of the half-life of HIV-1 within these cells, ranging from
6.3 months [18
] to 44 months [19
],
requiring as low as 7–10 years to over 60 years of continuous therapy
and complete viral suppression in order to achieve viral eradication.
The decay of the latent reservoir of HIV-1 has recently been shown to
be inversely correlated with the extent of residual viral replication,
in that the decay rate of 6.3 months is only found in patients with
continuous viral suppression below 50 copies/mL; intermittent episodes
of detectable virus result in prolonging the decay time
[20
].
A reduction in unintegrated viral DNA in peripheral blood mononuclear
cells (PBMCs) has been reported with successful HAART regimens
[21
]. This is to be expected because unintegrated viral
DNA has a short half-life in vivo and its presence indicates
ongoing viral replication. However, the persistence of unintegrated DNA
in cells from patients despite several years of plasma HIV RNA
suppression to below detectable levels suggests continuing viral
replication at low levels [16
]. To achieve eradication,
HAART would need to impact on the level of integrated HIV-1 DNA within
infected cells in blood and tissues. In a study of patients treated for
48 weeks the integrated HIV-1 DNA within PBMCs did not decrease
[22
].
|
HIV-1 CAN BE RECOVERED FROM MONOCYTES OF PATIENTS ON HAART WITH
VIRAL SUPPRESSION
|
|---|
Since the discovery that cells of macrophage lineage could serve
as a target for HIV replication, a number of authors have stated that
these cells provide an important reservoir of HIV-1 in infected
patients. This was largely based on knowledge of the pathogenesis of
other lentivirus infections [23
, 24
] and,
as with visna, monocytes are not as susceptible to infection with HIV-1
as macrophages [25
]. Monocyte-derived macrophages and
tissue macrophages have been found to be susceptible to HIV-1 infection
in vitro, and their long lifespan together with lack of
significant cytopathic effect would support their role as a viral
reservoir [25
26
27
]. Although there has been some minor
controversy within the literature, the majority of reports have
demonstrated relatively high numbers of infected macrophages within
tissues including brain, lymph node, spleen, lung, and liver, but low
numbers only within blood, suggesting that tissue macrophages but not
peripheral blood monocytes are an important viral reservoir in
HIV-1-infected individuals [28
29
30
31
32
33
34
35
].
Infectious virus has been recovered not only from latently infected T
cells and seminal cells but also from monocytes isolated from the blood
of HIV-1-infected individuals treated with HAART for periods up to 80
weeks who have undetectable plasma viral loads [Mutimer et al.,
unpublished results]. Similar to the reports for latently infected T
cells, we could find no evidence of multiple drug resistance or of
laboratory contamination of samples that might explain the recovery of
virus. All mutations in both the reverse transcriptase and protease
genes that have been reported to be associated with drug resistance
were examined. Although patterns of virus recovery varied from patient
to patient, HIV-1 could generally be detected within culture
supernatants by 14–21 days of co-culture (Table 1
). There was no apparent correlation between the period of viral
suppression by HAART and the ability to recover infectious virus from
the patient’s monocytes. Because monocytes have a relatively short
period of circulation within blood before differentiation into various
tissue macrophages, it is unlikely that these cells represent a
latently infected cellular reservoir. Rather, these and other findings
from our work suggest that the monocytes were recently infected from
reservoirs of virus within the body. The CNS is continuously patrolled
by small numbers of T cells and monocytes and such trafficking in and
out of the CNS or other sanctuary sites provides the potential for new
infection to occur [36
]. Although we and others have
shown that monocytes are much less permissive to infection in
vitro when first isolated than after differentiation in culture
[25
], a very small proportion of monocytes in
circulation (variously estimated at between 0.1 and 0.001%) can harbor
virus throughout the course of infection [27
,
33
]. Whether these cells represent a permissive subset of
monocytes is unknown. Other investigators have also recently detected
evidence of ongoing viral replication in monocytes from HIV-1-infected
persons who have had viral suppression by HAART for periods of up to 3
years [37
].
