HIV and Interferon Regulatory Factor 1: A Story of Manipulation and Control

Abstract

Members of the interferon regulatory factor (IRF) family control the expression of numerous proteins, many of which are central to regulating host immune responses. IRF1 is one of the central mediators of the innate and adaptive immune responses required for antigen processing and presentation, Th1/Th2 differentiation, and natural killer (NK) cell and macrophage function. Many viruses have evolved mechanisms to target the IRF1 pathway in order to promote viral pathogenesis. During early HIV infection, IRF1 acts as a double-edged sword, critical for driving viral replication as well as eliciting antiviral responses. In this review, we describe the strategies that HIV-1 has evolved to modulate IRF1 in order to enhance viral replication and to disarm the host immune system. IRF1 has been shown to be an important factor in natural protection against HIV in highly exposed seronegative (HESN) individuals and is crucial in regulating the initial stages of HIV replication and HIV disease progression, as well as the establishment of latency. An understanding of how the protective effects of IRF1 responses are controlled in HESN individuals, naturally resistant to HIV infection, may provide important clues on how to regain control of HIV and tip the balance of immunity in favor of the host, or provide new opportunities to eliminate HIV in its host altogether.

Introduction

A lthough the search for an HIV vaccine remains one of the highest public health priorities, the attempts to develop an effective vaccine against HIV-1, with one exception, have been largely unsuccessful.¹ While antiretroviral therapy is successful in controlling viral replication in HIV-infected people, viral eradication cannot be achieved due to the early establishment of latent viral reservoirs. Yet, the need for an HIV cure remains urgent with the increasing global burden of HIV, and costs and adverse effects associated with lifelong antiretroviral therapy. Many of the difficulties in developing a preventive and curative strategy lie with the properties of HIV and its complex relationship with the host.² As with all viruses HIV must utilize a number of cellular factors for successful viral replication.³ HIV's replication cycle is dependent on a direct and indirect interaction between numerous viral and host proteins⁴ and a full understanding of this complex interplay is likely to be the key in developing future treatment and prevention modalities. One key host cell factor crucial in HIV replication and early establishment of infection is interferon regulatory factor 1 (IRF1).

IRFs are a large family of transcriptional factors that play a crucial role in multiple biological processes including regulation of host immune responses, cell growth, and carcinogenesis. The genetic origin of IRFs coincides with the appearance of multicellularity in animals and it is thought to have coevolved in parallel with the Rel/NF-κB family, with which it shares an important role in regulating host immune responses.⁵ The evolution of these transcriptional factors was governed by an increased demand for more complex regulation of both embryogenesis and immunity in multicellular organisms. IRF genes are present in all five principal metazoan groups including simple organisms such as sea sponges, which are separated from vertebrates by more then 552 million years of independent evolution.⁶ Up to now 10 IRF members have been identified in vertebrates, with IRF10 not present in humans and mice.⁷ Depending on their mechanism of action, IRFs can be grouped into transcriptional-activators (IRF1, IRF3, IRF7, and IRF9) and transcriptional-repressors (IRF2 and IRF8). Depending on the target genes, some IRFs (IRF1, IRF2, IRF4, IRF5, and IRF8) can act as both activators and repressors.⁸ Structurally, all IRFs share a high degree of homology in the NH₂-terminal DNA binding domain. The DNA binding domain interacts with the interferon-stimulated response element (ISRE) and similar regulatory elements in interferon (IFN) and IFN-stimulated genes (ISGs) that are crucial in regulating host antiviral immune responses. The COOH-terminal domain acts as a regulatory domain and is involved in the interaction with other host and viral proteins and is responsible for the functional properties of different IRF members.

In addition to host IRF genes, some viruses, such as human herpes virus-8 (HHV8), encode for IRF homologs, named vIRFs, that inhibit the host interferon responses and, specifically, IRF1, thereby interfering with the antiviral defenses.⁹ Other viruses have developed different ways in exploiting IRF responses either by encoding their own vIRFs or through complex manipulation and control of host IRFs. Specific to HIV, IRF1, the first identified member of the IRF family,¹⁰ is an essential factor for successful HIV replication, especially in the earliest phases of infection before the expression of Tat. This article will discuss the complex interplay between HIV and IRF1, highlighting the potential of regulating IRF1 in prevention and treatment.

