Research ArticleHIV

Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption

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Science Translational Medicine  13 Jan 2021:
Vol. 13, Issue 576, eabd8179
DOI: 10.1126/scitranslmed.abd8179
  • Fig. 1 HIV-1 viral loads and CD4+ T cell counts in prospectively studied individuals.

    Viral loads (RNA copies/ml; red, left y axis) and CD4+ T cell counts (cells/μl; blue, right y axis) are shown for 10 HIV-1–infected individuals, who were followed from the onset of symptoms until 213 to 645 weeks (4.1 to 12.4 years) after infection (x axis). Participants are grouped on the basis of disease progression, (A) including typical progressors, (B) nonprogressors, and (C) rapid progressors. Gray shading indicates suppressive ART (alternating shading in WEAU indicates nonsuppressive zidovudine monotherapy). Purple arrows denote the time points of PBMC sample isolation that yielded QVOA isolates; open triangles denote superinfection, and dashed vertical lines indicate termination of the study or loss to follow up.

  • Fig. 2 Kinetics of IFN-I resistance over the course of HIV-1 infection.

    IFNα2 (A to C) and IFNβ (D to F) IC50 values (pg/ml) are shown for limiting dilution– (circles) and bulk culture–derived (squares) isolates from the onset of symptoms until 140 to 466 weeks (2.7 to 8.9 years) after infection. Each data point represents the average of two technical replicates. Colored lines denote the average IC50 values as estimated by a Bayesian model, with darker shading indicating the 95% credible intervals and lighter shading indicating the 95% prediction intervals. Gray shading indicates suppressive ART (alternating shading in WEAU indicates nonsuppressive zidovudine monotherapy). Blue circles indicate isolates obtained by viral outgrowth from CD4+ T cells after 1.2 to 4.1 years of suppressive ART. Open triangles denote superinfection. (A and D), (B and E), and (C and F) show typical progressors (orange), nonprogressors (green), and rapid progressors (pink), respectively.

  • Fig. 3 Dynamic changes in IFN-I resistance.

    A hierarchical Bayesian change point model used to estimate the IFN-I resistance of plasma viral isolates from 10 longitudinally sampled HIV-1–infected study participants is shown. The longitudinal patterns of IFNα2 and IFNβ IC50 values were inferred across individuals by first predicting resistance as a fall from acute IFN-I IC50 values to a nadir point and then as variation from nadir values based on changes in CD4+ T cell counts. (A and B) Predicted mean IFNα2 (A) or IFNβ (B) IC50 values (lines) are shown for plasma virus isolates modeled for typical progressor (orange), nonprogressor (green), and rapid progressor (pink) participants from the onset of symptoms through early infection (x axis), along with corresponding 95% credible (darker shading) and prediction (lighter shading) intervals. (C and D) Predicted mean IFNα2 (C) or IFNβ (D) IC50 values (lines) are shown for plasma virus isolates modeled for individual typical progressor (orange), nonprogressor (green), and rapid progressor (pink) participants based on changes in CD4+ T cell counts after the nadir (x axis indicates decreases and increases from the nadir, which is set to 0), along with corresponding 95% credible (darker shading) and prediction (lighter shading) intervals. Individual data points indicate virus isolates from the respective individuals, with shading reflecting the estimated posterior probability that the time of nadir preceded the plasma collection time point (from white, probability of 0, to black, probability of 1). Isolates estimated to have less than 5% probability after the time of nadir are not shown. For display, the nadir CD4+ T cell count was estimated as the posterior mean for that individual.

  • Fig. 4 Position of QVOA isolates within the evolving HIV-1 quasispecies of participant MM34.

    The evolutionary relationships of env nucleotide sequences generated by single-genome amplification either directly from plasma viral RNA or plasma viral isolates of participant MM34 are shown for a 6-year time period. Samples are colored by time point, with blue sequences derived early and red sequences derived late in infection. Purple leaves indicate the position of QVOA isolates obtained 2 and 3 years after ART initiation, whereas gray leaves indicate proviral sequences amplified from the corresponding PBMC sample. One hypermutated PBMC-derived sequence is shown with a gap in the branch. The scale bar indicates 0.05 substitutions per site.

  • Fig. 5 IFN-I resistance of QVOA versus rebound viruses.

