Candida albicans-Induced DC Activation Partially Restricts HIV Amplification in DCs and Increases DC to T-Cell Spread of HIV

Abstract

Dendritic cells (DCs) are central to the innate and adaptive responses needed to control pathogens, yet HIV exploits DCs to promote infection. The influence of other pathogens on DC-HIV interplay has not been extensively studied. We used Candida albicans (Candida) as a model pathogen which elicits innate DC responses that are likely important in controlling Candida by healthy immune systems. HIV did not impede Candida-specific DC activation. Candida-induced CD80 and CD83 upregulation was greater in DCs that had captured HIV, coinciding with increased amplification in presence of T cells and reduced but persistent low-level DC infection. In contrast, HIV-infected DCs matured normally in response to Candida, but this did not shut down HIV replication in DCs, and again Candida augmented HIV amplification in DC-T-cell mixtures. HIV-infected DCs secreted more IL-10 and IL-1beta earlier than uninfected DCs and initially induced a higher frequency of CD4CD25FoxP3 T-regulatory cells in response to Candida. Elevated early IL-10 production in cocultures was evident only when azidothymidine (AZT) was included to limit T-regulatory cell infection and destruction. Therefore, HIV manipulates the DC's innate and adaptive responses to Candida to further augment HIV spread, ultimately destroying the cells needed to limit candidiasis.

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

“…Although potently activating the DCs, cocktail maturation had the least impact on virus replication in the DCs. We recently reported a similar persistence of virus replication in DCs maturing in response to Candida albicans, which ultimately facilitated enhanced spread upon T-cell contact (72). These data underscore how different stimuli uniquely impact the fate of HIV in DCs and how critical it is to completely shut down HIV replication in imDCs.…”

“…Above all, our data suggest that type I IFN-mediated inhibition by poly(I:C) would be particularly effective during the earliest stages of HIV infection to prevent infection of imDCs. If poly(I:C) was applied too late, imDC infection would be reduced, but the persistence of lowlevel viral replication might continue to provide an infectious source of virus to spread to neighboring T cells (23,(70)(71)(72)74). Moreover, the activation of DCs without completely shutting down virus replication would further enhance DC-mediated transmission of HIV to T cells (55,70,72,74).…”

“…If poly(I:C) was applied too late, imDC infection would be reduced, but the persistence of lowlevel viral replication might continue to provide an infectious source of virus to spread to neighboring T cells (23,(70)(71)(72)74). Moreover, the activation of DCs without completely shutting down virus replication would further enhance DC-mediated transmission of HIV to T cells (55,70,72,74). Poly(I:C)-mediated activation through type I IFNs may be especially advantageous following mucosal (rather than systemic) application of poly(I:C) (35,73).…”

Mycobacterium tuberculosisPromotes HIVtrans-Infection and Suppresses Major Histocompatibility Complex Class II Antigen Processing by Dendritic Cells

“…These data extend our previous analysis of LPS-stimulated HIV sequestration into an identical structure (42) and suggest that pocket formation is a generalized response to activating stimuli. Indeed, Candida albicans exposure leads to partial activation of DCs along with increased HIV trans-infection (38), suggesting that innate immune responses to invading copathogens can act to stimulate HIV dissemination.…”

Kaposi's-sarcoma-associated-herpesvirus-activated dendritic cells promote HIV-1 trans-infection and suppress CD4+ T cell proliferation

“…We and others have previously proved that AIDS-associated pathogens can promote maturation of DCs (Diou et al, 2010a(Diou et al, , 2010bQin et al, 2011Qin et al, , 2012Reuter et al, 2010;Vachot et al, 2008). To determine the potential effects on MDDC maturation by KSHV, immature MDDCs were co-cultured with different amounts of rKSHV for 48 h. Cell phenotype was monitored by immunostaining of surface markers.…”