IRF1 and Its Role in Early HIV Replication

Like other viruses, HIV relies on host cellular machinery to synthesize and assemble new virions. HIV replication is controlled at the transcriptional level by the complex interaction between viral and host proteins acting on the viral promoter in the 5′ long terminal repeat (LTR) region. The HIV-1 5′ LTR can be subdivided into core promoter elements, enhancer, modulator, and negative regulatory elements, and the Tat-responsive element (TAR).¹¹ The LTR enhancer region contains two NF-κB binding sites (−109 to −79) that play a central role in initiation and Tat-mediated amplification of HIV transcription in blood CD4 T lymphocytes.¹² Region +200 to +217 downstream of the LTR was shown to have a sequence similarity to the ISRE present in the promoter of ISGs.¹³ This region is essential for efficient HIV-1 transcription and represents a binding site for members of the IRF family.^11,14

Deletion of this putative IRF1 binding site from the HIV LTR resulted in a virus with reduced replication kinetics, directly pointing to a role of IRF1 in HIV replication in monocyte-derived dendritic cells.¹⁵ The HIV-1 accessory protein Tat has been shown to act as a transcriptional activator of HIV-1 gene expression and is essential for HIV-1 replication. However, Tat expression after viral infection requires HIV-1 promoter activation, which is initially mediated by host transcriptional machinery. IRF1 was shown to increase HIV-1 LTR-directed gene expression in a dose-dependent fashion in Jurkat cells, in early phases of the infection when Tat is absent or present at low levels.¹⁶ In the presence of low doses of Tat, IRF1 was shown to amplify Tat-mediated HIV-1 transcription by direct physical interaction between Tat and the IRF1 COOH-terminal. Additionally, Sgarbanti et al. showed that IRF1 levels were up-regulated early in HIV-1 infection prior to the induction of Tat in both Jurkat T cells and primary CD4⁺ T cells, stimulated with anti-CD3 monoclonal antibody (mAb).^16,17

Similar early IRF1 up-regulation following HIV infection has also been described in both monocyte-derived dendritic cells (MDDCs)¹⁵ and monocyte-derived macrophages (MDMs).¹⁸ IRF1 was also shown to form a functional complex with NF-κB at the LTR κB sites, and this was shown to be required for full NF-κB transcriptional activity.¹⁹ Overall, these data clearly demonstrate that in early stages of HIV infection, when Tat is absent or present at low levels, the IRF1/NF-κB complex represents an essential factor in HIV transcription and thus HIV replication.

IRF1 as a Correlate of Protection in Highly HIV-Exposed Seronegative (HESN) Individuals

Exposure to HIV-1 in the absence of infection has been observed in multiple cohort studies around the world. These individuals are defined as HESN individuals and include different at-risk populations, including commercial sex workers (CSWs), men who have sex with men (MSM), infants born to HIV-positive mothers, injection drug users, hemophiliacs, and discordant couples.²⁰ Specific adaptive and innate factors have been correlated with reduced susceptibility to HIV-1 infection,^21,22 with innate immune responses acting as a front line defense against the establishment of productive infection and HIV-1 dissemination.

Polymorphisms in the IRF1 gene were identified as one of the strongest correlates of protection in the Pumwani sex worker cohort in Nairobi, Kenya. Three polymorphisms, including a single microsatellite allele (IRF1 179) and two SNP (619A>C and 6516G>T), were shown to be associated with resistance to HIV-1 infection and reduced likelihood of seroconversion.^23,24 Peripheral blood mononuclear cells (PBMCs) from patients with these “protective” IRF1 genotypes exhibited significantly lower basal IRF1 expression and reduced responsiveness to interferon (IFN)-γ stimulation.²⁴ In addition, unstimulated PBMCs from individuals with protective IRF1 genotypes show reduced ability to transactivate the HIV-1 LTR when infected with a single-cycle vesicular stomatitis virus (VSV)-G pseudotyped HIV-1 virus (HIV-1_VSV-G),²⁵ suggesting reduced ability to support HIV transcription.

