Human immunodeficiency virus 1 (HIV-1) is a highly pathogenic retrovirus that causes immune system degeneration (1). In the past 30 years, antiretroviral therapy has achieved considerable advances. However, despite remarkable scientific achievements in HIV-1 diagnosis and treatment, acquired immune deficiency syndrome (AIDS) still prevails and there are estimated 35 million people worldwide living with HIV-1 infection or AIDS (2, 3). The innate immune system, a significant alarm system in our body, has been caught more attention on resisting foreigner pathogens in recent years (4–6). One of the key effector molecules in innate system is interferons (IFNs), which rapidly respond to virus infection by a broadly, non-specific manner.

Interferons are classified into three groups based on the structure of their receptors: type I (IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ), type II (IFN-γ), type III (IFN-λ1, IFN-λ2, and IFN-λ3). Among these three types, IFN-I bind to a cell surface receptor complex known as the IFN-α/β receptor (IFNAR), which consists of IFNAR1 and IFNAR2 chains (7). Contrary to the limited expression of type II and type III interferons receptor, IFNAR is widely expressed on almost all kinds of immunocytes and epithelial tissue (5, 8, 9), suggesting that IFN-I have an extensive influence and are able to arouse quick activation of the whole immune system.

Innate immune responses mainly derive from the recognition of viral pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PPRs) such as toll-like receptors (TLRs), retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), and other DNA-sensing receptors (10–12). Upon sensing PAMPs, several downstream signal molecules and transcriptional factors will be recruited, subsequently production of IFNs, especially IFN-I, is stimulated. At the earliest stage of acute infection, the production of IFN-I and other inflammatory cytokines is an essential event to determine the rate of virus replication and spreads (11, 13, 14). Unfortunately, this response is usually ineffective to suppress HIV-1 activity, due to the ability of this virus to hijack host immune system and evade the IFN-mediated antiviral activities (4). Moreover, the persistent IFN-I secretion greatly disturbs the immune homeostasis, contributing to immune activation-dependent disease progression (15, 16).

The administration of IFN-I, especially IFN-α, as monotherapy or an adjunct to combined antiretroviral therapy (cART), has been intensively reported (17), but the results varied greatly. In addition, as the continuous IFN-I production impedes immune recovery and enhances T cells exhaustion, IFN-I blockade may provide another strategy to weaken the virus-induced immune hyperactivation in the chronic HIV-1 infection (18, 19). Actually, inhibition of IFN-I system is likely to be an efficient way to reverse excessively elevated IFN-I signaling and rescue specific anti-HIV-1 immunity (20). Concerning the extensive impact of IFN-I system, it is unclear whether this method to shut off the IFN-I system is beneficial to pathogenesis or merely a secondary effect.

In this review, we will discuss the stimulation of IFN-I by sensing viral pathogens after HIV-1 infection, the antiviral/immunomodulatory activities of IFN-I on different immunocytes, and the manipulation of IFN-I system as a therapeutic strategy in vivo.

Unlike the effective response in other infectious diseases, IFN-I in HIV-1 infection becomes rapidly dysfunctional and unable to purge the virus finally. Inversely, as the widely expression of IFNAR, prolonged virus replication and sustained stimulation of IFN-I progressively induce a generalized immune activation, injured inflammation, as well as T cell exhaustion (2, 46). Moreover, a strong correlation between the levels of IFN-I and disease progression has already been observed. In the models of simian immunodeficiency virus (SIV) infection, the common character of long time non-progression macaques is that they can induce rapid and transient high levels of IFN-I but declines in the chronic phase (19, 57, 58). Though the administration of cART can effectively suppress the replication of HIV-1, it cannot completely reverse the immune hyperactivation caused by IFN-I (59, 60). In the lymphocytic choriomeningitis virus (LCMV) mouse models, persistent production of IFN-I exacerbates CD4⁺ T cell exhaustion and is detrimental to its antiviral response (61–63). Other researches also indicate that chronic infection of LCMV induces inhibitory molecules expression and apoptosis of Treg (64, 65). These studies suggest that compare to a positive role of IFN-I on restricting virus spread and replication at the acute phase of infection, IFN-I tend to exert a negative effect on different immunocytes in chronic HIV-1 infection.