View this table:
[in this window]
[in a new window]
|
Table 1. Recovery of Replication-Competent HIV-1 from the Purified Monocytesa
of Patients on HAART with Undetectable Viral Loads After Co-culture with CD8-Depleted PBMCsb
|
|
The lifespan of tissue macrophages varies considerably according to
cell type and location, with the half-life of human alveolar
macrophages and perivascular macrophages within the brain estimated to
be about 3 months, whereas that of microglia ranges up to decades
[38
]. Reverse transcriptase inhibitors are unable to
control replication within chronically infected cell populations such
as macrophages [39
]. The only component of HAART that
has activity against chronically infected cells including macrophages
are the various protease inhibitors [40
,
41
]. However, relatively high concentrations of protease
inhibitors are required to inhibit HIV-1 replication within chronically
infected macrophages, when compared to chronically infected T cells
[42
], and the blood-brain barrier prevents the efficient
delivery of these drugs to the CNS. Thus the concentration of protease
inhibitors, at least as measured within CSF, is significantly lower
than plasma concentrations, and lower than the inhibitory
concentrations required to prevent HIV-1 replication within cells of
macrophage lineage within the brain.
|
MECHANISM OF VIRAL PERSISTENCE IN THE PRESENCE OF HAART
|
|---|
Several mechanisms may explain the failure to achieve eradication
of HIV in patients with plasma viral load levels that are undetectable
by ultrasensitive assays. There may be a population of latently
infected cells, including memory T cells that can persist during
prolonged periods of HAART, which can be reactivated in a certain
microenvironment to release infectious virions. There may also be new
infection and ongoing, low levels of viral replication occurring in
cells that are either resident in anatomical sanctuary sites or in
cells that passage through such sites. Such extremely low levels of
viral replication could occur within certain cells without appreciably
increasing the plasma viral load, but allowing continued infection and
replication of virus within a small number of local cells
[43
].
HIV-1 replication within the CNS may continue in the presence of HAART
because of lack of penetration across the blood-CSF and blood-brain
barriers. Although most studies only involve small numbers of patients,
the evidence to date suggests poor penetration of protease inhibitors
[44
45
46
], although nucleoside analogs such as abacavir
and zidovudine and non-nucleoside reverse transcriptase inhibitors such
as nevirapine have good penetration [47
]. The low
penetration of protease inhibitors across the blood-brain endothelial
barrier into the CNS is mostly due to their highly lipophilic nature,
together with their large molecular size [48
].
Expression of the ATP-dependent, efflux membrane drug transporter, at
the level of the blood-brain barrier has also been postulated to limit
entry of the protease inhibitors at this site [49
].
Small increases in the level of HIV RNA in plasma that are sporadically
observed in many patients receiving HAART may be due to alterations in
cytokine production within the microenvironment of the lymph node,
resulting in short-lived increases in HIV-1 replication. This would fit
with speculation that the recurrence of viremia after discontinuation
of HAART may result from cellular stimulation by cytokines such as
interleukin-2 (IL-2) [50
].
|
EVIDENCE OF VIRAL PERSISTENCE IN THE PRESENCE OF HAART
|
|---|
There is evidence from a number of laboratories of at least a
degree of ongoing viral replication and/or the maintenance of a viral
reservoir in the presence of HAART and viral suppression. Levels of
proviral DNA within PBMCs do not significantly decline during HAART,
indicating the persistence of a viral reservoir [22
].
