Hematopoietic Precursor Cells Isolated From Patients on Long-term Suppressive HIV Therapy Did Not Contain HIV-1 DNA

Josefsson, Lina; Eriksson, Susanne P.; Sinclair, Elizabeth; Ho, Terrence; Killian, Martin; Epling, Lorrie; Shao, Wei; Lewis, Bradley D.; Bacchetti, Peter; Loeb, Lisa; Custer, Jeff; Poole, Lauren; Hecht, Frederick M.; Palmer, Sarah

doi:10.1093/infdis/jis301

Cited by 81 publications

(79 citation statements)

References 14 publications

(23 reference statements)

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“…The monotypic HIV-1 templates that we sequenced likely include defective proviruses that were less likely to undergo lytic infection and less likely to be cleared by cellular immune responses and therefore were enriched over time on ART. Persistence of defective forms has been described previously (44,45). However, PBMCs harboring replicationcompetent HIV-1 that is genetically identical to persistent and predominant monotypic plasma variants have also been identified (28), indicating that not all identical sequences are defective.…”

Section: Discussionmentioning

confidence: 72%

An Increasing Proportion of Monotypic HIV-1 DNA Sequences during Antiretroviral Treatment Suggests Proliferation of HIV-Infected Cells

Wagner¹,

McKernan²,

Tobin

et al. 2013

J Virol

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Understanding how HIV-1 persists during effective antiretroviral therapy (ART) should inform strategies to cure HIV-1 infection. We hypothesize that proliferation of HIV-1-infected cells contributes to persistence of HIV-1 infection during suppressive ART. This predicts that identical or monotypic HIV-1 DNA sequences will increase over time during ART. We analyzed 1,656 env and pol sequences generated following single-genome amplification from the blood and sputum of six individuals during long-term suppressive ART. The median proportion of monotypic sequences increased from 25.0% prior to ART to 43.2% after a median of 9.8 years of suppressive ART. The proportion of monotypic sequences was estimated to increase 3.3% per year (95% confidence interval, 2.3 to 4.4%; P < 0.001). Drug resistance mutations were not more common in the monotypic sequences, arguing against viral replication during times with lower antiretroviral concentrations. Bioinformatic analysis found equivalent genetic distances of monotypic and nonmonotypic sequences from the predicted founder virus sequence, suggesting that the relative increase in monotypic variants over time is not due to selective survival of cells with viruses from the time of acute infection or from just prior to ART initiation. Furthermore, while the total HIV-1 DNA load decreased during ART, the calculated concentration of monotypic sequences was stable in children, despite growth over nearly a decade of observation, consistent with proliferation of infected CD4؉ T cells and slower decay of monotypic sequences. Our findings suggest that proliferation of cells with proviruses is a likely mechanism of HIV-1 DNA persistence, which should be considered when designing strategies to eradicate HIV-1 infection.

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Section: Discussionmentioning

confidence: 72%

An Increasing Proportion of Monotypic HIV-1 DNA Sequences during Antiretroviral Treatment Suggests Proliferation of HIV-Infected Cells

Wagner¹,

McKernan²,

Tobin

et al. 2013

J Virol

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show abstract

“…To quantify and genetically characterize HIV-1 viral populations in the cells isolated from peripheral blood and GALT, we used the single-proviral sequencing assay (47). This assay has been described before, but briefly, sorted cells are lysed and serially diluted and single HIV-1 molecules are PCR amplified using primers flanking the p6-RT region.…”

Section: Methodsmentioning

confidence: 99%

“…We estimated the HIV-1 infection frequency in each cell type using an ML statistical analysis as described in SI Materials and Methods, Statistical Methods, building on methods described previously (47).…”

Section: Methodsmentioning

confidence: 99%

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

Josefsson

Stockenström

Faria

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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250

296

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Significance Identifying the source and dynamics of persistent HIV-1 during combinational antiretroviral therapy (cART) is crucial for understanding the barriers to curing HIV infection. Through genetic characterization of HIV-1 DNA in infected cells from peripheral blood and gut-associated lymphoid tissue from patients after long-term suppressive cART, our study reveals that the primary barrier to a cure is a remarkably stable pool of infected memory CD4 + T cells. Through in-depth phylogenetic analyses, we determined that the HIV-1 reservoir in these cells from eight patients is kept stable during long-term cART and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.

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“…These findings are supported by additional studies demonstrating that HPCs are infected by HIV-1 in vivo (54,67). However, there are also conflicting studies reporting that HIV-1 genomes could not be detected in CD34 ϩ cells in the bone marrow of patients with undetectable viral loads on HAART (21,36). CD34 ϩ HPCs are rare cells, and only an extremely low rate of latent infection would be expected in most HAART-treated patients.…”

mentioning

confidence: 99%

Latent HIV-1 Infection Occurs in Multiple Subsets of Hematopoietic Progenitor Cells and Is Reversed by NF-κB Activation

McNamara

Ganesh

Collins

2012

J Virol

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The ability of HIV-1 to establish a latent infection presents a barrier to curing HIV. The best-studied reservoir of latent virus in vivo is resting memory CD4 + T cells, but it has recently been shown that CD34 + hematopoietic progenitor cells (HPCs) can also become latently infected by HIV-1 in vitro and in vivo . CD34 + cells are not homogenous, however, and it is not yet known which types of CD34 + cells support a latent infection. Furthermore, the mechanisms through which latency is established in this cell type are not yet known. Here we report the development of a primary cell model for latent HIV-1 infection in HPCs. We demonstrate that in this model, latent infection can be established in all subsets of HPCs examined, including HPCs with cell surface markers consistent with immature hematopoietic stem and progenitor cells. We further show that the establishment of latent infection in these cells can be reversed by tumor necrosis factor alpha (TNF-α) through an NF-κB-dependent mechanism. In contrast, we do not find evidence for a role of positive transcription elongation factor b (P-TEFb) in the establishment of latent infection in HPCs. Finally, we demonstrate that prostratin and suberoylanilide hydroxamic acid (SAHA), but not hexamethylene bisacetamide (HMBA) or 5-aza-2′-deoxycytidine (Aza-CdR), reactivate latent HIV-1 in HPCs. These findings illuminate the mechanisms through which latent infection can be established in HPCs and suggest common pathways through which latent virus could be reactivated in both HPCs and resting memory T cells to eliminate latent reservoirs of HIV-1.

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Hematopoietic Precursor Cells Isolated From Patients on Long-term Suppressive HIV Therapy Did Not Contain HIV-1 DNA

Cited by 81 publications

References 14 publications

An Increasing Proportion of Monotypic HIV-1 DNA Sequences during Antiretroviral Treatment Suggests Proliferation of HIV-Infected Cells

An Increasing Proportion of Monotypic HIV-1 DNA Sequences during Antiretroviral Treatment Suggests Proliferation of HIV-Infected Cells

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

Latent HIV-1 Infection Occurs in Multiple Subsets of Hematopoietic Progenitor Cells and Is Reversed by NF-κB Activation

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