Plasmacytoid dendritic cells are a special dendritic cell subset that produces a large amount of IFN-I in the process of HIV-1 infection. With the progression of HIV-1 infection, pDCs gradually decrease in blood while accumulate in lymph nodes. pDCs from these lymph nodes secrete higher titer of IFN-α spontaneously but not express co-stimulatory molecular (66). These nonfunctional cells are continuously produce IFN-I but cannot develop into mature antigen presentation cells. Instead, the redistributed pDCs increase staining of Annexin V and thus exhibit apoptosis (67). Even for cART treatment patients, the frequency and function of pDCs in peripheral blood is decline and accumulate in gut-associated lymphatic tissue (68). Moreover, in the chronic phase of HIV-1 infection, the excessive IFN-I may result in the dysregulated activation and even depletion in pDCs. In SIV models, a negative correlation between the decline of circulating pDCs and overexpression of IFN-I are observed during pathogenic SIV infection of macaques, but not in natural ones (69). Furthermore, pDCs with the upregulation of β7-integrin and CD103 are aggregated to the colorectum in chronic HIV-1 infected patients, which facilitates much more production of IFN-I (70, 71). Unfortunately, the amount of IFN-I produced by these lymphatic tissues is much more than what organisms really need to fight infection (71). Furthermore, these redundant IFN-I will lead to the activation of innate immune system and conversely damage the normal function of pDCs. However, the specific mechanism how IFN-I interacts with pDCs has not been clearly elucidated. There are two possible reasons for this phenomenon: On the one hand, pDCs that are persistently stimulated by IFN-I express low levels of migration receptors and regulatory factors, such as CCR7, CD40, and CD86. These pDCs produce IFN-I since pathogenic nucleic acid traffics to the endosome (72, 73), which induces apoptosis to these out-of-control cells mediated by the TNF-related apoptosis-inducing ligand (TRAIL) (74). On the other hand, IFN-I activates the non-canonical NF-κB signaling in pDCs. This pathway will promote the expression of indoleamine 2,3-dioxygenase, the most essential factor to gather regulatory T cells (Treg) (75). These pDCs-induced Treg intensively inhibit the maturation of pDCs through the engagement of cytotoxic T-lymphocyte antigen (CTLA)-4 and PD-1 on these activated pDCs (6).

Natural killer (NK) cells play a crucial role in innate immune system that act as the first line to defense HIV-1. First, the interaction between killer immunoglobulin-like receptors expressed on the surface of NK cells with their cognate HLA ligands sets a guarantee recognize specific HIV-derived peptides and eliminate HIV-1 infected cells (76, 77). Second, antibody-dependent cellular cytotoxicity (ADCC) is the other way of NK cells to control HIV-1 infection. Notably, ADCC activity was associated with the modest protective efficacy in the RV144 HIV vaccine trial (78). Moreover, new data show that the levels of NK cells activation is tightly associated with HIV-1 virological suppression in patients receiving cART (79). Patients who initiate ART early during infection obtain the improvement of cytotoxic function of the NK cells while decline of the levels of ADCC mediating antibodies (80, 81). These data suggest that NK cells. However, during the whole phase of HIV-1 infection, the relation between NK cells and IFN-I is complicated. In the acute infection, IFN-I has been observed to promote NK cells survival, expansion, maturation, activation and enhance their cytotoxic activity against virus (82, 83). In IFNAR^−/− mice, there are barely detectable mature NK cells in peripheral blood (84). Identically, impaired cytotoxicity ability as well as a loss of highly activated subset of NK cells has been found in rapid progressors (85). But in the chronic HIV-1 infection, IFN-I may greatly disturb the normal function of NK cells. First, despite viral control well, NK cells are consistently activated in the chronic HIV-1 infection after the establishment of reservoirs. In the presence of high level of IFN-I, activated NK cells attenuate the cytotoxicity of CD8⁺ T cells response to virus infection. As the suppressed function of NK cells and CD8⁺ T cells, HIV escape from ADCC and CTL effect (86). Another research demonstrates that NK cells-depletion mice promoted virus-specific T cells response and contributed to viral control (87). Second, IFN-I disturbs the balance between STAT1 and STAT4, two downstream transcriptional factors of IFNAR in NK cells. In HCV/HIV coinfected patients, high level of IFN-I is relevant to the upregulation of STAT1 while downregulation of STAT4, which increase the expression of perforin induced by interleukin (IL)-12 (88). This mechanism further prompts the nonfunctional activation of NK cells. Thirdly, IFN-I decreases the production of IFN-γ through upregulating the expression of IL-10 and PD-L1 in NK cells (89), which further weaken their cytotoxic effects.

