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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 2

Human memory T cells expressing CCR5 are the main human hematopoietic cell population in CVS and the FRT of BLT mice.

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Human memory T cells expressing CCR5 are the main human hematopoietic ce...
(A) Flow cytometric analyses of cells from the PB, FRT, and CVS of a representative HIV– BLT mouse demonstrate reconstitution with human CD4+ and CD8+ T cells in each compartment. (B and C) Further characterization of T cells in PB (dots), the FRT (diagonal stripes), and CVS (solid color). Box plot showing the percentages of CD4+ (blue) and CD8+ T cells (red) in PB (n = 60), the FRT (n = 6), and CVS (n = 57) of HIV– BLT mice. The middle line of the box plot is the median; box extends from the 25th to the 75th percentiles, and error bars extend down to the lowest value and up to the highest value (B). CD4+ and CD8+ T cells in PB (n = 9), the FRT (n = 4), and CVS (n = 46, CD4+ T cells; n = 37, CD8+ T cells) were analyzed for CCR5 expression with flow cytometry (C). (D and E) Bars represent mean values (± SEM). Further flow cytometric analyses characterizing the CD4+ (D) and CD8+ (E) T cell subsets. Naive T cells (CD45RA+CD27+), green; CM T cells (CD45RA–CD27+), pink; and EM T cells (CD45RA–CD27–), purple. Bars represent mean values for PB (n = 26), the FRT (n = 4), and CVS (n = 60, CD4+ T cells; n = 41, CD8+ T cells). Data represented as mean ± SEM. A Mann-Whitney U test with a Holm-Bonferroni step-down correction was used to compare the frequencies of immune cell populations within and between the PB, FRT, and CVS of BLT mice (*P < 0.05, **P < 0.01, ****P < 0.0001) (C–E).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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