. 2023 Oct 28;15(11):2171.

doi: 10.3390/v15112171.

HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing

Danielle E Lyons¹, Priti Kumar², Nadia R Roan^{1

3}, Patricia A Defechereux⁴, Cedric Feschotte⁵, Ulrike C Lange⁶, Niren Murthy^{7

8}, Pauline Sameshima⁹, Eric Verdin^{4

10}, Julie A Ake¹¹, Matthew S Parsons^{11

12

13}, Avindra Nath¹⁴, Sara Gianella¹⁵, Davey M Smith¹⁵, Esper G Kallas¹⁶, Thomas J Villa^{17

18}, Richard Strange¹⁷, Betty Mwesigwa¹⁹, Robert L Furler O'Brien²⁰, Douglas F Nixon²⁰, Lishomwa C Ndhlovu²⁰, Susana T Valente²¹, Melanie Ott^{1

4}

Affiliations

¹ Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
² Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06510, USA.
³ Department of Urology, University of California San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Medicine, University of California San Francisco, San Francisco, CA 94158, USA.
⁵ Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
⁶ Leibniz Institute of Virology, 20251 Hamburg, Germany.
⁷ Department of Bioengineering, University of California, Berkeley, CA 94720, USA.
⁸ Innovative Genomics Institute, Berkeley, CA 94720, USA.
⁹ Faculty of Education, Lakehead University, Thunder Bay, ON P7B 5E1, Canada.
¹⁰ Buck Institute for Research on Aging, Novato, CA 94945, USA.
¹¹ U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
¹² Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA.
¹³ Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand.
¹⁴ Section of Infections of the Nervous System, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20824, USA.
¹⁵ Division of Infectious Diseases, Department of Medicine, University of California San Diego, San Diego, CA 92093, USA.
¹⁶ Department of Infectious and Parasitic Diseases, University of Sao Paulo, São Paulo 04023-900, Brazil.
¹⁷ HOPE Martin Delaney Collaboratory for HIV Cure Research Community Engagement Ambassador, Washinton, DC 20004, USA.
¹⁸ National HIV & Aging Advocacy Network, Washington, DC 20004, USA.
¹⁹ Research Department, Makerere University Walter Reed Project, Kampala P.O Box 7062, Uganda.
²⁰ Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
²¹ Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA.

PMID: 38005849
PMCID: PMC10674359
DOI: 10.3390/v15112171

HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing

Danielle E Lyons et al. Viruses. 2023.

. 2023 Oct 28;15(11):2171.

doi: 10.3390/v15112171.

Authors

Affiliations

¹ Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
² Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06510, USA.
³ Department of Urology, University of California San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Medicine, University of California San Francisco, San Francisco, CA 94158, USA.
⁵ Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
⁶ Leibniz Institute of Virology, 20251 Hamburg, Germany.
⁷ Department of Bioengineering, University of California, Berkeley, CA 94720, USA.
⁸ Innovative Genomics Institute, Berkeley, CA 94720, USA.
⁹ Faculty of Education, Lakehead University, Thunder Bay, ON P7B 5E1, Canada.
¹⁰ Buck Institute for Research on Aging, Novato, CA 94945, USA.
¹¹ U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
¹² Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA.
¹³ Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand.
¹⁴ Section of Infections of the Nervous System, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20824, USA.
¹⁵ Division of Infectious Diseases, Department of Medicine, University of California San Diego, San Diego, CA 92093, USA.
¹⁶ Department of Infectious and Parasitic Diseases, University of Sao Paulo, São Paulo 04023-900, Brazil.
¹⁷ HOPE Martin Delaney Collaboratory for HIV Cure Research Community Engagement Ambassador, Washinton, DC 20004, USA.
¹⁸ National HIV & Aging Advocacy Network, Washington, DC 20004, USA.
¹⁹ Research Department, Makerere University Walter Reed Project, Kampala P.O Box 7062, Uganda.
²⁰ Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
²¹ Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA.

PMID: 38005849
PMCID: PMC10674359
DOI: 10.3390/v15112171

Abstract

Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite antiretroviral therapy and rekindle infection due to inefficient proviral silencing. We propose a novel "block-lock-stop" approach, entailing long term durable silencing of viral expression towards an irreversible transcriptionally inactive latent provirus to achieve long term antiretroviral free control of the virus. A graded transformation of remnant HIV-1 in PLWH from persistent into silent to permanently defective proviruses is proposed, emulating and accelerating the natural path that human endogenous retroviruses (HERVs) take over millions of years. This hypothesis was based on research into delineating the mechanisms of HIV-1 latency, lessons from latency reversing agents and advances of Tat inhibitors, as well as expertise in the biology of HERVs. Insights from elite controllers and the availability of advanced genome engineering technologies for the direct excision of remnant virus set the stage for a rapid path to an HIV-1 cure.

Keywords: HERV; HIV-1 cure; latency; transcriptional silencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
The block-lock-stop approach is multipronged to drive HIV-1 from reversible latency to deep silencing and permanent inactivation.

See this image and copyright information in PMC

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HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing

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HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing

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