There is also evidence of genetic sequence evolution over time (without
evidence of development of drug-resistant genotypes) in patients on
HAART with undetectable plasma virus, suggesting ongoing HIV-1
replication [18
, 51
]. Unintegrated viral
DNA has been detected within the resting T cell population despite
viral suppression being below the limits of the assays, indicating
recent infection [16
]. Unspliced HIV RNA has been
detected in the PBMCs of infected persons receiving HAART and with
viral suppression, indicating transcriptional activity within the cells
harboring HIV-1 [52
]. One recent study reporting
continuing low-level viral replication in patients on HAART has found
that the levels of unspliced HIV-1 RNA and proviral DNA in PBMCs reach
a steady state about 300 days after commencing HAART
[53
]. Low-level viral replication was confirmed by
finding labile products of viral infection such as short half-life,
circular forms of HIV-1 DNA containing one or two long-terminal repeats
[53
, 54
]. Multiply spliced and unspliced
RNA were not proportionally generated, emphasizing that residual HIV-1
replication is complicated in these patients [53
]. The
demonstration in other similar patients of multiply spliced RNA within
PBMCs provides further evidence of productive infection
[55
]. In cells from patients with incomplete viral
suppression, the presence of sequence changes consistent with viral
evolution has been reported, and provides evidence for ongoing
replication [56
].
|
OBSTACLES TO ERADICATION OF HIV
|
|---|
Currently available antiretroviral drugs, including those used in
HAART combinations, do not target transcription of proviral HIV DNA to
RNA. Thus viral transcription may potentially proceed within latently
infected cells, relying on inhibition of viral assembly by protease
inhibitors to prevent production of new infectious progeny virions. In
sites where protease inhibitors may not reach adequate levels such as
within the CNS, chronically infected cells of macrophage lineage may be
responsible for continuing low-level local production of HIV.
Immune enhancement should theoretically assist in eradicating HIV by
activation of the pool of latently infected T cells in patients on
HAART (as shown in vitro [50
]). This would
result in productively infected T cells, which have a short half-life
in vivo [3
], releasing infectious virions
whose further replication can be adequately controlled by HAART
[reviewed in ref. 57
]. Because HAART can also reduce HIV antigen
levels as a result of viral suppression, and thus reduce HIV-1-specific
immune responses, IL-2 could also theoretically augment immune
responses to HIV-1. Results from a small uncontrolled study suggest
that the number of latently infected T cells may be reduced by
intermittent treatment with an immune stimulator such as IL-2 in the
presence of continuous HAART [57
].
|
SUMMARY
|
|---|
Although HAART has provided extraordinary clinical benefit to
HIV-1-infected patients in terms of lowering morbidity and mortality,
the current drug regimens are unable to completely block HIV-1
replication. Replication-competent HIV-1 has been recovered from
resting memory T cells, seminal cells, and monocytes of patients
receiving HAART who have plasma HIV RNA levels below 50 copies/mL.
Residual HIV-1 replication is likely to arise from a combination of
activation of long-lived latently infected cells, new infection of
cells that come into contact with chronically infected cells or with
virus released during new, low-level bursts of viremia. Cells within
anatomic sanctuary sites such as the brain may harbor
replication-competent HIV-1. Drugs such as protease inhibitors that are
effective in inhibiting replication of HIV-1 within chronically
infected cells such as macrophages do not readily cross the blood-brain
barrier, resulting in potentially lower concentrations of
antiretroviral drug within these sites and thus potentially allowing
continued viral replication. Given the range of cells that are being
discovered as cellular reservoirs of HIV, and their differing biology,
it may be simplistic to think that immune stimulation with cytokines
such as interleukin-2 will result in eradication of HIV-1.
|
ACKNOWLEDGEMENTS
|
|---|
Funding for this work was provided by the Macfarlane Burnet Centre
Research Fund, the National Health and Medical Research Council, and
the National Centre for HIV Virology Research.
|
REFERENCES
|
|---|
-
Bucy, R. P., Kilby, J. M., Sillers, M. L., Hockett, R. D., Saag, M. S. (1999) Analysis of the second phase of viral load decline after HAART-macrophage clearance versus decline in antigen driven immune response. 4th International Workshop on HIV, Cells of Macrophage Lineage and Other Reservoirs Florence, Italy.
