title: Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size.
abstract: The dynamics of HIV reservoir accumulation off antiretroviral therapy (ART) is underexplored. Levels of integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) were longitudinally monitored before and after antiviral therapy. HIV integration increased over time in both elite controllers (ECs; n = 8) and noncontrollers (NCs; n = 6) before ART, whereas integration remained stable in patients on ART (n = 4). The median annual fold change was higher in NCs than in ECs and negatively correlated with CD4/CD8 T-cell ratio. Cytotoxic T lymphocyte (CTL) function as assessed by infected CD4 T-cell elimination (ICE) and granzyme B activity did not significantly change over time in ECs, suggesting that the gradual increase in integrated HIV DNA observed in ECs was not a result of progressive loss of immune-mediated control. Also, acutely infected (n = 7) but not chronically infected (n = 6) patients exhibited a significant drop in integrated HIV DNA 12 months after ART initiation. In conclusion, in the absence of ART, integrated HIV accumulates over time both in NCs and in ECs, at variable individual rates. Starting ART early in infection leads to a greater drop in integrated HIV DNA than does initiating treatment after years of infection. The increase in integrated HIV DNA over time suggests that early treatment may be of benefit in limiting HIV reservoirs.
  
  
  OBJECTIVE
  The establishment of a latent reservoir represents a barrier to cure among HIV-infected individuals. The dynamics of HIV reservoir accumulation over time in patients before antiviral therapy is underexplored, in large part because it is difficult to accurately and reproducibly measure the size of HIV reservoir in this setting. In our study, we compared the dynamics of integrated HIV DNA over time in ECs and NCs before and after ART was initiated. We found that integrated HIV DNA levels progressively increase over time in the absence of ART, but with a higher, albeit variable, rate in NCs compared to ECs. In addition, integrated HIV DNA declines more dramatically when ART is initiated in acute rather than chronic HIV infection, suggesting important differences between acute and chronic infection. Our study highlights the role of HIV replication and CTL control in reservoir accumulation in sanctuary sites and why ART appears to be more effective in acute infection.
authors.affiliation: Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.|Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Marilia Rita
authors.initials: MR
authors.lastname: Pinzone
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Graf
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Lynch
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Brigit
authors.initials: B
authors.lastname: McLaughlin
authors.affiliation: Department of Medicine, University of California, San Francisco, and Positive Health Program, San Francisco General Hospital, San Francisco, California, USA.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Migueles
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hwang
authors.affiliation: Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nunnari
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA unao@mail.med.upenn.edu.
authors.forename: Una
authors.initials: U
authors.lastname: O'Doherty
mesh_terms: D000208:Acute Disease; D019380:Anti-HIV Agents / Q000627:therapeutic use; D002908:Chronic Disease; D004279:DNA, Viral / Q000097:blood / Q000235:genetics; D004197:Disease Reservoirs / Q000821:virology; D006678:HIV / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D006801:Humans; D008137:Longitudinal Studies; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D019562:Viral Load / Q000276:immunology; D016662:Virus Integration / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral