Analysis of Human Immunodeficiency Virus Type 1 Viremia and Provirus in Resting CD4+ T Cells Reveals a Novel Source of Residual Viremia in Patients on Antiretroviral Therapy

Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Journal of Virology (Impact Factor: 4.44). 07/2009; 83(17):8470-81. DOI: 10.1128/JVI.02568-08
Source: PubMed


Highly active antiretroviral therapy (HAART) can reduce human immunodeficiency virus type 1 (HIV-1) viremia to clinically
undetectable levels. Despite this dramatic reduction, some virus is present in the blood. In addition, a long-lived latent
reservoir for HIV-1 exists in resting memory CD4+ T cells. This reservoir is believed to be a source of the residual viremia and is the focus of eradication efforts. Here,
we use two measures of population structure—analysis of molecular variance and the Slatkin-Maddison test—to demonstrate that
the residual viremia is genetically distinct from proviruses in resting CD4+ T cells but that proviruses in resting and activated CD4+ T cells belong to a single population. Residual viremia is genetically distinct from proviruses in activated CD4+ T cells, monocytes, and unfractionated peripheral blood mononuclear cells. The finding that some of the residual viremia
in patients on HAART stems from an unidentified cellular source other than CD4+ T cells has implications for eradication efforts.

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Available from: Timothy P Brennan, Oct 07, 2015
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    • "In virtually all patients, when HAART is interrupted circulating HIV levels rebound within 2 to 8 weeks and uncontrolled replication resumes (Chun et al., 1999; Stöhr et al., 2013) although a few rare patients are able to spontaneously control their infections (Sáez-Cirión et al., 2013). However, residual virus recovered from treated patients (Brennan et al., 2009), and the rebounding virus recovered during the short treatment interruptions (Joos et al., 2008), have much less sequence heterogeneity than seen in actively replicating viral populations, suggesting that replenishment of the viral population arises from reactivation of a very restricted set of latently infected cells. HIV-1 subsets in the GALT of patients under HAART initiated at the acute phase have low diversity, suggesting highly restricted viral replication in this anatomical compartment (Evering et al., 2012). "
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    ABSTRACT: Replication-competent latent HIV-1 proviruses that persist in the genomes of a very small subset of resting memory T cells in infected individuals under life-long antiretroviral therapy present a major barrier towards viral eradication. Multiple molecular mechanisms are required to repress the viral trans-activating factor Tat and disrupt the regulatory Tat feedback circuit leading to the establishment of the latent viral reservoir. In particular, latency is due to a combination of transcriptional silencing of proviruses via host epigenetic mechanisms and restrictions on the expression of P-TEFb, an essential co-factor for Tat. Induction of latent proviruses in the presence of antiretroviral therapy is expected to enable clearance of latently infected cells by viral cytopathic effects and host antiviral immune responses. An in-depth comprehensive understanding of the molecular control of HIV-1 transcription should inform the development of optimal combinatorial reactivation strategies that are intended to purge the latent viral reservoir.
    Virology 02/2014; 454-455(1). DOI:10.1016/j.virol.2014.02.008 · 3.32 Impact Factor
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    • "In order to determine the contribution of each of these factors to the low-level viraemia in the body, phylogenetic studies were performed on the viral sequences isolated from the residual viraemia. The results were contradictory: while some studies showed a lack of evolution among the sequences found, suggesting that the progeny virions came from one stable reservoir among CD4 + T-cells (Bailey et al., 2006; Joos et al., 2008; Ruff et al., 2002), others found viral sequences that were not detected among the resting T-cell population, indicating another cellular source for the residual viraemia (Bailey et al., 2006; Brennan et al., 2009; Sahu et al., 2009). Another indication of on-going productive infection would be if treatment intensification (the addition of a fourth anti-retroviral to the standard three-drug regime) reduced the basal level of viraemia further. "
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    ABSTRACT: Almost 30 years after its initial discovery, infection with the human immunodeficiency virus-1 (HIV-1) remains incurable and the virus persists due to reservoirs of latently infected CD4+ memory T-cells and sanctuary sites within the infected individual where drug penetration is poor. Reactivating latent viruses has been a key strategy to completely eliminate the virus from the host but many difficulties and unanswered questions remain. In this review, the latest developments in HIV-persistence and latency research are presented.
    Journal of General Virology 01/2013; 94(Pt 5). DOI:10.1099/vir.0.049296-0 · 3.18 Impact Factor
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    • "Since HIV-1 persists as a latent provirus in resting memory CD4 + T-lymphocytes (Chun et al., 1997b; Wong et al., 1997), one possible explanation for the residual viraemia is the reactivation of latently infected cells. But other authors question if these cells are the origin of the residual viraemia (Bailey et al., 2006; Brennan et al., 2009). Residual viraemia could also be explained by the existence of a low-level continuous viral replication in an unknown reservoir. "
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    ABSTRACT: ABSTRACT Human immunodeficiency virus type 1 (HIV-1) persistently infected cell lines are characterized by the continuous viral production without cytopathic effect. However, it is not completely clear if this production is contributed only by viral transcription or also by new cycles of viral replication. We studied an HIV-1 persistently infected cell line, designated H61-D, providing evidence of new replication cycles as sustained by: i) a decrease in viral production, measured by p24 protein, after treatment of the culture with 3'-Azydo-3'-Deoxythymydine (AZT); ii) detection of new integration events in the course of cell culture, and iii) finding of two-long terminal repeat (2-LTR) circles in the cells. H61-D cells were not infected by cell free virus, but infection was possible by co-culture with another productive infected cell line. In conclusion, ongoing viral replication is taking place in H61-D persistent cells and new infections are mediated by a cell-to-cell spread mechanism.
    Journal of General Virology 01/2013; 94(Pt_5). DOI:10.1099/vir.0.046573-0 · 3.18 Impact Factor
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