    (A and B) IFNα2 (A) and IFNβ (B) IC50 values are shown for plasma isolates of individuals experiencing rebound viremia after ART cessation (red) and QVOA isolates generated from the PBMCs of ART-suppressed individuals before (blue) or after (turquoise) ATI (each data point is the average of two technical replicates). Isolates are grouped by individuals (shaded boxes), with pre-ATI, rebound, and post-ATI isolates depicted in temporal order when available. Two post-ATI QVOA isolates from participant A08 with elevated IFN-I resistance are boxed. Also shown are the IFNα2 (A) and IFNβ (B) IC50 values for outgrowth isolates (blue) and plasma viruses (gray) from the longitudinal cohort (acute, <30 days since onset of symptoms; early, >300 days and less than nadir; nadir, time point with lowest mean IC50 value; late, greater than nadir and less than last; last, last time point before ART initiation) and previously reported donor-recipient transmission pairs (50). For the latter, IC50 values were adjusted to account for potency differences among commercial IFN-I batches. Diamonds indicate isolates from fast progressing individuals. (C and D) The fold-change in IFNα2 and IFNβ IC50 values from acute infection isolates is shown for rebound (red), chronic (gray), and pre-ATI (blue) and post-ATI (turquoise) QVOA isolates. Violin plots indicate the estimated posterior probability of the mean fold change between isolate types, with the darker shading indicating the 95% credible interval and the lighter indicating the 95% prediction interval. The dashed horizontal line indicates a fold change of 1, which indicates no change.

  • Fig. 6 Genotype and IFN-I phenotype of rebound and outgrowth viruses before and after treatment interruption of individual A08.

    The phylogenetic relationships of env gene sequences from pre-ATI QVOA (blue), plasma rebound (red), and post-ATI QVOA (teal) isolates are shown for participant A08, along with available IFNα2 and IFNβ IC50 values (pg/ml). Asterisks indicate bootstrap values >90%; the scale bar indicates 0.01 substitutions per site. A clade of near-identical rebound and post-ATI QVOA isolates is highlighted by bold text and a bracket, with two rebound-like post-ATI QVOA isolates with heightened IFN-I resistance denoted by teal arrows. Two other closely related rebound and post-ATI QVOA isolates that differ in their IFN-I resistance are indicated by red and teal triangles.

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/13/576/eabd8179/DC1

    Methods

    Fig. S1. Inference and enumeration of TF viruses.

    Fig. S2. HIV-1 quasispecies diversification over time.

    Fig. S3. Determination of IFN-I IC50 values.

    Fig. S4. IFN-I resistance of bulk and limiting dilution isolates from the same plasma samples.

    Fig. S5. Correlation of IFNα2 and IFNβ IC50 values.

    Fig. S6. Phylogenetic relationships of rebound isolates.

    Fig. S7. Closely related rebound and post-ATI QVOA isolates from participant A08.

    Table S1. Generation of HIV-1 isolates from plasma and PBMCs of 10 individuals sampled from acute infection throughout their clinical course.

    Table S2. IFN-I resistance of plasma and QVOA isolates from longitudinally sampled study participants.

    Table S3. Generation of viral isolates from ART-suppressed individuals with and without treatment interruption.

    Table S4. IFN-I resistance of viral outgrowth and rebound isolates.

    Data file S1. GenBank accession numbers.

  • The PDF file includes:

    • Methods
    • Fig. S1. Inference and enumeration of TF viruses.
    • Fig. S2. HIV-1 quasispecies diversification over time.
    • Fig. S3. Determination of IFN-I IC50 values.
    • Fig. S4. IFN-I resistance of bulk and limiting dilution isolates from the same plasma samples.
    • Fig. S5. Correlation of IFNα2 and IFNβ IC50 values.
    • Fig. S6. Phylogenetic relationships of rebound isolates.
    • Fig. S7. Closely related rebound and post-ATI QVOA isolates from participant A08.
    • Table S1. Generation of HIV-1 isolates from plasma and PBMCs of 10 individuals sampled from acute infection throughout their clinical course.
    • Table S2. IFN-I resistance of plasma and QVOA isolates from longitudinally sampled study participants.
    • Table S3. Generation of viral isolates from ART-suppressed individuals with and without treatment interruption.
    • Table S4. IFN-I resistance of viral outgrowth and rebound isolates.

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Data file S1 (Microsoft Excel format). GenBank accession numbers.

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