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      Total HIV DNA: a global marker of HIV persistence

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          Abstract

          Among the different markers of HIV persistence in infected cells, total HIV DNA is to date the most widely used. It allows an overall quantification of all viral forms of HIV DNA in infected cells, each playing a different role in HIV replication and pathophysiology. The real-time PCR technology is to date, a precise, sensitive and reproducible technology that allows the description of the distribution of HIV infected cells in blood and tissues. The objective of this review is to present some examples which show the interest to quantify total HIV DNA levels. This marker brought an undeniable and considerable contribution to reservoir studies. Many results, both in clinical and basic research, allowed to get a large overview of the distribution of infected cells in the body, at all stages of HIV disease and during therapy. Future clinical studies aiming at reducing HIV reservoirs will benefit from HIV DNA quantification in blood and tissues, in association with other markers of HIV reservoir activity.

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          Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy.

          Hiromi Imamichi, Robin Dewar, Joseph Adelsberger … (2016)
          Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. By combining 5'LTR-to-3'LTR single-genome amplification and direct amplicon sequencing, we have identified the presence of "defective" proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection. Although these novel usHIV-RNA transcripts had exon structures that were different from those of the known spliced HIV-RNA variants, they maintained translationally competent ORFs, involving elements of gag, pol, env, rev, and nef to encode a series of novel HIV-1 chimeric proteins. These novel usHIV-RNAs were detected in five of five patients, including four of four patients with prolonged viral suppression of HIV-RNA levels <40 copies per milliliter for more than 6 y. Our findings suggest that the persistent defective proviruses of HIV-1 are not "silent," but rather may contribute to HIV-1 pathogenesis by stimulating host-defense pathways that target foreign nucleic acids and proteins.
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            Impact of Multi-Targeted Antiretroviral Treatment on Gut T Cell Depletion and HIV Reservoir Seeding during Acute HIV Infection

            Jintanat Ananworanich, Alexandra Schuetz, Claire Vandergeeten … (2012)
            Background Limited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy. Methods and Findings We prospectively screened 24,430 subjects in Bangkok and identified 40 AHI individuals. Thirty Thais were enrolled (8 Fiebig I, 5 Fiebig II, 15 Fiebig III, 2 Fiebig IV) of whom 15 completed 24 weeks of megaHAART (tenofovir/emtricitabine/efavirenz/raltegravir/maraviroc). Sigmoid biopsies were completed in 24/30 at baseline and 13/15 at week 24. At baseline, the median age was 29 years and 83% were MSM. Most were symptomatic (87%), and were infected with R5-tropic (77%) CRF01_AE (70%). Median CD4 was 406 cells/mm3. HIV RNA was 5.5 log10 copies/ml. Median total blood HIV DNA was higher in Fiebig III (550 copy/106 PBMC) vs. Fiebig I (8 copy/106 PBMC) (p = 0.01) while the median %CD4+CCR5+ gut T cells was lower in Fiebig III (19%) vs. Fiebig I (59%) (p = 0.0008). After 24 weeks of megaHAART, HIV RNA levels of 0.050); subjects with less than 40% at baseline had a significant increase in CD4+CCR5+ T cells from baseline to week 24 (14% vs. 71%, p = 0.02). Conclusions Gut T cell depletion and HIV reservoir seeding increases with progression of AHI. MegaHAART was associated with immune restoration and reduced reservoir size. Our findings could inform research on strategies to achieve HIV drug-free remission.
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              Cross-clade ultrasensitive PCR-based assays to measure HIV persistence in large-cohort studies.

              Claire Vandergeeten, Remi Fromentin, Esther Merlini … (2014)
              A small pool of infected cells persists in HIV-infected individuals receiving antiretroviral therapy (ART). Here, we developed ultrasensitive assays to precisely measure the frequency of cells harboring total HIV DNA, integrated HIV DNA, and two long terminal repeat (2-LTR) circles. These assays are performed on cell lysates, which circumvents the labor-intensive step of DNA extraction, and rely on the coquantification of each HIV molecular form together with CD3 gene sequences to precisely measure cell input. Using primary isolates from HIV subtypes A, B, C, D, and CRF01_A/E, we demonstrate that these assays can efficiently quantify low target copy numbers from diverse HIV subtypes. We further used these assays to measure total HIV DNA, integrated HIV DNA, and 2-LTR circles in CD4(+) T cells from HIV-infected subjects infected with subtype B. All samples obtained from ART-naive subjects were positive for the three HIV molecular forms (n = 15). Total HIV DNA, integrated HIV DNA, and 2-LTR circles were detected in, respectively, 100%, 94%, and 77% of the samples from individuals in which HIV was suppressed by ART. Higher levels of total HIV DNA and 2-LTR circles were detected in untreated subjects than individuals on ART (P = 0.0003 and P = 0.0004, respectively), while the frequency of CD4(+) T cells harboring integrated HIV DNA did not differ between the two groups. These results demonstrate that these novel assays have the ability to quantify very low levels of HIV DNA of multiple HIV subtypes without the need for nucleic acid extraction, making them well suited for the monitoring of viral persistence in large populations of HIV-infected individuals.
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                Author and article information

                Contributors
                Christine Rouzioux: christine.rouzioux@aphp.fr
                Véronique Avettand-Fenoël: veronique.avettand-fenoel@aphp.fr
                Journal
                Journal ID (nlm-ta): Retrovirology
                Journal ID (iso-abbrev): Retrovirology
                Title: Retrovirology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1742-4690
                Publication date (Electronic): 3 April 2018
                Publication date PMC-release: 3 April 2018
                Publication date Collection: 2018
                Volume: 15
                Electronic Location Identifier: 30
                Affiliations
                [1 ]ISNI 0000 0004 0593 9113, GRID grid.412134.1, Laboratoire de Virologie, , APHP Hôpital Necker Enfants Malades, ; Paris, France
                [2 ]ISNI 0000 0001 2188 0914, GRID grid.10992.33, EA 7327, , Université Paris Descartes, Sorbonne Paris-Cité, ; Paris, France
                Article
                Publisher ID: 412
                DOI: 10.1186/s12977-018-0412-7
                PMC ID: 5883363
                PubMed ID: 29615133
                SO-VID: 664f6c98-4d1f-473a-974a-7a5d7f9399a2
                Copyright © © The Author(s) 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 6 November 2017
                Date accepted : 26 March 2018
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: total hiv dna,real time pcr,reservoirs,cd4 + t cell subsets
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: total hiv dna, real time pcr, reservoirs, cd4 + t cell subsets

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