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Title: Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers}
Article:
Abstract:
The majority of HIV-1 elite controllers( EC) restrict HIV-1 replication through highly functional HIV-1-specific T cell responses, but mechanisms supporting the evolution of effective HIV-1-specific T cell immunity in these patients remain undefined. Cytosolic immune recognition of HIV-1 in conventional dendritic cells( cDC) can facilitate priming and expansion of HIV-1-specific T cells; however, HIV-1 seems to be able to avoid intracellular immune recognition in cDCs in most infected individuals. Here, we show that exposure of cDCs from EC to HIV-1 leads to a rapid and sustained production of type I interferons and upregulation of several interferon-stimulated effector genes. Emergence of these cell-intrinsic immune responses was associated with a reduced induction of SAMHD1 and LEDGF/p75, and an accumulation of viral reverse transcripts, but inhibited by pharmacological blockade of viral reverse transcription or siRNA-mediated silencing of the cytosolic DNA sensor cGAS. Importantly, improved cell-intrinsic immune recognition of HIV-1 in cDCs from elite controllers translated into stronger abilities to stimulate and expand HIV-1-specific CD8 T cell responses. These data suggest an important role of cell-intrinsic type I interferon secretion in dendritic cells for the induction of effective HIV-1-specific CD8 T cells, and may be helpful for eliciting functional T cell immunity against HIV-1 for preventative or therapeutic clinical purposes.
Introduction:
Elite controllers can maintain undetectable levels of HIV-1 viral replication in the absence of antiretroviral therapy, at least in part through the generation of highly-efficient HIV-1-specific T cell responses[1–4]. As such, these patients provide living evidence that in principle, the human immune system is capable of generating a T cell-mediated immune response that allows to effectively controlling HIV-1 replication. However, it is uncertain why such immune responses occur only in very few patients, and what mechanisms support the development of highly-effective T cell immune responses in such a small number of individuals, and not in the majority of alternative individuals. Dendritic cells( DCs) represent the most effective naturally-occurring antigen-presenting cells and have critical roles for inducing and maintaining antigen-specific T cell responses[5–10]. However, specific functional characteristics of DCs that are instrumental in generating protective HIV-1-specific T- cell responses in elite controllers are unclear, and represent an understudied area of investigation. Understanding the mechanisms that facilitate the induction of effective HIV-1-specific T cells by dendritic cells is of critical interest for developing improved immunologic approaches for HIV-1 treatment and prevention, specifically since most HIV-1 vaccine candidates rely on dendritic cells for inducing HIV-1-specific immune responses. Human cells have the ability to respond to viral infections by cell-intrinsic immune responses that lead to secretion of type I interferons( IFN-I) and upregulation of a wide panel of IFN-stimulated genes( ISG) with antiviral effector functions[11, 12]. This cell-intrinsic immune response is extremely effective in defending the host against a panel of different viruses[13], but early reports suggested that human cells are unable to mount such immune responses against HIV-1[14, 15]. However, recent discoveries have shown that human conventional DCs( cDC) are generally capable of generating IFN-I responses to HIV-1, but HIV-1 seems to be able to escape from such cell-intrinsic immunity in most patients[16–18]. A dominant mechanism that may allow HIV-1 to avoid cell-intrinsic immune responses in cDC includes the expression of SAMHD1, a host protein that can block HIV-1 reverse transcription by hydrolyzing dNTPs[19–22] or inhibit HIV-1 RNA through direct degradation[23]. In the presence of experimental SAMHD1 knockdown, viral replication in host cells progresses beyond the level of reverse transcription, and viral reverse transcripts or proteins can be sensed by host molecules that can initiate secretion of type I interferons[16, 24–27]. In this way, restriction of HIV-1 replication by SAMHD1 may paradoxically benefit the virus more than the host, which likely explains why SAMHD1 represents the only effective HIV-1 restriction factor that HIV-1 does not neutralize through the activity of accessory proteins[28]. In addition to SAMHD1, cell-intrinsic immune responses in DCs are inhibited by the host protein TREX1, a host exonuclease that degrades HIV-1 reverse transcripts, which otherwise trigger microbial DNA sensors, leading to cell-intrinsic secretion of type I interferons[18, 29]. In the present study, we demonstrate that unlike chronic progressors, dendritic cells from elite controllers have the ability to effectively mount cell-intrinsic type I IFN secretion in response to HIV-1 infection, likely through an accumulation of viral reverse transcripts that serve as substrates for the cytosolic DNA sensor cGAS( cyclic guanosine monophosphate-adenosine monophosphate( GMP-AMP) synthase). Recognition of these early viral replication products in elite controllers seemed to be facilitated by an enhanced upregulation of cGAS, led to rapid and sustained secretion of type I IFNs, and was functionally relevant for supporting effective HIV-1-specific CD8 T cell responses. Together, these results suggest previously unrecognized innate mechanisms of HIV-1 immune recognition that contribute to T cell-mediated immune control of HIV-1.
