Increased HIV-1 transcriptional activity and infectious burden in peripheral blood and gut-associated CD4+ T cells expressing CD30

Abstract

HIV-1-infected cells persist indefinitely despite the use of combination antiretroviral therapy (ART), and novel therapeutic strategies to target and purge residual infected cells in individuals on ART are urgently needed. Here, we demonstrate that CD4+ T cell-associated HIV-1 RNA is often highly enriched in cells expressing CD30, and that cells expressing this marker considerably contribute to the total pool of transcriptionally active CD4+ lymphocytes in individuals on suppressive ART. Using in situ RNA hybridization studies, we show co-localization of CD30 with HIV-1 transcriptional activity in gut-associated lymphoid tissues. We also demonstrate that ex vivo treatment with brentuximab vedotin, an antibody-drug conjugate (ADC) that targets CD30, significantly reduces the total amount of HIV-1 DNA in peripheral blood mononuclear cells obtained from infected, ART-suppressed individuals. Finally, we observed that an HIV-1-infected individual, who received repeated brentuximab vedotin infusions for lymphoma, had no detectable virus in peripheral blood mononuclear cells. Overall, CD30 may be a marker of residual, transcriptionally active HIV-1 infected cells in the setting of suppressive ART. Given that CD30 is only expressed on a small number of total mononuclear cells, it is a potential therapeutic target of persistent HIV-1 infection.

CD32 expressing doublets in HIV-infected gut-associated lymphoid tissue are associated with a T follicular helper cell phenotype

“…Some groups have shown an enrichment of HIV DNA or RNA expression in this CD32 high population. 11,12,18,19 Even though we have shown that these are largely doublets, this finding could still be of further interest if these doublets were of physiological interest or provided information about the HIV reservoir. We found CD32 high cells at a higher frequency in GALT sites compared with blood with an enrichment for markers of TFH in the T-cell portion of the doublets.…”

“…Recent work suggesting that CD32a (a low-affinity IgG receptor not generally expressed on T cells 10 ) was a specific marker for latent HIV infection 11 was initially supported by studies showing that CD32 may be found on cells that are transcriptionally active, and was associated with HIV DNA levels in some patients. [12][13][14][15][16][17][18][19] However, the finding that CD32 co-expression with CD4 is predominantly due to T-cell-B-cell doublets 17 likely undermines the argument that CD32 is a definitive marker of latency.…”

Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis

“…2a) and is predicted by PROSITE database 17 to disrupt a disulfide bond between Cys in positions 273 and 259 in the extracellular domain of the protein. CD30 is expressed on the surface of activated lymphocytes and eosinophils and has been implicated in activation, proliferation and apoptosis via NFκB activation [18][19][20][21] . p.Cys273Tyr has been reported to associate with reduced eosinophil count 22 and reduced mosquito bite size 23 .…”

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…In addition, high levels of CD2 receptor expression on latently infected resting memory CD4 + T cells in virally suppressed HIV-1-infected subjects has been also identified (Iglesias-Ussel et al, 2013). Moreover, CD30 receptor was identified on transcriptionally active CD4 + lymphocytes in individuals on suppressive ART suggesting that it might be a marker of residual, transcriptionally active HIV-1 infected cells in the setting of suppressive ART (Hogan et al, 2018). Last but not least, very recently the B lymphocyte antigen CD20 has also been identified as a marker of transcriptionally-active HIV-infected cells .…”