Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Nov 15;37(14):2119-2130.
doi: 10.1097/QAD.0000000000003667. Epub 2023 Aug 22.

Long-term persistence of transcriptionally active 'defective' HIV-1 proviruses: implications for persistent immune activation during antiretroviral therapy

Kanal Singh  1 , Ven Natarajan  2 , Robin Dewar  2 , Adam Rupert  2 , Yuden Badralmaa  2 , Tracey Zhai  1 , Nicole Winchester  1 , Francesca Scrimieri  2 , Mindy Smith  1 , Ivery Davis  2 , Perrine Lallemand  2 , Aude Giglietti  1 , Jack Hensien  1 , Thomas Buerkert  1 , Bruktawit Goshu  1 , Catherine A Rehm  3 , Zonghui Hu  4 , H Clifford Lane  1 , Hiromi Imamichi  1
Affiliations

Long-term persistence of transcriptionally active 'defective' HIV-1 proviruses: implications for persistent immune activation during antiretroviral therapy

Kanal Singh et al. AIDS. .

Abstract

Objectives: People with HIV-1 (PWH) on effective antiretroviral therapy (ART) continue to exhibit chronic systemic inflammation, immune activation, and persistent elevations in markers of HIV-1 infection [including HIV-DNA, cell-associated HIV-RNA (CA HIV-RNA), and antibodies to HIV-1 proteins] despite prolonged suppression of plasma HIV-RNA levels less than 50 copies/ml. Here, we investigated the hypothesis that nonreplicating but transcriptionally and translationally competent 'defective' HIV-1 proviruses may be one of drivers of these phenomena.

Design: A combined cohort of 23 viremic and virologically suppressed individuals on ART were studied.

Methods: HIV-DNA, CA HIV-RNA, western blot score (measure of anti-HIV-1 antibodies as a surrogate for viral protein expression in vivo ), and key biomarkers of inflammation and coagulation (IL-6, hsCRP, TNF-alpha, tissue factor, and D-dimer) were measured in peripheral blood and analyzed using a combined cross-sectional and longitudinal approaches. Sequences of HIV-DNA and CA HIV-RNA obtained via 5'-LTR-to-3'-LTR PCR and single-genome sequencing were also analyzed.

Results: We observed similar long-term persistence of multiple, unique, transcriptionally active 'defective' HIV-1 provirus clones (average: 11 years., range: 4-20 years) and antibody responses against HIV-1 viral proteins among all ART-treated participants evaluated. A direct correlation was observed between the magnitude of HIV-1 western blot score and the levels of transcription of 'defective' HIV-1 proviruses ( r = 0.73, P < 0.01). Additional correlations were noted between total CD8 + T-cell counts and HIV-DNA ( r = 0.52, P = 0.01) or CA HIV-RNA ( r = 0.65, P < 0.01).

Conclusion: These findings suggest a novel interplay between transcription and translation of 'defective' HIV-1 proviruses and the persistent immune activation seen in the setting of treated chronic HIV-1 infection.

PubMed Disclaimer

Conflict of interest statement

There are no conflicts of interest.

Figures

Fig. 1
Fig. 1
Long-term persistence of antibody responses to HIV-1 antigens in the absence of active viral replication during plasma HIV-RNA less than 50 copies/ml on antiretroviral therapy.
Fig. 2
Fig. 2
Long-term persistence of multiple transcriptionally active ‘defective’ HIV-1 provirus clones during suppression of plasma HIV-RNA less than 50 copies/ml on antiretroviral therapy.
Fig. 2 (Continued)
Fig. 2 (Continued)
Long-term persistence of multiple transcriptionally active ‘defective’ HIV-1 provirus clones during suppression of plasma HIV-RNA less than 50 copies/ml on antiretroviral therapy.
Fig. 2 (Continued)
Fig. 2 (Continued)
Long-term persistence of multiple transcriptionally active ‘defective’ HIV-1 provirus clones during suppression of plasma HIV-RNA less than 50 copies/ml on antiretroviral therapy.
Fig. 3
Fig. 3
Associations between levels of HIV-1, western blot score, D-dimer, and T cells.
See this image and copyright information in PMC

Comment in

References

    1. Antiretroviral Therapy Cohort Colloboration. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis 2010; 50:1387–1396. - PMC - PubMed
    1. Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, et al. Insight Start Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 2015; 373:795–807. - PMC - PubMed
    1. Ingle SM, May MT, Gill MJ, Mugavero MJ, Lewden C, Abgrall S, et al. Antiretroviral Therapy Cohort Collaboration. Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients. Clin Infect Dis 2014; 59:287–297. - PMC - PubMed
    1. Trickey A, May MT, Vehreschild J, Obel N, Gill MJ, Crane H, et al. Antiretroviral Therapy Cohort Collaboration (ART-CC). Cause-specific mortality in HIV-positive patients who survived ten years after starting antiretroviral therapy. PLoS One 2016; 11:e0160460. - PMC - PubMed
    1. Boulware DR, Hullsiek KH, Puronen CE, Rupert A, Baker JV, French MA, et al. INSIGHT Study Group. Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death. J Infect Dis 2011; 203:1637–1646. - PMC - PubMed

Publication types