-
Perelson, A. S., Neumann, A. U., Markowitz, M., Leonard, I. M., Ho, D. D. (1996) HIV-1 dynamics in vivo; virion clearance rate, infected cell lifespan, and viral generation time Science 271,1582-1586[Abstract]
-
Perelson, A. S., Essunger, P., Cao, Y., Vesanen, M., Hurley, A., Saksela, K., Markowitz, M., Ho, D. D. (1997) Decay characteristics of HIV-1-infected compartments during combination therapy Nature 187,188-191
-
Saag, M. S., Kilby, J. M. (1999) HIV-1 and HAART: A time to cure, a time to kill Nat. Med. 5,609-611[Medline]
-
Garcia, F., Niebla, G., Romeu, J., Vidal, C., Plana, M., Ortega, M., Ruiz, L., Gallart, T., Clotet, B., Miro, J. M., Pumarola, T., Gatell, J. M. (1999) Cerebrospinal fluid-HIV-1 RNA levels in asymptomatic patients with early stage chronic HIV-1 infection; support for the hypothesis of local virus replication AIDS 13,1491-1496[Medline]
-
Liuzzi, G., Chirianni, A., Clementi, M., Nam, D. S., Moor-Jankowski, R., Cooper, D. A., Ho, D. D. (1996) Analysis of HIV-1 load in blood, semen and saliva; evidence for different viral compartments in a cross sectional and longitudinal study AIDS 10,F51-F56[Medline]
-
Zhu, T., Wang, N., Carr, A., Nam, D. S., Moor-Jankowski, R., Cooper, D. A., Ho, D. D. (1996) Genetic characterization of human immunodeficiency virus type 1 in blood and genital secretions; evidence for viral compartmentalization and selection during sexual transmission J. Virol. 79,3098-3107
-
Ho, D. D., Pomerantz, R. J., Kaplan, J. C. (1987) Pathogenesis of infection with human immunodeficiency virus N. Engl. J. Med. 317,278-286[Medline]
-
Pomerantz, R. J., Kuritzkes, D. R., de la Monte, S. M., Rota, T. R., Baker, A. S., Albert, D., Bor, D. H., Feldman, E. L., Schooley, R. T., Hirsch, M. S. (1987) Infection of the retina by human immunodeficiency virus type 1 N. Engl. J. Med. 317,1643-1647[Medline]
-
Zhang, H., Geethanjali, D., Beumont, M., Livornese, L., van Uiteri, B., Henning, K., Pomerantz, R. J. (1998) Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy N. Engl. J. Med. 339,1803-1891[Abstract/Free Full Text]
-
Ghorpade, A., Xia, M. Q., Hyman, B. T., Persidsky, Y., Nukuna, A., Bock, P., Che, M., Limoges, J., Gendelman, H. E., Mackay, C. R. (1998) Role of the beta-chemokine receptors CCR3 and CCR5 in human immunodeficiency virus type 1 infection of monocytes and microglia J. Virol. 72,3351-3361[Abstract/Free Full Text]
-
Hanly, A., Petito, C. K. (1998) HLA-DR positive dendritic cells of the normal human choroid plexus; a potential reservoir of HIV in the central nervous system Hum. Pathol. 39,88-93
-
Eggers, C. C., van Lunzen, J., Buhk, T., Stellbrink, H. J. (1999) HIV infection of the central nervous system is characterized by rapid turnover of viral RNA in cerebrospinal fluid J. AIDS 20,259-264
-
Finzi, D., Hermankova, M., Pierson, T., Carruth, L. M., Buck, C., Chaisson, R. E., Quinn, T. C., Chadwick, K., Margolick, J., Brookmeyer, R., Gallant, J., Markowitz, M., Ho, D. D., Richman, D. D., Siliciano, R. F. (1997) Identification of a reservoir of HIV-1 in patients on highly active antiretroviral therapy Science 278,1295-1300[Abstract/Free Full Text]
-
Wong, J. K., Hezarch, M., Gunthard, H. F., Havlir, D. V., Ignacio, C. C., Spina, C. A., Richman, D. D. (1997) Recovery of replication competent HIV despite prolonged suppression of plasma viremia Science 278,1291-1295[Abstract/Free Full Text]
-
