Monocyte and Myeloid Dendritic Cell Activation Occurs Throughout HIV Type 2 Infection, an Attenuated Form of HIV Disease

Abstract

Monocytes and myeloid dendritic cells (mDCs) are important orchestrators of innate and human immunodeficiency virus (HIV)-specific immune responses and of the generalized inflammation that characterizes AIDS progression. To our knowledge, we are the first to investigate monocyte and mDC imbalances in HIV type 2 (HIV-2)-positive patients, who typically feature reduced viremia and slow disease progression despite the recognized ability of HIV-2 to establish viral reservoirs and overcome host restriction factors in myeloid cells. We found a heightened state of monocyte and mDC activation throughout HIV-2 infection (characterized by CD14(bright)CD16(+) expansion, as well as increased levels of soluble CD14, HLA-DR, and CD86), together with progressive mDC depletion. Importantly, HIV-2-positive patients also featured overexpression of the inhibitory molecule PD-L1 on monocytes and mDCs, which may act by limiting the production of proinflammatory molecules. These data, from patients with a naturally occurring form of attenuated HIV disease, challenge current paradigms regarding the role of monocytes in HIV/AIDS and open new perspectives regarding potential strategies to modulate inflammatory states.

Different Expression of Interferon-Stimulated Genes in Response to HIV-1 Infection in Dendritic Cells Based on Their Maturation State

“…Our results showing ISG induction after infection of IDCs with HIV-1 plus Vpx or HIV-2, which degrade SAMHD1 and allow reverse transcription, support a role for cGAS sensing under these conditions. Taking into consideration the different virulence of HIV-1 and HIV-2, our data confirm previous observations (22,37,45,48) suggesting that through restriction of replication in DCs, lentiviruses avoid triggering class I IFN responses. As a consequence and paradoxically, low infection of DCs would result in higher virulence due to escape from early immune surveillance, thereby allowing broader dissemination of infected cells.…”

“…To validate the results observed in our models of productive HIV-1 infection in which Vpx was artificially loaded in viral particles, human DCs were infected with HIV-2 carrying the vpx gene, which increases productive infection in cells of the myeloid lineage (45)(46)(47). DCs were generated as described in Materials and Methods and infected with the HIV-2 ROM10 strain.…”

Brief Report: Macrophage Activation in HIV-2–Infected Patients Is Less Affected by Antiretroviral Treatment—sCD163 in HIV-1, HIV-2, and HIV-1/2 Dually Infected Patients

“…This was accompanied by upregulation of the immunoinhibitory molecules PD-L1/PD-1, leading the authors to suggest that this may be an explanation for the more benign outcome in those with HIV-2 infection. 21 In this study, we found no differences in sCD163 levels between HIV types at baseline or at follow-up among patients without ART. However, for patients on ART, HIV-2-infected patients had a significantly lower decrease in sCD163 levels than HIV-1-infected patients.…”

“…21 An increased monocyte activation in HIV-2 infection has previously been described. This was accompanied by upregulation of the immunoinhibitory molecules PD-L1/PD-1, leading the authors to suggest that this may be an explanation for the more benign outcome in those with HIV-2 infection.…”

Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid

“…LPS levels were elevated in an African cohort with HIV-2 infection and correlated with disease progression [88]. However, this was not observed in a European cohort, even though there was evidence of significant T cell and monocyte activation [89]. In marked contrast to HIV-1 infection, mucosal integrity and gut-associated lymphocyte numbers are preserved in aviraemic HIV-2 infection (with or without ART), despite the presence of replicating virus in the gut mucosa [82].…”