The IRF1 polymorphisms associated with protection did not associate with altered HIV disease progression, as defined by CD4 decline and HIV viral load (VL), suggesting that the protective effect is limited to the initial stages of HIV-1 infection.^24,26 Once HIV-1 infection is established and disseminates systemically, as with many other antiviral factors, HIV-1 seems able to override protective mechanisms present at the time of exposure.

Newer data from the same cohort show that while both HESN- and HIV-susceptible individuals had a robust IRF1 response to exogenous IFN-γ stimulation, the response was transient and immediately controlled in HESN individuals,²⁷ while susceptible subjects had a more sustained IRF1 response. Together this indicates that resistant individuals are better able to regulate their IRF1 expression; regulating IRF1 protein expression to a transient, low state potentially allows the early induction of IRF1-mediated antiviral responses while at the same time limits IRF1 levels, reduces IRF1 binding to the HIV-1 LTR, and thus prevents sustained HIV-1 replication.

IRF1 and Its Role in Latency and HIV Disease Progression

The establishment of proviral latency within the genome of HIV target cells, despite being a rare event, occurs in the early stages of HIV infection. HIV latency represents a cellular reservoir of HIV-1 that is unaffected by current antiretroviral therapy regimens and as latent, is undetected by the host immune response. While the exact mechanism of proviral latency is not fully understood, it is thought to occur when a newly HIV-1-infected cell exits the cell cycle and returns to the resting state, most frequently occurring in resting memory CD4⁺ T cells.²⁸ Current estimates, based on long-term clinical studies, put the half-life of these stable infected resting cells at 44 months in patients on highly active antiretroviral therapy (HAART), meaning that complete viral eradication would take more then 60 years on antiretroviral therapy, which makes current treatment strategies highly impractical.^2,28
–30

Several mechanisms have been implicated in the establishment and maintenance of a low level of transcription in HIV-1 latency, including the absence of viral protein Tat and its associated cofactors.^3,28,31 Differential expression of Tat and host factors, such as NF-κB and IRF1, in activated versus resting cells may be involved in the establishment of productive versus latent infection and influence viral reactivation.⁸ This is supported by observations that latent proviruses can be reactivated by stimulating the host T cells with mitogens and anti-CD3-CD28 antibodies,^4,32,33 where both IRF1 and NF-κB are present at higher levels in activated T cells compared to resting cells.^10,34,35 Consistent with this, proinflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β, induced by HIV infection, lead to cell activation and are strong activators of IRF1 and NF-κB expression.^8,35,36 Thus, increasing intracellular levels of IRF1 and NF-κB would create an environment favorable for viral replication in the absence of Tat resulting in viral reactivation.

Other IRFs, IRF2 and IRF8 in particular, play an important role in governing the HIV-1 LTR/IRF1 interaction and may, in part, regulate HIV latency. IRF2 and IRF8 are known to inhibit IRF1; IRF2 directly competes with IRF1 for ISRE binding spots at the target promoter, while IRF8 forms a complex with IRF1 preventing the protein–protein interaction and hindering its transcriptional activity. IRF8, but not IRF2, was shown to repress the IRF1-Tat-mediated HIV-LTR transactivation by interfering with the IRF1-Tat protein complex formation.^11,16,37 Additionally, in human CD4⁺ lymphocytic and monocytic cell lines, IRF8 was shown to exhibit an inhibitory effect on HIV-1 replication.^12,14,16

Moreover, further evidence suggests that IRF8 plays a critical role in maintaining viral latency by transcriptional repression of the HIV-1 ISRE element.^13,37 Thus, the intricate interactions between HIV-1 and host IRF1, IRF2, and IRF8 may have an important role in regulating HIV-1 latency and reactivation. One could speculate that the ability to modulate proviral latency through manipulation of the IRF proteins could allow for reactivation of latent viral reservoirs and allow for successful viral clearance in HIV-1-infected patients.