Chun, T. W., Stuyver, L., Mizell, S. B., et al (1997) Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy Proc. Natl. Acad. Sci. USA 94,13193-13197[Abstract/Free Full Text]
-
Chun, T. W., Engel, D., Berrey, M. M., Shea, T., Corey, L., Fauci, A. S. (1998) Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection Proc. Natl. Acad. Sci. USA 95,8869-8873[Abstract/Free Full Text]
-
Zhang, L., Ramratnam, B., Tenner-Racz, K., He, Y., Vesanen, M., Lewin, S., Talal, A., Racz, P., Perelson, A. S., Korber, B. T., Markowitz, M., Ho, D. D. (1999) Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy N. Engl. J. Med. 340,1605-1613[Abstract/Free Full Text]
-
Finzi, D., Blankson, J., Siliciano, J. D., Margolick, J. B., Chadwick, K., Pierson, T., Smith, K., Lisziewicz, J., Lori, F., Flexner, C., Quinn, T. C., Chaisson, R. E., Rosenberg, E., Walker, B., Gange, S., Gallant, J., Siliciano, R. (1999) Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy Nat. Med. 5,512-517[Medline]
-
Ramratnam, B., Mittler, J. E., Zhang, L., Boden, D., Hurley, A., Fang, F., Macken, C. A., Perelson, A. S., Markowitz, M., Ho, D. D. (2000) The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy Nat. Med. 6,62-85[Medline]
-
Tamalet, C., Lafeuillade, A., Fantini, J., Poggi, C., Yahi, N. (1997) Quantification of HIV-1 viral load in lymphoid and blood cells, assessment during four drug combination therapy AIDS 11,895-901[Medline]
-
Ibanez, A., Puig, T., Elias, J., Clotet, B., Ruiz, I., Martinez, M. A. (1999) Quantification of integrated and total HIV-1 DNA after long term highly active antiretroviral therapy in HIV-1 infected patients AIDS 13,1045-1049[Medline]
-
Gendelman, H. E., Narayan, O., Molineaux, S., Clements, J. E., Ghotbi, Z. (1985) Slow, persistent replication of lentiviruses; role of tissue macrophages and macrophage precursors in bone marrow Proc. Natl. Acad. Sci. USA 82,7086-7090[Abstract/Free Full Text]
-
Meltzer, M. S., Gendelman, H. E. (1992) Mononuclear phagocytes as targets, tissue reservoirs and immunoregulatory cells in human immunodeficiency virus disease Curr. Topics Microbiol. Immunol. 181,239-263[Medline]
-
Sonza, S., Maerz, A., Deacon, N. J., Meanger, J., Mills, J., Crowe, S. M. (1996) HIV-1 replication is blocked prior to reverse transcription and integration in freshly isolated peripheral blood monocytes J. Virol. 70,3863-3869[Abstract]
-
Crowe, S. M., Mills, J., McGrath, M. S. (1987) Quantitative immunofluorescent cytofluorographic analysis of CD4 surface antigen expression and HIV infection of human peripheral blood monocyte/macrophages AIDS Res. Hum. Retrovir. 1,145-146
-
Lewin, S. R., Kirihara, J., Sonza, S., Irving, L., Mills, J., Crowe, S. M. (1998) HIV-1 DNA and mRNA concentrations are similar in peripheral blood monocytes and alveolar macrophages in HIV-1 infected individuals AIDS 12,719-727[Medline]
-
Clarke, J. R., Krishnan, V., Bennete, J., Mitchell, D., Jeffries, D. J. (1990) Detection of HIV-1 in human lung macrophages using the polymerase chain reaction AIDS 4,1123-1136
-
Hufert, F. T., Schmitz, J., Schreiber, M., Schmitz, H., Racz, P., Laer, D. D. (1993) Human Kupffer cells infected with HIV-1 in vivo J. Acquir. Immune Defic. Syndr. 6,772-777
-
McIIroy, D., Autran, B., Cheynier, R., Cauvel, P., Oksenhendler, E., Debre, P., Hosmalin, A. (1996) Low infection frequency of macrophages in the spleen of HIV+ patients Res. Virol. 147,115-121[Medline]
-
