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Monitoring integration over time supports a role for CTL and ongoing replication as determinants of reservoir size.

Monitoring integration over time supports a role for CTL and ongoing replication as determinants of reservoir size.
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Pinzone MR, Graf E, Lynch L, McLaughlin B, Hecht FM, Connors M, Migueles SA, Hwang WT, Nunnari G, O'Doherty U,


Pinzone MR, Graf E, Lynch L, McLaughlin B, Hecht FM, Connors M, Migueles SA, Hwang WT, Nunnari G, O'Doherty U, (click to view)

Pinzone MR, Graf E, Lynch L, McLaughlin B, Hecht FM, Connors M, Migueles SA, Hwang WT, Nunnari G, O'Doherty U,

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Journal of virology 2016 9 14() pii

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 Non-Controllers (NCs, n=6) before ART, whereas integration remained stable in patients on ART (n=4). The median annual fold-change was higher in NCs compared to ECs and negatively correlated with CD4/CD8 T-cell ratio. CTL function as assessed by infected CD4 T-cell elimination (ICE) and granzyme B activity did not significantly change over time in ECs, suggesting 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 compared to initiating treatment after years of infection. The increase in integrated HIV DNA over time suggests early treatment may be of benefit in limiting HIV reservoirs.

IMPORTANCE
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 is initiated. We found that integrated HIV DNA levels progressively increase over time in the absence of ART, but with a faster, 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.

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