No evidence of HIV replication in children on antiretroviral therapy
Gert U. Van Zyl, … , John W. Mellors, Mary F. Kearney
Gert U. Van Zyl, … , John W. Mellors, Mary F. Kearney
Published September 11, 2017
Citation Information: J Clin Invest. 2017;127(10):3827-3834. https://doi.org/10.1172/JCI94582.
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Concise Communication AIDS/HIV Virology

No evidence of HIV replication in children on antiretroviral therapy

Abstract

It remains controversial whether current antiretroviral therapy (ART) fully suppresses the cycles of HIV replication and viral evolution in vivo. If replication persists in sanctuary sites such as the lymph nodes, a high priority should be placed on improving ART regimes to target these sites. To investigate the question of ongoing viral replication on current ART regimens, we analyzed HIV populations in longitudinal samples from 10 HIV-1–infected children who initiated ART when viral diversity was low. Eight children started ART at less than ten months of age and showed suppression of plasma viremia for seven to nine years. Two children had uncontrolled viremia for fifteen and thirty months, respectively, before viremia suppression, and served as positive controls for HIV replication and evolution. These latter 2 children showed clear evidence of virus evolution, whereas multiple methods of analysis bore no evidence of virus evolution in any of the 8 children with viremia suppression on ART. Phylogenetic trees simulated with the recently reported evolutionary rate of HIV-1 on ART of 6 × 10–4 substitutions/site/month bore no resemblance to the observed data. Taken together, these data refute the concept that ongoing HIV replication is common with ART and is the major barrier to curing HIV-1 infection.

Authors

Gert U. Van Zyl, Mary Grace Katusiime, Ann Wiegand, William R. McManus, Michael J. Bale, Elias K. Halvas, Brian Luke, Valerie F. Boltz, Jonathan Spindler, Barbara Laughton, Susan Engelbrecht, John M. Coffin, Mark F. Cotton, Wei Shao, John W. Mellors, Mary F. Kearney

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Figure 3

Comparison of analytical approaches.

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Comparison of analytical approaches. (A) NJ tree of the sequences from a...
(A) NJ tree of the sequences from a child (PID ZA004) who started treatment at less than 3 months of age and had full viremia suppression for 8.9 years (Supplemental Table 1). This tree is identical to that shown in Figure 1D for the same child. Red triangles indicate single-genome DNA sequences obtained 9 months after ART initiation. Black triangles indicate single-genome DNA sequences obtained 8 years later. The distance tree shows that the populations did not shift for 8 years on ART; populations at both time points were almost completely homogeneous, with only 8 nucleotide differences in 16,800 bases at baseline and 9 nucleotide differences in 19,200 bases 8 years later. The founder sequences persisted across the sampling time points. (B) The same sequences analyzed by BEAST using a strict molecular clock (as in ref. 10) show divergence over time, despite the identity of most sequences at both time points. Individual sequences are numbered identically in the 2 trees shown in A and B. (C) Simulated NJ distance tree using the estimated HIV evolution rate of 6.24 × 10–4 substitutions/site/month from ref. 10, applying the baseline sequences from the same child as in A and B. The simulated tree shows artifactual evolution, while the actual tree shows no evidence of sequence divergence after 8 years of ART.