Embretson, M., Zupanic, M., Ribas, J. L., Burke, P., Racz, P., Tenner-Racz, K., Haase, A. T. (1993) Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS Nature 362,359-362[Medline]
-
Orenstein, J. M., Fox, C., Wahl, S. M. (1997) Macrophages as a source of HIV during opportunistic infections Science 376,1857-1861
-
McElrath, M., Pruett, J., Cohn, Z. (1989) Mononuclear phagocytes of blood and bone marrow; comparative roles as viral reservoirs in human immunodeficiency virus type-1 infections Proc. Natl. Acad. Sci. USA 86,675-679[Abstract/Free Full Text]
-
Glass, J. D., Fedor, H., Wesselingh, S. L., McArthur, J. C. (1995) Immunocytochemical quantitation of human immunodeficiency virus in the brain, correlations with dementia Ann. Neurol. 38,755-762[Medline]
-
Smith, P. D., Meng, G., Shaw, G. M., Li, L. (1997) Infection of gastrointestinal tract macrophages by HIV-1 J. Leukoc. Biol. 62,72-77[Abstract]
-
Thomas, E. D., Ramberg, R. E., Sale, G. E., Sparkes, R. S., Golde, D. W. (1976) Direct evidence for a bone marrow origin of the alveolar macrophages in man Science 192,1016-1018[Abstract/Free Full Text]
-
Zhu, T., Chang, Y. H., Muthui, D., Feng, F., Holte, S., Nickle, D., Berry, M., Shea, T., Brodie, S. J., Self, S., Mullins, J., Corey, L. (1999) HIV-1 in monocyte-macrophages of patients receiving potent therapy 4th International Workshop on HIV and Cells of Macrophage Lineage and Other Reservoirs Florence, Italy.
-
Lassmann, H., Schmied, M., Vass, K., Hickey, W. F. (1993) Bone marrow derived elements and resident microglia in brain inflammation Glia 7,19-24[Medline]
-
Crowe, S. M., McGrath, M. S., Elbeik, T., Kirihara, J., Mills, J. (1989) Comparative assessment of antiretrovirals in human monocyte-macrophages and lymphoid cell lines infected with the human immunodeficiency virus J. Med. Virol. 29,176-180[Medline]
-
Perno, C. F., Newcomb, F. M., Davis, D. A., Aquaro, S., Humphrey, R. W., Calio, R., Yarchoan, R. (1998) Relative potency of protease inhibitors in monocytes/macrophages acutely and chronically infected with human immunodeficiency virus J. Infect. Dis. 178,413-422[Medline]
-
Aquaro, S., Perno, C. F., Balestra, E., Balzarini, J., Cenci, A., Francesconi, M., Panti, S., Serra, F., Villani, N., Calio, R. (1997) Inhibition of replication of HIV in primary monocyte/macrophages by different antiviral drugs and comparative efficacy in lymphocytes J. Leukoc. Biol. 62,138-143[Abstract]
-
Aquaro, S., Balestra, E., Cenci, A., Francesconi, M., Calio, R., Perno, C. F. (1997) HIV infection in macrophage: role of long-lived cells and related therapeutical strategies J. Biol. Regul. Homeost. Agents 11,69-73[Medline]
-
Pomerantz, R. J. (1993) Residual HIV-1 disease in the era of highly active antiretroviral therapy N. Engl. J. Med. 340,1672-1674[Free Full Text]
-
Kravcik, S., Gallicano, K., Roth, V., Cassol, S., Hawley-Foss, N., Badley, A., Cameron, D. W. (1999) Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir J. Acquir. Immune Defic. Syndr. 21,371-375
-
Aweeka, F., Jayewardene, A., Staprans, S., Bellibas, S. E., Kearney, B., Lizak, P., Novakovic-Agopian, T., Price, R. W. (1999) Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1-infected patients with and without AIDS dementia complex J. Acquir. Immune Defic. Syndr. 20,39-43
-
Lin, J. H., Chiba, M., Balani, S. K., Chen, I. W., Kwei, G. Y., Vastag, K. J., Nishime, J. A. (1996) Species differences in the pharmacokinetics and metabolism of indinavir, a potent human immunodeficiency virus protease inhibitor Drug Metab. Disposit 24,1111-1120[Abstract]