IRF1 and HIV-Related Immune Responses

IRF1 represents a critical component of the host innate immune response against a diverse array of pathogens, including HIV-1. Expressed at low basal levels in all cells, including host immune cells, IRF1 regulates both innate and adaptive immune responses by binding to the ISRE present in the promoters of ISGs. Analysis of the IRF1 knock-out mice indicates that IRF is a key regulator of macrophage function, DC differentiation and maturation, NK responses, Th1/Th2 differentiation, and MHC class I and II expression.^36,38,39 Interestingly, all of these processes have been implicated in natural resistance to HIV-1 infection,^22,40 highlighting the potential role of IRF1-mediated anti-HIV immune responses in decreased susceptibility to infection.

It is generally believed that the epithelial microenvironment and innate immune responses represent the main barrier that the HIV-1 has to overcome in HESN individuals. IFNs, regulating the activities of IRFs, are secreted by infected cells to elicit the establishment of an antiviral state by stimulating the expression of IRFs and, hence, the majority of ISGs.⁴¹ Many of the ISGs have direct intrinsic antiviral effects or act to recruit and enhance the adaptive immune system. Several studies have demonstrated that IFNs inhibit HIV replication both in primary cells such as macrophages and PBMCs as well as monocyte and T cell lines,^42
–44 indicating that it is possible to elicit antiviral immune responses capable of hindering HIV replication.

These antiviral immune responses provide protection immediately after exposure and potentially contribute to the low probability of vaginal transmission, the failure of most infected foci to become established, and the restricted cellular tropism observed in HIV infection.^45,46 However, early innate antiviral responses can facilitate viral spreading by contributing to the generation of more HIV target cells via immune activation and recruitment of systemic T cells to the infection site. Additionally, IFN responses have been shown to be ineffective in suppressing HIV infection in vivo due to the ability of HIV to manipulate the host machinery avoiding the antiviral mechanism, resulting in nonspecific immune activation and disease progression.⁴⁷ Controlled, early robust, but transient antiviral IFN/ISG response, such as the IRF1 response observed in HESN individuals,²⁷ may be sufficient in controlling viral replication at the exposure site while at the same time preventing immune activation and systemic infection.

IRF1 and HIV Pathogenesis

The role of IRF1 in HIV pathogenesis is largely determined by its physical interaction with Tat. Tat, in addition to acting as an intracellular transcription factor, can be secreted by the infected cells and acts extracellularly.⁴⁸ Neighboring cells can take up Tat, allowing it to affect both infected and uninfected cells. Tat then is able to activate and/or suppress expression of numerous cellular genes, causing deregulation of the host immune response. Extracellular Tat was shown to increase IRF1 expression in Jurkat cells.⁴⁹ This initial Tat-mediated increase in IRF1 expression can be an important mechanism in preparing new cells for viral infection. However, once inside the cell Tat can directly interact with IRF1 and modulate antiviral responses allowing HIV replication and spread. Internalized Tat forms a complex with IRF1 impairing IRF1 transcriptional activity.^16,49 Binding of the Tat-IRF1 complex resulted in the repression of low-molecular-mass polypeptide 2 proteosome subunit expression, and consequently, changes in the processing and presentation of epitopes in the context of MHC class I.⁴⁹

Tat-mediated induction and manipulation of IRF1 expression also play a role in Tat-induced apoptosis of CD4 and CD8 T cells, which is a hallmark of HIV disease progression. Tat has been implicated as the inducer of apoptosis in both infected and uninfected T cells, potentially by Fas-dependent mechanisms.⁵⁰ It seems likely that these effects are mediated in part by IRF1, which is shown to be an essential regulator of apoptosis in several cell types driven by IRF1-mediated induction of caspase 1 and 7³⁶ and FasL.^8,51 The exact role of IRF1 in HIV-1-induced apoptosis remains to be defined. However, HIV-1-mediated control of IRF1 expression and the close relationship between Tat and IRF1 suggest that IRF1 could emerge as one of the key players in HIV-1-mediated T cell depletion and disease progression.

