HIV-1 replicates and persists in vaginal epithelial dendritic cells
Victor Pena-Cruz, … , Suryaram Gummuluru, Manish Sagar
Victor Pena-Cruz, … , Suryaram Gummuluru, Manish Sagar
Published May 3, 2018
Citation Information: J Clin Invest. 2018;128(8):3439-3444. https://doi.org/10.1172/JCI98943.
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Concise Communication AIDS/HIV Infectious disease

HIV-1 replicates and persists in vaginal epithelial dendritic cells

Abstract

HIV-1 acquisition occurs most commonly after sexual contact. To establish infection, HIV-1 must infect cells that support high-level replication, namely CD4+ T cells, which are absent from the outermost genital epithelium. Dendritic cells (DCs), present in mucosal epithelia, potentially facilitate HIV-1 acquisition. We show that vaginal epithelial DCs, termed CD1a+ VEDCs, are unlike other blood- and tissue-derived DCs because they express langerin but not DC-SIGN, and unlike skin-based langerin+ DC subset Langerhans cells (LCs), they do not harbor Birbeck granules. Individuals primarily acquire HIV-1 that utilizes the CCR5 receptor (termed either R5 or R5X4) during heterosexual transmission, and the mechanism for the block against variants that only use the CXCR4 receptor (classified as X4) remains unclear. We show that X4 as compared with R5 HIV-1 shows limited to no replication in CD1a+ VEDCs. This differential replication occurs after fusion, suggesting that receptor usage influences postentry steps in the virus life cycle. Furthermore, CD1a+ VEDCs isolated from HIV-1–infected virologically suppressed women harbor HIV-1 DNA. Thus, CD1a+ VEDCs are potentially infected early during heterosexual transmission and also retain virus during treatment. Understanding the interplay between HIV-1 and CD1a+ VEDCs is important for future prevention and cure strategies.

Authors

Victor Pena-Cruz, Luis M. Agosto, Hisashi Akiyama, Alex Olson, Yvetane Moreau, Jean-Robert Larrieux, Andrew Henderson, Suryaram Gummuluru, Manish Sagar

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Figure 3

Limitation in X4 variant replication occurs after entry.

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Limitation in X4 variant replication occurs after entry. (A–F) Fusion ob...
(A–F) Fusion observed in CD1a+ VEDCs that were (A) mock infected or exposed to pseudovirions with (B) NL4-3 (X4), (C) YU-2 (R5), (D) VSV-G (positive control), (E) Lai, and (F) Bal envelope. Numbers at the bottom show the percentage of fusion. (G–J) Late reverse transcription products (G and H) and integrated provirus (I and J) in CD1a+ VEDCs among R5 (blue) and X4 (red) envelope viruses in the absence and presence of CCR5 blocker Maraviroc (MVC) (blue outline) and CXCR inhibitor AMD3100 (red outline). Experiments were done with replication-competent infectious molecular clones YU-2 (R5) and NL4-3 (X4) (n = 3 tissues; comparisons used a 2-sided t test) (G and I) or a single-cycle reporter virus pseudotyped with either a CCR5-using (Bal) or CXCR4-using (Lai) envelope (n = 7 tissues; comparisons used a 2-sided Wilcoxon signed rank test with Lai set as the reference) (H and J). (K) Fold difference in luciferase expression in CD1a+ VEDCs (n = 7 tissues) 3 days after exposure to either media alone (set as reference), Lai/Bal (R5), or Lai/Lai (X4) reporter pseudotypes in the presence and absence of entry inhibitors (comparisons used a 2-sided Wilcoxon signed rank test). (L) Fold difference in luciferase expression in CD1a+ VEDCs (n = 4 tissues) 3 days after exposure to either media alone (set as reference) or Lai/Lai (X4) in the presence or absence of entry inhibitor and SIV Vpx (light red shading)(comparison with and without Vpx done with a 2-sided Mann-Whitney U test). (M and N) RLUs generated from TZM-bl cells 48 hours after being exposed to virus supernatants from CD1a+ VEDCs exposed to NL4-3 or NL4-3 in the presence of SIV Vpx. *P < 0.05.