-
Daluge, S. M., Good, S. S., Faletto, M. B., Miller, W. H., St. Clair, M. H., Boone, L. R., Tisdale, M., Parry, N. R., Reardon, J. E., Dornsife, R. E., Averett, D. R., Krenitsky, T. A. (1997) 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity Antimicrob. Agents Chemother. 41,1082-1093[Abstract]
-
Glynn, S. L., Yazdanian, M. (1998) In vitro blood brain barrier permeability of nevirapine compared to other HIV antiretroviral agents J. Pharmaceut. Sci. 87,306-310[Medline]
-
Kim, R. B., Fromm, M. F., Wandel, C., Leake, B., Wood, A., Roden, D. M. (1998) The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors J. Clin. Invest. 101,289-294[Medline]
-
Chun, T. W., Engel, D., Mizell, S. B., Ehler, L. A., Fauci, A. S. (1998) Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines J. Exp. Med. 188,83-91[Abstract/Free Full Text]
-
Martinez, M. A., Cababa, M., Ibancz, A., Clotet, B., Arno, A., Ruiz, L. (1999) Human immunodeficiency virus type 1 genetic evolution in patients with prolonged suppression of plasma viremia Virology 256,180-187[Medline]
-
Lewin, S. R., Vesanen, M., Kostrikis, L., Hurley, A., Duran, M., Zhang, L., Ho, D. D., Markowitz, M. (1999) Use of real-time PCR and molecular beacons to detect virus replication in human immunodeficiency virus type 1-infected individuals on prolonged effective antiretroviral therapy J. Virol. 73,6099-6103[Abstract/Free Full Text]
-
Furtado, M. R., Callaway, D. S., Phair, J. R., et al (1999) Persistence of HIV-1 transcription in peripheral blood mononuclear cells in patients receiving potent antiretroviral therapy N. Engl. J. Med. 340,1614-1622[Abstract/Free Full Text]
-
Sharkey, M. E., Teo, I., Greenough, T., Sharova, N., Luzuriaga, K., Sullivan, J. L., Bucy, P., Kostrikis, L. G., Haase, A., Veryard, C., Davaro, R. E., Cheeseman, S. H., Daly, J. S., Bova, C., Ellison, R. T., Mady, B., Lai, K. K., Moyle, G., Nelson, M., Gazzard, B., Shaunak, S., Stevenson, M. (2000) Persistence of episomal HIV-1 infection inter-mediates in patients on highly active antiretroviral therapy Nat. Med. 6,76-81[Medline]
-
Natarajan, V., Bosche, M., Metcalf, J. A., Ward, D. J., Lane, H. C., Kovacs, J. A. (1999) HIV-1 replication in patients with undetectable plasma virus receiving HAART Lancet 353,119-120[Medline]
-
Gunthard, H. F., Frost, S. D. W., Leigh-Brown, A. J., Ignacio, C. C., Kee, K., Perelson, A. S., Spina, C. A., Havlir, D. V., Hezareh, M., Looney, D. J., Richman, D. D., Wong, J. K. (1999) Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular reservoirs in the setting of potent antiviral therapy J. Virol. 73,9404-9412[Abstract/Free Full Text]
-
Chun, T. W., Fauci, A. S. (1999) Latent reservoirs of HIV: Obstacles to the eradication of virus Proc. Natl. Acad. Sci. USA 96,10958-10961[Free Full Text]
-
Lewin, S. R., Sonza, S., Irving, L. B., McDonald, C. F., Mills, J., Crowe, S. M. (1996) Surface CD4 is critical to in vitro HIV infection of human alveolar macrophages AIDS Res. Hum. Retrovir. 12,877-883[Medline]
This article has been cited by other articles:
|
|
|
|
 
I. Komuro, T. Sunazuka, K. S. Akagawa, Y. Yokota, A. Iwamoto, and S. Omura
Erythromycin derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small isoforms of C/EBP{beta}
PNAS,
August 26, 2008;
105(34):