Discussion:
Cell-intrinsic secretion of type I IFN represents an efficient antimicrobial immune defense strategy, but the clinical significance of these types of immune responses against HIV-1 remains uncertain. Recent studies show that in principle, human cells have the ability to respond to HIV-1 infection with increased secretion of type I interferons; however, several negative regulators of IFN secretion seem to actively prevent these immune responses in most patients[48–50]. In this study, we have conducted a detailed analysis of cell-intrinsic immune responses to HIV-1 in primary dendritic cells from elite controllers, a small subgroup of patients who control HIV-1 replication in the absence of treatment and arguably represent the best patients for detecting effective immune defense mechanisms against HIV-1 disease progression. Our data indicate that cDCs from EC differed from those of other patients by cell-intrinsic type I IFN secretion that occurred rapidly and sustainably after HIV-1 infection, was associated with increased cell activation, and resulted in improved abilities to stimulate HIV-1-specific CD8 T cells. As such, our data demonstrate that type I IFN responses to HIV-1 in cDCs may play an important role in the network of immune defense mechanisms in elite controllers, and delineate specific connections between innate HIV-1 immune recognition and the generation of adaptive immune responses in this specific patient population. Dendritic cells represent a relatively hostile environment for HIV-1 and do not effectively support HIV-1 replication steps, likely due to specific myeloid host proteins that effectively block HIV-1 replication steps. SAMHD1 is one of the most prominent myeloid restriction factors, and can effectively inhibit HIV-1 reverse transcription by hydrolyzing dNTPs, which are typically only available in limited amounts in resting myeloid cells. Despite evidence that SAMHD1 sequences have been under positive selection pressure[51], it is interesting that HIV-1 has not developed effective measures to counteract the antiviral activity of this host factor, suggesting that this protein may not significantly impair the ability of HIV-1 to establish a long-lasting, progressive infection of the host. Our study demonstrates the paradoxical finding that cDCs from EC are more permissive to early steps of HIV-1 replication while cDCs from patients with progressive infection are more resistant to HIV-1 infection. This corresponded to our observation that upregulation of SAMHD1 in response to HIV-1 was lower in EC, leading to more efficient reverse transcription in cDCs from these patients. Whether this reduced induction of SAMHD1 in cDC from EC represents a constitutive, cell-intrinsic aspect of cDC from these patients, or occurs as a result of specific interactions with other cell types[52] is uncertain at present and requires further investigation. Overall, these data suggest that the SAMHD1-dependent restriction of HIV-1 replication in cDCs benefits the virus more than the host, and that a higher susceptibility of cDCs to HIV-1 paradoxically allows for more effective systemic immune defense against HIV-1. Notably, ISG expression and levels of IFNα/β expression prior to ex-vivo infection with HIV-1 tended to be elevated in cDC from CP, consistent with higher levels of immune activation in this cohort; it is possible that this increased baseline immune activation may make cDC from these patients refractory to HIV-1-induced cell-intrinsic immune responses. Cell-intrinsic immune responses in cDCs from EC in our study appeared to be facilitated by an accumulation of reverse transcripts. These viral products seem to represent the main viral substrate that is responsible for the induction of cellular type I IFN responses, as pharmacological inhibition of viral reverse transcripts almost completely inhibited cell-intrinsic IFN-I secretion, while inhibition of HIV-1 integration did not. These observations support previous data suggesting that single-stranded HIV-1 DNA transcripts represent the predominant HIV-1 replication product that cell-intrinsic microbial sensors recognize[27, 53]. The exact reasons responsible for the accumulation of reverse transcripts in EC are not entirely clear; however, relative to the levels of reverse transcripts, HIV-1 integration in cDCs from EC was disproportionately reduced, and the ratio of reverse transcripts to integrated HIV-1 DNA was exceedingly higher in cDCs from EC compared to all other patient cohorts. Together these data suggest that cDCs from EC preferentially support a form of abortive HIV-1 infection that progresses effectively through reverse transcription, but is restricted at the level of viral integration, possibly through as of yet undefined host factors. Notably, prior studies found evidence for restriction of HIV-1 integration in resting CD4+ T cells from EC[54], although the underlying reason remained uncertain. The weak induction of host factors required for HIV-1 integration in cDCs from EC, such as LEDGF/p75, may represent one important aspect contributing to the accumulation of RT products in cDCs from EC, but a closer