Effect of analytical treatment interruption and reinitiation of antiretroviral therapy on HIV reservoirs and immunologic parameters in infected individuals

Therapeutic strategies aimed at achieving antiretroviral therapy (ART)-free HIV remission in infected individuals are under active investigation. Considering the vast majority of HIV-infected individuals experience plasma viral rebound upon cessation of therapy, clinical trials evaluating the efficacy of curative strategies would likely require inclusion of ART interruption. However, it is unclear what impact short-term analytical treatment interruption (ATI) and subsequent reinitiation of ART have on immunologic and virologic parameters of HIV-infected individuals. Here, we show a significant increase of HIV burden in the CD4+ T cells of infected individuals during ATI that was correlated with the level of plasma viral rebound. However, the size of the HIV reservoirs as well as immune parameters, including markers of exhaustion and activation, returned to pre-ATI levels 6–12 months after the study participants resumed ART. Of note, the proportions of near full-length, genome-intact and structurally defective HIV proviral DNA sequences were similar prior to ATI and following reinitiation of ART. In addition, there was no evidence of emergence of antiretroviral drug resistance mutations within intact HIV proviral DNA sequences following reinitiation of ART. These data demonstrate that short-term ATI does not necessarily lead to expansion of the persistent HIV reservoir nor irreparable damages to the immune system in the peripheral blood, warranting the inclusion of ATI in future clinical trials evaluating curative strategies

Profiles of HIV-infected study participants.

<p>Profiles of HIV-infected study participants.</p

Immunologic parameters monitored for the duration of the trial.

<p>(<b>A</b>) CD4⁺ and (<b>B</b>) CD8⁺ T cell counts and percentages prior to treatment interruption (Pre-ATI), during ATI (ATI), and following reinitiation of ART (Post-ATI) and levels of (<b>C</b>) B cells, (<b>D</b>) NK cells, and (<b>E</b>) CD8⁺ T cells expressing CD38 and HLA-DR prior to treatment interruption (Pre-ATI), during ATI (ATI), and following reinitiation of ART (Post-ATI).</p

Impact of ATI and reinitiation of ART on HIV reservoirs.

<p>(<b>A</b>) Longitudinal measurements of plasma viremia (red triangles) and the frequency of CD4⁺ T cells carrying HIV DNA (blue triangles) from study participants are shown. The grey bars indicate duration of ATI. One participant (N04) self-administered antiretroviral drugs for 3 days during the ATI period. (<b>B</b>) Relationship between the level of peak plasma viremia and % increase of the frequency of CD4⁺ T cells carrying HIV DNA during the ATI phase over baseline. The % HIV DNA increase was calculated as follows: ((copy number of HIV DNA/10⁶ CD4⁺ T cells at ATI—copy number of HIV DNA/10⁶ CD4⁺ T cells at baseline)/copy number of HIV DNA/10⁶ CD4⁺ T cells at baseline)*100. (<b>C</b>) Kinetics of HIV DNA burden in CD4⁺ T cells of 10 study participants prior to ATI (Pre-ATI), during ATI (ATI), and after reinitiation of ART (Post-ATI). (<b>D</b>) Dynamics of cell-associated HIV RNA in CD4⁺ T cells of study participants prior to ATI (Pre-ATI) during ATI (ATI) and after reinitiation of ART (Post-ATI). (E) Ratios between the level of cell-associated HIV RNA and DNA. (<b>F</b>) Impact of ATI and reinitiation of ART on the level of CD4⁺ T cells carrying replication-competent HIV in 6 study participants in whom longitudinal leukapheresis was performed. Statistical significance was tested with Wilcoxon’s signed rank test for panels C, D, E, and F. A correlation was determined by the Spearman rank method for panel b. **<i>P</i> < 0.01, ns, not significant.</p