In monocyte-derived dendritic cells IRF1, IRF2, and IRF8 have been implicated in HIV pathogenesis. HIV-1_BAL infection of monocyte-derived DCs (mDCs) showed a time-dependent induction of specific IRFs¹⁵ where the early and persistent induction of IRF1 was coupled with up-regulation of its two inhibitors, IRF2 and IRF8. IRF8 was induced early in the infection process but then steadily decreased while IRF2 was up-regulated at a later time of the infection. By modifying IRF-1 response via a time-dependent increase in IRF1 inhibitors (IRF2 and IRF8), HIV induces a distinct subset of ISG genes without detectable induction of antiviral Type I and II IFN responses.¹⁵ Altogether this indicates that in addition to the role of IRF1 in driving HIV replication, the regulation of IRF1 and its negative regulators (IRF1 and IRF8) is an important strategy utilized by HIV to counteract IFN-mediated host defenses and drive disease progression.

Modulating IRF1 as a Component of Prevention and Treatment Strategies

HIV's dependence on IRF1 for initial replication, latency, and evasion of the host immune responses could ideally be exploited to the host's advantage in the development of both preventive and therapeutic strategies. Preliminary studies (Su et al., unpublished observations) show that ex-vivo CD4⁺ T cells where IRF-1 expression was reduced via siRNA by modest amounts (∼25–60%) exhibit a normal ability to up-regulate IRF1 target immune genes following IFN-γ or HIV-1 stimulation.

More importantly, however, activation of LTR-driven transcriptions were markedly reduced in these same CD4⁺ T cells, infected with HIV-1_VSV-G, HIV-1_IIIB, or HIV-1_BAL, indicating impaired HIV replication with the reduced IRF1 expression. Together, reducing endogenous IRF1 expression could significantly limit HIV replication without impacting the generation of the antiviral immune responses. Thus, targeting IRF1, as a part of prevention, or curative strategies may be a promising approach in limiting HIV replication during the early stages of infection, allowing the immune responses to take control of the infection. Additionally, IRF1, as an important modulator of the host immune response, represents a good candidate for use as a vaccine adjuvant. In vivo administration of plasmid DNA encoding IRF1 or IRF1 lacking the DNA binding domain was shown to enhance the efficacy of Tat-DNA vaccination with increasing polarized Th1 and CTL responses.⁵² Interestingly, the adjuvant effect of the mutated IRF1 (lacking the DNA binding domain) and the wild-type form showed similar efficacy. This suggests that the mutated IRF1, due to the lack of the DNA binding domain, would retain the ability to enhance protective immune response but not be able to stimulate HIV-1 LTR, thereby limiting HIV replication.

The potential to utilize our knowledge of IRF1 to cure HIV by eliminating latent HIV also remains a possibility. An ideal cure for targeting latent HIV infection would efficiently activate latent viral cellular reservoirs, induce local host innate immunity to supplement ART in tissues/cells where bioavailability of drugs is problematic, and drive “appropriate” antiviral immune responses, without triggering immune activation. Methods to induce IRF1 expression could potentially accomplish this due to the ability of IRF1 to drive HIV transcription and induce antiviral immune responses at the same time. Further studies are needed to provide a better understanding of the regulation of the IRF1 responses in order to optimize antiviral effects and minimize viral replication early in the infection process.

Conclusions

With 2.5 million new HIV infections and an estimated 34 million people living with HIV in 2011, the search for an effective vaccine and treatment remains a global priority. The success of HIV infection is in part due to its ability to hijack the host cellular machinery and the dual roles that innate immune responses play in restricting and facilitating viral replication. HIV-1-mediated induction, manipulation, and control of IRF1 is the perfect example of the ability of the pathogen to evolve mechanisms to evade and utilize host cellular factors to its advantage. IRF1 plays a crucial role in both the establishment of HIV infection and viral replication as well as the initiation of antiviral immune response. Virus control requires a balance between the activation of IRF1-mediated antiviral response and the limitation of viral replication. Data from the HESN cohorts suggest that regulation of IRF1 responses to a robust but transient state could potentially allow the early induction of strong IRF1-mediated antiviral responses while simultaneously limiting the temporal length of IRF1 responses, and thereby reduce IRF1 binding to the HIV-1 LTR, thus preventing sustained HIV-1 replication. Further study of the complex relationship between HIV-1 infection and IRF1 is required in order to exploit it for the development of novel vaccine and therapeutic strategies.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

McMichael

, Haynes

. Lessons learned from HIV-1 vaccine trials: New priorities and directions. Nat Immunol, 2012; 13:423–427.