It is well established that HIV-infected patients maintain persistently high circulating CD8⁺ T cells number, in spit of many years of therapy (90). The CD4/CD8 ratio often fails to become normal despite CD4 count normalization. Notably, new data showed that the majority of CD8⁺ T proliferation and activation was induced in an antigen-independent manner (91). The great disturbing of T cell homeostasis makes the immune system dysfunctional and exhausted in the chronic HIV-1 infection. It is intensely investigated that IFN-I is responsible for the expansion of CD8⁺ T cells. On the one hand, IFN-I has been shown to induce memory CD8⁺ T cells proliferation and differentiation through bystander effect (92, 93). Thus, it is hypothesis that sustained exposure to IFN-I could contribute to CD8⁺ T cell persistence. On the other hand, during the chronic infection, IFN-I favor the formation of terminally differentiated CD8⁺ T cells that do not renew but enhanced cytotoxic function. This subset skewing likely contributes to the progressive IFN-I-mediated immune dysregulation (61, 89).

As we all known, HIV-1 features as the destroyer of CD4⁺ T cells. It is the death of this kind of cell that propels the late phase of clinical procession, AIDS (2, 26). Although IFN-I could silence T cells to limit viral replication and program cells death to get rid of HIV-1 infection, IFN-I also influence the differentiation of T cells and induce death of HIV-1 uninfected cells via bystander effect (92, 94). On the one hand, depending on cytokine environment, naïve CD4⁺ T cells mainly differentiate into Th1, Th2, Treg, and follicular T helper (Tfh) cell populations that have different biological functions (95). Actually, continuously stimulated by IFN-I facilitate naïve CD4⁺ T cells differentiate toward Th2 cells, leading to a severe disproportionality of Th1 and Th2 (96, 97). On the other hand, IFN-I induces apoptosis of uninfected CD4⁺ T cells in peripheral blood and in secondary lymphatic tissue by upregulating TRAIL expression on CD4⁺ T cells, leading to the destruction of lymph node in gastrointestine in the acute phase of HIV-1 infection (98). Recent studies revealed that the death of 95% resting, non-permissive CD4⁺ T cells are caused by caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death (99, 100). With the stimulation of IFN-I, the expression of PD-1 is upregulated in exhausted T cell. Instead, blockade of PD-1/PD-L1 pathway helps to restore the function of T cells and decrease the viral load (101). Another studies also show that IFN-I significantly suppress HIV-1-specific CD4⁺ T response, while blockade of IFN-I signaling pathway inactivates immune system, downregulates the expression of negative immune-regulatory factors and maintains the lymphoid structure after chronic LCMV infection (89, 102). In the model of humanized mice, blocking IFNAR rapidly enhances CD4⁺ T recovery and reduces HIV-1 reservoirs (103).

Recently, a special subset of CD4⁺ T cells, Tfh cells, has been intensively reported for its function to induce memory B cells activation, survival, differentiation, as well as assist B cells to produce antigen-specific neutralizing antibodies. At the same time, Tfh cells act as the major CD4⁺ T cells compartment for HIV-1 infection, replication, and long-lived viral reservoirs (104, 105). In the chronic HIV-1 infection, the differentiation of Tfh cells impairs greatly as the repressive effect by excessive production of IFN-I and the activation of signal transducer and activator of transcription 3 (106). But this effect can be partly conversed by blocking the IFNAR in mice (107). Moreover, the population of HIV-specific Tfh cells expand during the chronic phase in patients who have a relatively high level of plasma HIV-RNA and IFN-I, which in turn leads to perturbation of B-cell differentiation, resulting in dysregulation antibody production (108). While in elite controllers, a stronger capacity to induce B cells maturation in Tfh cells is always tightly correlated to the low level of IFN-I (109, 110).

In addition, several studies indicate that the IFN-I also damage the normal function of B cells in the consistent presence of IFN-I. Indeed, IFN-I, especially IFN-α, is one of the most essential factor that contribute to the B-cell hyperactivation and exhaustion in HIV-1 viremic individuals (111–113). The loss of CD21 expression on exhausted B lymphocytes is a reliable marker of HIV-1 disease progression (114). It has been demonstrated that these cells that express low levels of CD21 is associated with the high expression of inhibitory markers as PD-1 and CTLA-4 (115, 116). Interestingly, IFNAR also express highly in these cells, which suggests that IFN-I plays a role on B cells dysfunction (117, 118). Another subpopulation of lymphocytes response to IFN-I is Treg, who work as a dominant role in immunosuppressive function to protect body from unwanted immune responses and maintain the homeostasis of immune system (119). However, the function of Treg is suppressed during the process of HIV-1 infection. When IFN persistently stimulated by IFNAR expressed on Treg, downstream signaling molecules will have impact on the expansion and suppressed function of Treg in turn (120). On the one hand, IFN-I inhibits Treg proliferation through a higher phosphorylation of STAT1 and a lower expression of suppressor of cytokine signaling 1 (121). Notably, this inhibition is tightly correlated with lower frequency of virus-specific CD8⁺ T response and viral clearance (122). On the other hand, chronic HIV-1 infection also leads to the downregulation of Foxp3. Foxp3 appears to act as a master regulator on the development and suppression function of Treg (123, 124). The possible mechanism is that IFN-I induces the secretion of IL-10 and decreases transforming growth factor-β. The overexpression of inhibitory inflammatory factors will competitively inhibit the suppressive function of Treg to rectify the disorder in immune system, which causes dysregulation in Foxp3 (125–127).

