Florian Hladik

Research Professor, University of Washington
  • United States of America

Recent Comments

Dec 14, 2023

The current study by Huang Y et al reports the unexpected finding that the anti-HIV antibody VRC01 is cleared more quickly from circulation in people taking oral Truvada® (tenofovir/emtricitabine) preexposure prophylaxis (PrEP) than in non-PrEP users. Interestingly, the VRC01 clearance rate positively correlated with serum levels of intestinal fatty acid binding protein (I-FABP), indirectly suggesting some damage to the intestinal mucosa by oral PrEP. Because tenofovir and emtricitabine are also mainstay components of combination antiretroviral treatment (cART), these data could be important for people living with HIV (PWH) as well. cART has dramatically extended the lifespan of PWH, but they still experience higher morbidity than the general population.1 The reasons for this elevated morbidity remain largely unclear, but it is possible that antiretroviral drugs contribute to the etiology of HIV-associated co-morbidities.

That tenofovir/emtricitabine may cause some undesired changes in the gut is supported by our finding that oral Truvada PrEP induces type I/III interferon (IFN-I/III) pathway activation in the duodenal and rectal mucosa.2 Chronic IFN stimulation is known to have some deleterious effects on health.3 In the current and in our prior study, the drugs’ impact was relatively subtle. However, after long periods of treatment, these effects could incrementally contribute to the observed increase of co-morbidities in PWH.

Our prior study may also hold a clue regarding a possible mechanism for faster antibody clearance during oral PrEP use. A correlate of increased IFN-I/III pathway activation in the intestinal mucosa was an increase in the frequency of microfold or M cells in the columnar epithelium.2 M cells are immunologically hyperactive enterocytes, which constitutively express high levels of interferon-stimulated genes (ISGs). They are also primary transporter cells of macromolecules across the intestinal epithelium, which includes shuttling of antigens and antiviral antibodies from and to the intestinal lumen.4,5 The close relationship between M cells and humoral immunity is highlighted by the pairing of nearly every M cell with a B lymphocyte in its basolateral groove. Thus, it stands to reason to hypothesize that a higher number of M cells, as occurs with oral PrEP use, leads to increased shuttling of VRC01 antibody towards the lumen, thereby enhancing its clearance rate.

How this hypothesis ties in with the systemic increase of I-FABP in the current study remains to be determined. We have intestinal biopsies stored from our oral PrEP trial in Seattle (ACTU-3500, NCT02621242), with the duodenal tissues likely being the only ones in the world taken from such a cohort. According to the Human Protein Atlas, I-FABP is much more abundant in the small intestine than in the colorectum. As a first step, these specimens could be studied for I-FABP expression and distribution in oral PrEP users in comparison to their own pre-PrEP biopsies.

Two additional articles are of interest in light of the current report. Murata K et al showed that tenofovir suppresses the anti-inflammatory cytokine interleukin 10 (IL-10) and induces the pro-inflammatory cytokine interleukin 12 (IL-12) in peripheral blood monocytes, but only upon stimulation with bacterial lipopolysaccharide.6 This result might help explain why tenofovir’s (or oral PrEP’s) in vivo effect seems most pronounced in the gastrointestinal tract, where LPS levels are high.

The second article pertains to the mechanism of how these drugs might initiate the reported immunological changes. Rajurkar M et al studied 3TC (lamivudine), which is a drug of the same class as tenofovir and emtricitabine (nucleoside/nucleotide analogue reverse transcriptase inhibitor [NRTI]). Lamivudine inhibited reverse transcription of repeat RNA species such as long interspersed nuclear element-1 (LINE-1) retrotransposons and human endogenous retroviruses (HERV) in human colorectal cancer cells. By inhibiting reverse transcription of these RNAs, lamivudine caused accumulation of DNA:RNA hybrids, which are immunogenic and linked to the stimulation of interferon-response genes.7

Synthesizing the findings of these two studies, I speculate that LPS may activate endogenous retroelements in enterocytes, and NRTI drugs such as tenofovir and 3TC may inhibit subsequent reverse transcription of the resulting repeat RNA species. Finally, innate immune recognition of the DNA:RNA hybrids stemming from incomplete reverse transcription initiates off-target immunological effects, such as intestinal ISG activation, cytokine production, M cell proliferation, and increased immunoglobulin leakiness.

The views and opinions expressed herein are solely those of the author and do not necessarily reflect those of the other authors of the cited publications.

Florian Hladik, PhD MD                                                                                                                            Department of Obstetrics and Gynecology                                                                                    University of Washington                                                                                                                              Seattle, United States

 

Citations

  1. Lerner AM, Eisinger RW, Fauci AS. Comorbidities in Persons With HIV: The Lingering Challenge. JAMA. Dec 11 2019;doi:10.1001/jama.2019.19775
  2. Hughes SM, Levy CN, Calienes FL, et al. Treatment with commonly used antiretroviral drugs induces a type I/III interferon signature in the gut in the absence of HIV infection. Cell Rep Med. Sep 22 2020;1(6):100096. doi:10.1016/j.xcrm.2020.100096
  3. Reich NC. Too much of a good thing: Detrimental effects of interferon. Semin Immunol. Jun 2019;43:101282. doi:10.1016/j.smim.2019.101282
  4. Mabbott NA, Donaldson DS, Ohno H, Williams IR, Mahajan A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. Jul 2013;6(4):666-77. doi:10.1038/mi.2013.30
  5. Neutra MR, Frey A, Kraehenbuhl JP. Epithelial M cells: gateways for mucosal infection and immunization. Cell. 1996;86(3):345-8.
  6. Murata K, Tsukuda S, Suizu F, et al. Immunomodulatory mechanism of acyclic nucleoside phosphates in treatment of hepatitis B virus infection. Hepatology. Sep 17 2019;doi:10.1002/hep.30956
  7. Rajurkar M, Parikh AR, Solovyov A, et al. Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer. Cancer Discov. Jun 2 2022;12(6):1462-1481. doi:10.1158/2159-8290.CD-21-1117