In Vivo Evidence for Instability of Episomal Human Immunodeficiency Virus Type 1 cDNA

Sharkey, Mark E.; Triques, Karine; Kuritzkes, Daniel R.; Stevenson, Mario

doi:10.1128/jvi.79.8.5203-5210.2005

Cited by 97 publications

(90 citation statements)

References 47 publications

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“…It is well established that a replication-competent virus may be recovered from circulating peripheral blood monocytes of HIV-1-infected individuals, including those receiving HAART and who have maintained viral loads below detectable limits (Ͻ50 HIV-1 RNA copies per milliliter of plasma) for prolonged periods (12,13). The fact that monocytes remain in circulation for up to 3 days (14) suggests ongoing recent infection of these cells or their precursors (5); this is supported by the detection of labile unintegrated circularized forms of viral DNA (2-long terminal repeat (LTR) circles) (13,15,16), multiply spliced viral mRNA species in freshly isolated monocytes (13), and viral evolution within this compartment (17). Strains of HIV-1 that infect cells of the macrophage lineage typically use CCR5 as a coreceptor for viral entry, and increasing CCR5 expression on monocytes during differentiation correlates with the permissiveness of these cells to infection (18,19).…”

mentioning

confidence: 82%

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

305

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.

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mentioning

confidence: 82%

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

305

276

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“…In turn, virions released during the reactivation process may spread to and infect neighboring resting as well as activated CD4 + T cells; direct cell-to-cell spread in the absence of virion release may also occur. In this regard, the presence of unintegrated HIV DNA in resting CD4 + T cells (2) and circularized HIV DNA in CD4 + T cells (13,14) has been demonstrated in patients receiving effective antiviral therapy, indicating recent infection. Although the half-life of integrated HIV DNA in resting CD4 + T cells has been firmly demonstrated to exceed the previous estimates (5), the reactivation events described above could allow continual replenishment of the CD4 + T cell viral reservoir and reset the overall half-life of HIV in infected patients receiving effective therapy.…”

Section: Discussionmentioning

confidence: 99%

“…However, a number of studies over the past several years have suggested that low levels of ongoing viral replication continue to persist and consequently prolong the overall half-life of HIV in patients receiving antiviral therapy (9)(10)(11)(12). These include the persistence of replication-competent virus (2-4), unintegrated proviral DNA, both linear (2) and circularized (13,14), and cell-associated HIV RNA (6,7,11,15,16). In addition, other studies have demonstrated that intensification of conventional antiviral regimens in patients who remained aviremic accelerated the decay of the latent HIV reservoir in the resting CD4 + T cell compartment (12) and further suppressed plasma viremia to well below the limit of detection (3.2-23 copies of HIV RNA per ml) (17).…”

Section: Introductionmentioning

confidence: 99%

HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir

Chun¹

2005

Journal of Clinical Investigation

245

203

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The persistence of latently infected, resting CD4 + T cells is considered to be a major obstacle in preventing the eradication of HIV-1 even in patients who have received effective antiviral therapy for an average duration of 5 years. Although previous studies have suggested that the latent HIV reservoir in the resting CD4 + T cell compartment is virologically quiescent in the absence of activating stimuli, evidence has been mounting to suggest that low levels of ongoing viral replication persist and in turn, prolong the overall half-life of HIV in patients receiving antiviral therapy. Here, we demonstrate the persistence of replication-competent virus in CD4 + T cells in a cohort of patients who had received uninterrupted antiviral therapy for up to 9.1 years that rendered them consistently aviremic throughout that time. Surprisingly, substantially higher levels of HIV proviral DNA were found in activated CD4 + T cells when compared with resting CD4 + T cells in the majority of patients we studied. Phylogenetic analyses revealed evidence for cross infection between the resting and activated CD4 + T cell compartments, suggesting that ongoing reactivation of latently infected, resting CD4 + T cells and spread of virus by activated CD4 + T cells may occur in these patients. Such events may allow continual replenishment of the CD4 + T cell reservoir and resetting of the half-life of the latently infected, resting CD4 + T cells despite prolonged periods of aviremia.

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“…ϩ T cells as a whole will be affected by the underlying decay of this DNA species and the halflives of the cells being considered, and taking these different mechanisms into consideration may partly explain the controversy surrounding in vitro and ex vivo 2-LTR decay estimates (18,(36)(37)(38). Approximately 0.36% of these resting memory cells expressed the proliferation marker Ki-67 after week 12.…”

Section: Cd38mentioning

confidence: 99%

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 ⁺ T Cells during Antiretroviral Therapy

Murray

Zaunders²,

McBride

et al. 2014

J Virol

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The latent HIV reservoir is a major impediment to curing HIV infection. The contribution of CD4؉ T cell activation status to the establishment and maintenance of the latent reservoir was investigated by enumerating viral DNA components in a cohort of 12 individuals commencing antiretroviral therapy (ART) containing raltegravir, an integrase inhibitor. Prior to ART, the levels of total HIV DNA were similar across HLA-DR IMPORTANCE It is generally believed that HIV is not cleared by extensive antiretroviral therapy (ART) due to the difficulty in eradicating the latent reservoir in resting CD4؉ T cells. New therapies that attempt to activate this reservoir so that immune or viral cytopathic mechanisms can remove those infected cells are currently being investigated. However, results obtained in this research indicate that activation, at least on some level, already occurs within this reservoir. Furthermore, we are the first to describe the dynamics of different HIV DNA species in resting and activated memory CD4؉ T cell subsets that point to the role different levels of activation play in maintaining the HIV reservoir.

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In Vivo Evidence for Instability of Episomal Human Immunodeficiency Virus Type 1 cDNA

Cited by 97 publications

References 47 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

HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 ⁺ T Cells during Antiretroviral Therapy

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In Vivo Evidence for Instability of Episomal Human Immunodeficiency Virus Type 1 cDNA

Cited by 97 publications

References 47 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

HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir

HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 + T Cells during Antiretroviral Therapy

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HIV DNA Subspecies Persist in both Activated and Resting Memory CD4 ⁺ T Cells during Antiretroviral Therapy