EBV renders B cells susceptible to HIV-1 in humanized mice

Abstract

HIV and EBV are human pathogens that cause a considerable burden to worldwide health. In combination, these viruses are linked to AIDS-associated lymphomas. We found that EBV, which transforms B cells, renders them susceptible to HIV-1 infection in a CXCR4 and CD4-dependent manner in vitro and that CXCR4-tropic HIV-1 integrates into the genome of these B cells with the same molecular profile as in autologous CD4+ T cells. In addition, we established a humanized mouse model to investigate the in vivo interactions of EBV and HIV-1 upon coinfection. The respective mice that reconstitute human immune system components upon transplantation with CD34+ human hematopoietic progenitor cells could recapitulate aspects of EBV and HIV immunobiology observed in dual-infected patients. Upon coinfection of humanized mice, EBV/HIV dual-infected B cells could be detected, but were susceptible to CD8+ T-cell–mediated immune control.

Probing Reconstituted Human Immune Systems in Mice With Oncogenic γ-Herpesvirus Infections

“…In addition, however, low levels of latency I and II with EBNA1 as the sole or in addition LMP1 and 2 protein expression could be detected (18,23). Low levels of these lower latencies were also verified by detection of characteristic viral transcripts (21,24,25). While latency III is found in naïve B cells of healthy EBV carriers, latency II predominates in germinal center B cells and latency I in homeostatically replicating memory B cells (26,27).…”

“…Similarly in humanized mice antibody mediated T cell depletion increased EBV viral loads and DLBCL-like lymphomagenesis ( 16 , 60 ) ( Figure 1 ). While primarily CD8 + T cells seemed to protect from EBV induced lymphomagenesis in humanized mice, antibody depletion, pharmacological inhibition by FK506 or destruction of CD4 + T cells by HIV co-infection also compromised EBV specific immune control in humanized mice ( 16 , 21 , 25 ). Along these lines, late lytic EBV antigen specific CD4 + T cells have been reported to restrict EBV transformed B cell growth in mice ( 61 ).…”

Advances in Humanized Mouse Models to Improve Understanding of HIV-1 Pathogenesis and Immune Responses

“…Currently animal models for HIV co-infection with other pathogens are lacking. Although Hu-mice have been used to investigate HIV co-infection with pathogens such as Epstein–Barr virus and Neisseria gonorrhoeae ( 30 , 122 ), co-infection with Mycobacterium tuberculosis (Mtb) is of particular interest as it is the most common cause of AIDS-related death ( 1 ). HIV-1 infection increases the risk of latent tuberculosis (TB) reactivation ( 123 ).…”

Modification of EBV Associated Lymphomagenesis and Its Immune Control by Co-Infections and Genetics in Humanized Mice

“…Indeed CD4 + T cell responses seem essential to maintain efficient immune control of EBV in humanized mice. Both, iatrogenic immune suppression with tacrolimus (FK506) that mainly affects CD4 + T cell activation and expansion after EBV infection of humanized mice, and CD4 + T cell depletion by HIV co-infection leads to elevated viral loads and increased EBV associated B cell lymphoma formation ( 71 , 72 ). During HIV co-infection CD8 + T cell depletion does not further increase EBV viral loads or lymphoma formation ( 72 ).…”

“…Both, iatrogenic immune suppression with tacrolimus (FK506) that mainly affects CD4 + T cell activation and expansion after EBV infection of humanized mice, and CD4 + T cell depletion by HIV co-infection leads to elevated viral loads and increased EBV associated B cell lymphoma formation ( 71 , 72 ). During HIV co-infection CD8 + T cell depletion does not further increase EBV viral loads or lymphoma formation ( 72 ). This suggests that HIV induced CD4 + T cell depletion compromises T cell help to maintain protective CD8 + T cell function because CD8 + T cell depletion during only EBV infection of humanized mice significantly affects immune control ( 22 , 36 , 72 , 73 ).…”