12509 - 12514.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Rossi, P. Franchetti, F. Pierige, L. Cappellacci, S. Serafini, E. Balestra, C.-F. Perno, M. Grifantini, R. Calio, and M. Magnani
Inhibition of HIV-1 replication in macrophages by a heterodinucleotide of lamivudine and tenofovir
J. Antimicrob. Chemother.,
April 1, 2007;
59(4):
666 - 675.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Cassol, M. Alfano, P. Biswas, and G. Poli
Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence
J. Leukoc. Biol.,
November 1, 2006;
80(5):
1018 - 1030.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Pinti, P. Biswas, L. Troiano, M. Nasi, R. Ferraresi, C. Mussini, J. Vecchiet, R. Esposito, R. Paganelli, and A. Cossarizza
Different Sensitivity to Apoptosis in Cells of Monocytic or Lymphocytic Origin Chronically Infected with Human Immunodeficiency Virus Type-1
Experimental Biology and Medicine,
December 1, 2003;
228(11):
1346 - 1354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Crowe, T. Zhu, and W. A. Muller
The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection
J. Leukoc. Biol.,
November 1, 2003;
74(5):
635 - 641.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. G. Brooks, P. A. Arlen, L. Gao, C. M. R. Kitchen, and J. A. Zack
Identification of T cell-signaling pathways that stimulate latent HIV in primary cells
PNAS,
October 28, 2003;
100(22):
12955 - 12960.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Fraternale, A. Casabianca, L. Rossi, L. Chiarantini, G. F. Schiavano, A. T. Palamara, E. Garaci, and M. Magnani
Erythrocytes as carriers of reduced glutathione (GSH) in the treatment of retroviral infections
J. Antimicrob. Chemother.,
October 1, 2003;
52(4):
551 - 554.
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Komuro, Y. Yokota, S. Yasuda, A. Iwamoto, and K. S. Kagawa
CSF-induced and HIV-1-mediated Distinct Regulation of Hck and C/EBP{beta} Represent a Heterogeneous Susceptibility of Monocyte-derived Macrophages to M-tropic HIV-1 Infection
J. Exp. Med.,
August 4, 2003;
198(3):
443 - 453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Sonza, H. P. Mutimer, K. O'Brien, P. Ellery, J. L. Howard, J. H. Axelrod, N. J. Deacon, S. M. Crowe, and D. F. J. Purcell
Selectively Reduced tat mRNA Heralds the Decline in Productive Human Immunodeficiency Virus Type 1 Infection in Monocyte-Derived Macrophages
J. Virol.,
November 13, 2002;
76(24):
12611 - 12621.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Rice, R. Connor, S. Worgall, J. P. Moore, P. L. Leopold, R. J. Kaner, and R. G. Crystal
Inhibition of HIV-1 Replication in Alveolar Macrophages by Adenovirus Gene Transfer Vectors
Am. J. Respir. Cell Mol. Biol.,
August 1, 2002;
27(2):
214 - 219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Davis, E. Read-Connole, K. Pearson, H. M. Fales, F. M. Newcomb, J. Moskovitz, and R. Yarchoan
Oxidative Modifications of Kynostatin-272, a Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor: Potential Mechanism for Altered Activity in Monocytes/Macrophages
Antimicrob. Agents Chemother.,
February 1, 2002;
46(2):
402 - 408.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
C. Chougnet, C. Freitag, M. Schito, E. K. Thomas, A. Sher, and G. M. Shearer
In Vivo CD40-CD154 (CD40 Ligand) Interaction Induces Integrated HIV Expression by APC in an HIV-1-Transgenic Mouse Model
J. Immunol.,
March 1, 2001;
166(5):
3210 - 3217.
[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
