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ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions
Rikke Olesen, … , Angela Wahl, J. Victor Garcia
Rikke Olesen, … , Angela Wahl, J. Victor Garcia
Published February 8, 2016
Citation Information: J Clin Invest. 2016;126(3):892-904. https://doi.org/10.1172/JCI64212.
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Research Article AIDS/HIV Article has an altmetric score of 78

ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions

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Abstract

The recently completed HIV prevention trials network study 052 is a landmark collaboration demonstrating that HIV transmission in discordant couples can be dramatically reduced by treating the infected individual with antiretroviral therapy (ART). However, the cellular and virological events that occur in the female reproductive tract (FRT) during ART that result in such a drastic decrease in transmission were not studied and remain unknown. Here, we implemented an in vivo model of ART in BM/liver/thymus (BLT) humanized mice in order to better understand the ability of ART to prevent secondary HIV transmission. We demonstrated that the entire FRT of BLT mice is reconstituted with human CD4+ cells that are shed into cervicovaginal secretions (CVS). A high percentage of the CD4+ T cells in the FRT and CVS expressed CCR5 and therefore are potential HIV target cells. Infection with HIV increased the numbers of CD4+ and CD8+ T cells in CVS of BLT mice. Furthermore, HIV was present in CVS during infection. Finally, we evaluated the effect of ART on HIV levels in the FRT and CVS and demonstrated that ART can efficiently suppress cell-free HIV-RNA in CVS, despite residual levels of HIV-RNA+ cells in both the FRT and CVS.

Authors

Rikke Olesen, Michael D. Swanson, Martina Kovarova, Tomonori Nochi, Morgan Chateau, Jenna B. Honeycutt, Julie M. Long, Paul W. Denton, Michael G. Hudgens, Amy Richardson, Martin Tolstrup, Lars Østergaard, Angela Wahl, J. Victor Garcia

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Figure 7

ART suppresses cell-free HIV-RNA in CVS and PB but does not consistently suppress cell-associated HIV-RNA in the FRT and CVS.

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ART suppresses cell-free HIV-RNA in CVS and PB but does not consistently...
(A) Viral load analyses of the plasma (black solid line, filled circles) and CVS supernatant (black dashed line, open circles) demonstrated sustained viral load in the plasma and CVS supernatant of 8 HIV-infected ART-naive mice (left panel) and a dramatic decrease in viral load to undetectable levels in both plasma and CVS supernatant in 5 representative ART-treated mice (right panel). Time points corresponding to ART are shaded gray. (B) Cell-associated HIV-RNA in the PB, FRT, and CVS of mice receiving ART for 5–8 weeks (n = 8) and of ART-naive mice (No ART) (n = 8). RNA was isolated from mononuclear cells, and the RNA determination for each sample was performed in triplicate. (C) The level of infectious cells in PB and CVS from BLT mice was determined in 8 ART-treated mice and 5 ART-naive mice. Samples from all mice in each group (ART vs. No ART) were pooled at each time point: week –1 (ART n = 8, No ART n = 5), week 2 (ART n = 4, No ART n = 5), and week 3 (ART n = 3, No ART n = 5). (D) The level of infectious cells in the FRT of mice treated with ART for 5 weeks and in ART-naive mice (ART n = 4, No ART n = 5). (B–D) Bars represent mean values. Data are represented as ± SEM. (C and D) Limit of detection was 2 infectious units per 1 × 106 cells. (E) BLT mice were exposed vaginally to 2 different doses of HIV-infected PBMC (open symbols: 5,000 PBMC, n = 4; closed symbols: 10,000 PBMC, n = 4). Plasma levels of HIV-RNA were monitored for 8 weeks. A Mann-Whitney U test was used to compare levels of cell-associated HIV-RNA and infectious cells between ART-naive and ART-treated mice (*P < 0.05, ***P < 0.001) (B and D). The assay limit of detection is indicated with a dashed gray line.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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