Walker

, Burton

. Toward an AIDS vaccine. Science, 2008; 320:760–764.

Kirchhoff

. Immune evasion and counteraction of restriction factors by HIV-1 and other primate lentiviruses. Cell Host Microbe, 2010; 8:55–67.

Pinney

, Dickerson

, Fu

, Sanders-Beer

, Ptak

, Robertson

. HIV–host interactions: A map of viral perturbation of the host system. AIDS, 2009; 23:1.

Nehyba

, Hrdlicková

, Bose

. Dynamic evolution of immune system regulators: The history of the interferon regulatory factor family. Mol Biol Evol, 2009; 26:2539–2550.

Nehyba

, Hrdlicková

, Bose

Jr . Evolution of the Interferon Regulatory Factor Family. John Wiley & Sons, Ltd.: Chichester, UK, 2001.

Huang

, Qi

, Xu

, Nie

. Global characterization of interferon regulatory factor (IRF) genes in vertebrates: Glimpse of the diversification in evolution. BMC Immunol, 2010; 11:22.

Marsili

, Borsetti

, Sgarbanti

. On the role of interferon regulatory factors in HIV-1 replication. Ann NY Acad Sci, 2003; 1010:29–42.

Mamane

, Heylbroeck

, Génin

, Algarté

, Servant

, LePage

et al. Interferon regulatory factors: The next generation. Gene, 1999; 237:1–14.

10.

Fujita

, Sakakibara

, Sudo

et al. Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-beta gene regulatory elements. EMBO J, 1988; 7:3397.

11.

Liang

, Li

, Quan

, Laughrea

, Kleiman

, Hiscott

et al. Sequence elements downstream of the human immunodeficiency virus type 1 long terminal repeat are required for efficient viral gene transcription. J Mol Biol, 1997; 272:167–177.

12.

Alcamí

, Lain de Lera

, Folgueira

et al. Absolute dependence on kappa B responsive elements for initiation and Tat-mediated amplification of HIV transcription in blood CD4 T lymphocytes. EMBO J, 1995; 14:1552.

13.

Harada

, Fujita

, Miyamoto

, Kimura

, Maruyama

, Furia

et al. Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell, 1989; 58:729–739.

14.

Thornton

, Buller

, DeVico

, Wang

, Ozato

. Inhibition of human immunodeficiency virus type 1 and vaccinia virus infection by a dominant negative factor of the interferon regulatory factor family expressed in monocytic cells. Proc Natl Acad Sci USA, 1996; 93:383–387.

15.

Harman

, Lai

, Turville

, Samarajiwa

, Gray

, Marsden

et al. HIV infection of dendritic cells subverts the interferon induction pathway via IRF1 and inhibits type 1 interferon production. Blood, 2011; 118:298–308.

16.

Sgarbanti

, Borsetti

, Moscufo

, Bellocchi

, Ridolfi

, Nappi

et al. Modulation of human immunodeficiency virus 1 replication by interferon regulatory factors. J Exp Med, 2002; 195:1359–1370.

17.

Sgarbanti

, Marsili

, Remoli

, Ridolfi

, Stellacci

, Borsetti

et al. Analysis of the signal transduction pathway leading to human immunodeficiency virus-1-induced interferon regulatory factor-1 upregulation. Ann NY Acad Sci, 2004; 1030:187–195.

18.

Nasr

, Maddocks

, Turville

, Harman

, Woolger

, Helbig

et al. HIV-1 infection of human macrophages directly induces viperin which inhibits viral production. Blood, 2012; 120:778–788.

19.