Overall, these observations confirm that the detrimental effect of IFN-I on immunocytes is evident during chronic HIV-1 infection. Despite the effective suppression of HIV viral load achieved by cART, it cannot completely reverse the immune hyperactivation and negative function induced by IFN-I. How to take advantage of IFN-I to restrict HIV-1 replication while restore the normal function of immunocytes is a key point we must balance.

As is mentioned earlier, although it is apparent for the importance of IFN-I on limiting HIV-1 in the acute phase of infection, dysfunctional IFN-I is more likely to disturb the balance of immune system and be detrimental to the function of pDCs, NK cells, CD4⁺ T cells and Treg in the chronic phase. Considering the complexity of IFN-I system, manipulating this system may have unpredictable consequences in vivo. Thus, it is reasonable to use or block this system in the treatment and prevention of HIV infection, but the virological and immunological effects must weigh against the possible adverse events. Nowadays, therapeutic strategies toward IFN-I system consists of two aspects: administration of IFN-I or inhibiting its signaling pathway. Next, we will summarize the related studies about IFN-I system in clinical trials or in HIV-1/SIV/LCMV models.

Innate immune system provides an immediate defense against pathogens to protect our body from infection by other organisms. As the most important effector molecule, IFN-I is powerful to suppress HIV and stimulate the expression of a bunch of antiviral genes replication at the early phase of infection. Although IFN response seems to be effective, HIV evades the IFN-mediated antiviral activities later since the stimulation of resistance factors. According to the results of clinical trials mentioned earlier, administration of IFN-I may have no benefit on clinical outcome, confirming that it fails to restrict and clear HIV in vivo. However, several aspects about this process still require further investigation: in addition to IFN-α and IFN-β, the role of the other subtypes of IFN-I in this process has not been clear; the separate pathways to recognize HIV nucleic acid (ssRNA, dsRNA, or cDNA) needs to be identified in all types of infected cells; and the exact mechanism of HIV escape also have to be clarified. Future studies should address these uncertain questions.

Even if IFN-I do function in the early HIV infection, continuously production promotes immune activation and ultimately exhaustion of immune system in the chronic phase. The detrimental effects of IFN-I on different lymphocyte have been intensely reported. But the regulatory mechanism in different lymphocytes has to be figured out.

Although the long-term clinical results of the administration of exogenous IFN-α seem to be invalid in the acute phase of HIV-1 infection with or without cART, it has been identified that this treatment could reduce the viral load transiently. Future studies should lay emphasis on whether supplementation of IFN-I to cART therapy during chronic infection could further decrease the HIV-1 reservoirs.

Moreover, in animal infectious model, IFN-I blockade strategy contributing to the recovery of T cells and decline in HIV reservoirs have been observed, suggesting that animals obtain benefits from this strategy. Although the results are encouraging, this approach has not been tried in human for its complicate effects. Further proof needs to be provided whether it is effective to decrease the morbidity of AIDS and reduce reservoirs through blocking IFN-I signaling, as this strategy may decrease immune activation whereas increase T cell responses. What is more, if it is possible, clinical trials about effective monoclonal antibody toward IFN-I blockade are expected to conduct in human.

In summary, despite long terms of research, the exact relationship between the production of IFN-I, the pathway of viral evasion, and the induction of pathogenic cellular immunological injury has not been clearly deciphered. Numerous questions remain to answer. A better understanding of the role of IFN-I in HIV pathogenesis will aid in managing this pathway for therapeutic purposes.

BW reviewed the mechanisms about the production of IFN-1 in the acute phase of HIV-1 infection; WK provided the data of the clinical trials by administration of IFN-1 in HIV patients; JZ gathered the information of negative effect of IFN-1 on different immunocytes in the chronic phase of HIV-1 infection. As corresponding authors, WK and YS carefully checked the whole manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.