analysis of molecular mechanisms regulating and possibly restricting HIV-1 integration in cDCs from EC will likely be highly informative. In addition, it is interesting that higher levels of integrated HIV-1 DNA in CP and HAART-treated patients did not translate in higher levels of HIV-1 mRNA transcription, as determined by GFP expression; this suggests that additional restriction at the level of viral gene transcription may be operational in these patients. An important aspect of this work is the identification of cGAS as a critical factor for the generation of cell-intrinsic type I IFN responses in primary cDCs. cGAS can act as a cytosolic microbial DNA sensor that induces interferon secretion by production of the second messenger cGAMP[43, 55, 56] and can play an important role for innate recognition of HIV-1 DNA in myeloid cells[42]. However, in prior studies, cGAS-dependent immune recognition of HIV-1 was mostly analyzed in monocyte-derived DCs, which are highly resistant to HIV-1 unless co-transfected with viral inhibitors of SAMHD1[27]. Our experiments in more physiologic primary cDCs from EC demonstrated that HIV-1 infection led to a rapid induction of cGAS expression, and cGAS silencing in primary cDCs effectively inhibited type I IFN secretion. As such, our work strongly suggests that cGAS can sense HIV-1 DNA under physiologically relevant conditions, and that a more rapid induction of cGAS expression facilitates the generation of cell-intrinsic type I IFN secretion in cDCs from EC. Notably, STING, an adaptor molecule that acts downstream of cGAS-dependent immune recognition[43, 57], also tended to be more effectively induced in cDCs from EC, suggesting combined activity of the cGAS/STING pathway for HIV-1 immune recognition in these patients. Interestingly, IFI16, which can act as a cellular sensor for HIV-1 DNA in lymphoid CD4+ T cells and induces pyroptosis after abortive infection with HIV-1[45], was similarly induced in cDCs from all cohorts early after infection, and therefore unlikely to be responsible for the early type I IFN responses observed in EC. While the role of highly-functional HIV-1-specific CD8 T cells for HIV-1 immune defense in elite controllers is supported by a large number of studies[58–61], the ontogeny of these effective immune responses still remains largely obscure. Our data suggest that more efficient cell-intrinsic responses against HIV-1 in cDCs from EC translate into an enhanced ability to stimulate HIV-1-specific T cell responses. This may correspond to prior description to specific expression patterns of immunoregulatory receptors on cDC from EC[62]. As such, more effective cell-intrinsic IFN secretion in cDCs may represent a distinguishing feature of elite controllers, and a key mechanism supporting the evolution of effective adaptive cellular immune responses. Yet, growing evidence suggests that the ability of elite controllers to maintain undetectable levels of viral replication is associated with increased levels of immune activation[63, 64], which may put patients at risk for higher frequencies of cardiovascular events and accelerated immune aging. Therefore, it is tempting to speculate that improved abilities for cytosolic microbial immune recognition may represent a constitutive characteristic of ECs that predisposes them for more potent immune activity against HIV-1, at the expense of elevated generalized levels of immune activation. An improved understanding of interactions between innate immune recognition in cDCs, immune activation and the evolution of adaptive CD8 T cell responses in elite controllers will therefore be necessary for designing clinical strategies aiming at inducing an elite controller-like phenotype in broader populations of HIV-1 patients.
Elite controllers ( EC ) , a small group of HIV-1-infected individuals that are able to control viral replication in the absence of antiretroviral therapy , provide living evidence that the human immune system is able to spontaneously control HIV-1 infection and serve as a model for inducing a functional cure of HIV-1 infection in broader patient populations . Prior studies indicated that T cell-mediated immune responses represent the backbone of effective antiviral immune defense in EC; however , emerging studies suggest that innate and cell-intrinsic immune activities may have critical roles for supporting and enhancing HIV-1-specific T cells . Here , we performed a detailed investigation of conventional dendritic cells ( cDC ) from elite controllers and their responses to HIV-1 infection . These studies indicate that cDC from EC have improved abilities to sense cytosolic HIV-1 replication products , and can more effectively mount cell-intrinsic type I interferon ( IFN ) secretion in response to HIV-1 infection . Notably , such increased production of type I IFN in response to viral antigen translated into enhanced abilities to prime and expand HIV-1-specific T cells . Together , these data suggest that a fine-tuned interplay between innate dendritic cell responses and adaptive HIV-1-specific CD8 T cells represents a critical component of antiviral immune defense in elite controllers .