Sgarbanti

, Remoli

, Marsili

, Ridolfi

, Borsetti

, Perrotti

et al. IRF-1 is required for full NF-kappaB transcriptional activity at the human immunodeficiency virus type 1 long terminal repeat enhancer. J Virol, 2008; 82:3632–3641.

20.

Horton

, McLaren

, Fowke

, Kimani

, Ball

. Cohorts for the study of HIV‐1–exposed but uninfected individuals: Benefits and limitations. J Infect Dis, 2010; 202:S377–S381.

21.

Lederman

, Alter

, Daskalakis

, Rodríguez

, Sieg

, Hardy

et al. Determinants of protection among HIV-exposed seronegative persons: An overview. J Infect Dis, 2010; 202:S333–338.

22.

Tomescu

, Abdulhaqq

, Montaner

. Evidence for the innate immune response as a correlate of protection in human immunodeficiency virus (HIV)-1 highly exposed seronegative subjects (HESN) Clin Exp Immunol, 2011; 164:158–169.

23.

, Ball

, Kimani

, Plummer

. Novel interferon regulatory factor-1 polymorphisms in a Kenyan population revealed by complete gene sequencing. J Hum Genet, 2004; 49:528–535.

24.

Ball

, Ji

, Kimani

, McLaren

, Marlin

, Hill

et al. Polymorphisms in IRF-1 associated with resistance to HIV-1 infection in highly exposed uninfected Kenyan sex workers. AIDS, 2007; 21:1091.

25.

, Ball

, Ao

, Kimani

, Yao

, Plummer

. Reduced HIV-1 long terminal repeat transcription in subjects with protective interferon regulatory factor-1 genotype: A potential mechanism mediating resistance to infection by HIV-1. Scand J Infect Dis, 2010; 42:389–394.

26.

Sivro

, McKinnon

, Ji

, Kimani

, Jaoko

, Plummer

et al. Interferon regulatory factor 1 polymorphisms previously associated with reduced HIV susceptibility have no effect on HIV disease progression. PLoS One, 2013; 8:e66253.

27.

R-C

, Sivro

, Kimani

, Jaoko

, Plummer

, Ball

. Epigenetic control of IRF1 responses in HIV-exposed seronegative versus HIV-susceptible individuals. Blood, 2011; 117:2649–2657.

28.

Margolis

. Mechanisms of HIV latency: An emerging picture of complexity. Curr HIV/AIDS Rep, 2010; 7:37–43.

29.

Joos

, Fischer

, Kuster

, Pillai

, Wong

, Böni

et al. HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proc Natl Acad Sci USA, 2008; 105:16725–16730.

30.

Siliciano

, Kajdas

, Finzi

, Quinn

, Chadwick

, Margolick

et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med, 2003; 9:727–728.

31.

Williams

SAF

, Greene

. Host factors regulating post-integration latency of HIV. Trends Microbiol, 2005; 13:137–139.

32.

Finzi

, Hermankova

, Pierson

, Carruth

, Buck

, Chaisson

et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science, 1997; 278:1295–1300.

33.

Wong

. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science, 1997; 278:1291–1295.

34.

Nelson

, Kanno

, Hong

, Contursi

, Fujita

, Fowlkes

et al. Expression of IFN regulatory factor family proteins in lymphocytes. Induction of Stat-1 and IFN consensus sequence binding protein expression by T cell activation. J Immunol, 1996; 156:3711–3720.

35.

Oeckinghaus

, Ghosh

. The NF- B family of transcription factors and its regulation. Cold Spring Harb Perspect Biol, 2009; 1:a000034.

36.

Taniguchi

, Ogasawara

, Takaoka

, Tanaka

. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol, 2001; 19:623–655.

37.

Munier

, Delcroix-Genête

, Carthagéna

, Gumez

, Hazan

. Characterization of two candidate genes, NCoA3 and IRF8, potentially involved in the control of HIV-1 latency. Retrovirology, 2005; 2:73.

38.

Kröger

, Köster

, Schroeder

, Hauser

, Mueller

. Review: Activities of IRF-1. J Interferon Cytokine Res, 2002; 22:5–14.

39.

Gabriele

, Fragale

, Borghi

, Sestili

, Stellacci

, