108 - Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy

Background: HIV-1 proviruses persist in people on antiretroviral therapy (ART) but most are defective and do not constitute a replication-competent reservoir. The decay of infected cells carrying intact compared with defective HIV-1 proviruses has not been well-defined in people on ART.

Methods: We separately quantified intact and defective proviruses (using an intact proviral DNA assay), residual plasma viremia, and markers of inflammation and activation in people on long-term ART. Longitudinal measurements were done at three timepoints: timepoint 1 was a median of 7.1 years on ART; timepoint 2 was a median of 3.7 years later; timepoint 3 was a median of 5.5 years after timepoint 1 and a median 12 years after starting ART (Figure 1).Figure 1: Study timepoints


Results: Among 40 participants tested longitudinally from a median of 7.1 years to 12 years after ART initiation, intact provirus levels declined significantly over time (median half-life 7.1 years; 95% confidence interval [CI], 3.9, 18), whereas defective provirus levels did not decrease. The median half-life of total HIV-1 DNA was 41.6 years (95% CI, 13.6, 75). When we evaluated the change in proviral DNA per year, intact proviral DNA declined significantly more (p< 0.001) than defective proviral DNA (the latter did not change) (Figure 2). The proportion of all proviruses that were intact diminished over time on ART, from about 10% at the first on-ART timepoint to about 5% at the last timepoint (Figure 3). At timepoint 1, intact provirus levels on ART correlated with total HIV-1 DNA and residual plasma viremia, but there was no evidence for associations between intact provirus levels and inflammation or immune activation.Figure 2: Percent change in HIV-1 proviral DNA per year
Figure 3: Total HIV-1 proviruses (grey bars) and the percentage of intact proviruses (red lines, displaying median, Q1, Q3) by timepoint.


Conclusion: Cells containing intact, replication-competent proviruses are selectively lost during suppressive ART. Defining the mechanisms involved should inform strategies to accelerate HIV-1 reservoir depletion.

Presenting Author(s)

• 

  Rajesh Gandhi, MD

  Professor of Medicine
  Harvard Medical School
  Boston, Massachusetts

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.

  Slides Slides and Audio

Co-Author(s)

• JC

  Joshua Cyktor, PhD

  Research Assistant Professor of Medicine
  University of Pittsburgh
  Pittsburgh, Pennsylvania

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• RB

  Ronald Bosch, PhD

  Principal Research Scientist
  Harvard TH Chan School of Public Health
  Boston, Massachusetts

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• HM

  Hanna Mar, MSPH

  Biostatistician
  Harvard TH Chan School of Public Health
  Boston, Massachusetts

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• GL

  Gregory Laird, PhD

  Co-Founder
  Accelevir Diagnostics
  Baltimore, Maryland

  Disclosure: Accelevir Diagnostics (Shareholder, Other Financial or Material Support, Employee)
• AM

  Albine Martin, PhD

  Co-Founder
  Accelevir Diagnostics
  Baltimore, Maryland

  Disclosure: Accelevir Diagnostics (Shareholder, Other Financial or Material Support, Employee)
• AC

  Ann Collier, MD

  Professor of Medicine
  University of Washington
  Seattle, Washington

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• SR

  Sharon Riddler, MD

  Associate Professor of Medicine
  University of Pittsburgh
  Pittsburgh, Pennsylvania

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• BM

  Bernard Macatangay, MD

  Assistant Professor of Medicine
  University of Pittsburgh
  Pittsburgh, Pennsylvania

  Disclosure: Gilead (Grant/Research Support)
• CR

  Charles Rinaldo, PhD

  Professor and Chair, Infectious Diseases and Microbiology; Professor, Pathology
  University of Pittsburgh
  Pittsburgh, Pennsylvania

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• 

  Joseph J. Eron, MD

  Professor
  University of North Carolina at Chapel Hill
  Chapel Hill, North Carolina

  Disclosure: Gilead Sciences (Consultant, Research Grant or Support)Janssen (Consultant, Research Grant or Support)Merck (Consultant)ViiV Healthcare (Consultant, Research Grant or Support)
• JS

  Janet Siliciano, PhD

  Associate Professor of Medicine
  Johns Hopkins University School of Medicine
  Baltimore, Maryland

  Disclosure: Gilead (Advisor or Review Panel member)US Military HIV Research Program (Advisor or Review Panel member)
• DM

  Deborah McMahon, MD

  Professor of Medicine
  University of Pittsburgh
  Pittsburgh, Pennsylvania

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• JM

  John Mellors, MD

  Professor of Medicine
  University of Pittsburgh
  Pittsburgh, Pennsylvania

  Disclosure: Abound Bio (Shareholder)Accelevir Diagnostics (Consultant)Co-Crystal Pharmaceuticals (Shareholder)Gilead (Consultant, Grant/Research Support)Merck (Consultant)