Quantifying Residual HIV-1 Replication in Patients Receiving Combination Antiretroviral Therapy

Zhang, Linqi; Ramratnam, Bharat; Tenner-Rácz, Klara; He, Yuxian; Vesanen, Mika; Lewin, Sharon R.; Talal, Andrew H.; Rácz, Paul; Perelson, Alan S.; Korber, Bette T.; Markowitz, Martin; Ho, David D.

doi:10.1056/nejm199905273402101

Cited by 761 publications

(561 citation statements)

References 22 publications

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“…The CD4 ϩ CD45RO ϩ HLA DR Ϫ resting memory T cell is recognized as a major HIV-1 reservoir (1)(2)(3)(4)(61)(62)(63). We found that CD16 ϩ monocytes had about half the number of HIV-1 DNA copies contained within memory T cells with this sample size (n ϭ 11), although there was no significant difference between these cell populations.…”

Section: Discussionmentioning

confidence: 68%

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The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo

Ellery

Tippett

Chiu

et al. 2007

The Journal of Immunology

302

276

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HIV-1 persists in peripheral blood monocytes in individuals receiving highly active antiretroviral therapy (HAART) with viral suppression, despite these cells being poorly susceptible to infection in vitro. Because very few monocytes harbor HIV-1 in vivo, we considered whether a subset of monocytes might be more permissive to infection. We show that a minor CD16+ monocyte subset preferentially harbors HIV-1 in infected individuals on HAART when compared with the majority of monocytes (CD14highCD16−). We confirmed this by in vitro experiments showing that CD16+ monocytes were more susceptible to CCR5-using strains of HIV-1, a finding that is associated with higher CCR5 expression on these cells. CD16+ monocytes were also more permissive to infection with a vesicular stomatitis virus G protein-pseudotyped reporter strain of HIV-1 than the majority of monocytes, suggesting that they are better able to support HIV-1 replication after entry. Consistent with this observation, high molecular mass complexes of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) were observed in CD16+ monocytes that were similar to those observed in highly permissive T cells. In contrast, CD14highCD16− monocytes contained low molecular mass active APOBEC3G, suggesting this is a mechanism of resistance to HIV-1 infection in these cells. Collectively, these data show that CD16+ monocytes are preferentially susceptible to HIV-1 entry, more permissive for replication, and constitute a continuing source of viral persistence during HAART.

show abstract

Section: Discussionmentioning

confidence: 68%

“…However, current HAART regimens do not eradicate HIV-1 infection. This is in part attributed to the presence of anatomical and cellular sanctuary sites where HIV-1 can persist due to a combination of poor drug penetration, viral latency, and lowlevel ongoing replication (1)(2)(3).…”

mentioning

confidence: 99%

The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo

Ellery

Tippett

Chiu

et al. 2007

The Journal of Immunology

302

276

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“…P ersistence of HIV-1 proviral DNA and viral RNA in PBMC after prolonged suppression of viral replication by highly active antiretroviral chemotherapy emphasizes the importance of understanding viral latency and the mechanism of viral reactivation in provirally infected cells (1,2). The lung is a particularly important target organ for HIV-1 reactivation.…”

Section: Differentiation Of Monocytes To Macrophages Switches the Mycmentioning

confidence: 99%

Differentiation of Monocytes to Macrophages Switches theMycobacterium tuberculosisEffect on HIV-1 Replication from Stimulation to Inhibition: Modulation of Interferon Response and CCAAT/Enhancer Binding Protein β Expression

Weiden

Tanaka

Qiao³

et al. 2000

The Journal of Immunology

118

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HIV-1 replication is inhibited in uninflamed lung macrophages and is stimulated during tuberculosis. Attempts to recapitulate activation of HIV-1 replication in primary monocytes and macrophages ex vivo and in the untreated and PMA-treated THP-1 cell line model in vitro have produced opposite results depending on the state of differentiation of the cells. After infection with Mycobacterium tuberculosis, monocytes enhanced HIV-1 replication and produced a stimulatory 37-kDa CCAAT/enhancer binding protein β (C/EBPβ) transcription factor, whereas macrophages suppressed HIV-1 replication and produced an inhibitory 16-kDa C/EBPβ transcription factor. IFN-β induced inhibitory 16-kDa C/EBPβ in macrophages, but had no effect on C/EBPβ expression in monocytes. Macrophages, but not monocytes, were able to activate IFN-stimulated gene factor-3 (ISGF-3), a transcription factor composed of STAT-1, STAT-2, and IFN regulatory factor (IRF)-9, after infection with M. tuberculosis or stimulation with type I IFN. Macrophages expressed IRF-9 DNA-binding activity, but monocytes did not, and addition of the IRF-9 component reconstituted ISGF-3 in extracts of IFN-treated monocytes. Modulation of IFN responsiveness upon differentiation occurred at least in part through a post-transcriptionally regulated increase in IRF-9 expression. Both monocytes and macrophages maintained IFN responsiveness, activating STAT-1 homodimer formation and transcription of the STAT-1 gene after IFN stimulation. In addition, both monocytes and macrophages were able to activate NF-κB upon infection with M. tuberculosis. These results show that induction of ISGF-3, expression of the inhibitory 16-kDa C/EBPβ, and suppression of HIV-1 replication via a transcriptional mechanism are macrophage-specific responses to infection with M. tuberculosis.

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“…The introduction of HAART has resulted in a major reduction of virus load and in a significant decline in mortality and morbidity among HIV-infected individuals (17,18,32,49). Unfortunately, HAART is unable to eradicate HIV infection due to its limited effects on viral reservoirs carrying replicationcompetent HIV (5,7,10,35).…”

Section: Discussionmentioning

confidence: 99%

“…In the majority of HIVinfected individuals, the introduction of highly active antiretroviral therapy (HAART) induces suppression of viral replication, which is associated with at least partial reconstitution of the CD4 ϩ T-cell pool and ultimately results in a significant decline in mortality/morbidity. Unfortunately, HAART does not eradicate the infection, and in fact, after its suspension, HIV RNA rapidly rebounds to pretherapy levels, indicating the existence of refractory reservoirs (17,31,40,42,49). Cellular sources of reemerging HIV include latently infected resting CD4 ϩ T cells as well as monocytes/macrophages (M/M) and dendritic cells.…”

mentioning

confidence: 99%

Administration of Fludarabine-Loaded Autologous Red Blood Cells in Simian Immunodeficiency Virus-Infected Sooty Mangabeys Depletes pSTAT-1-Expressing Macrophages and Delays the Rebound of Viremia after Suspension of Antiretroviral Therapy

Cervasi

Paiardini

Serafini

et al. 2006

J Virol

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Quantifying Residual HIV-1 Replication in Patients Receiving Combination Antiretroviral Therapy

Cited by 761 publications

References 22 publications

The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo

The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo

Differentiation of Monocytes to Macrophages Switches theMycobacterium tuberculosisEffect on HIV-1 Replication from Stimulation to Inhibition: Modulation of Interferon Response and CCAAT/Enhancer Binding Protein β Expression

Administration of Fludarabine-Loaded Autologous Red Blood Cells in Simian Immunodeficiency Virus-Infected Sooty Mangabeys Depletes pSTAT-1-Expressing Macrophages and Delays the Rebound of Viremia after Suspension of Antiretroviral Therapy

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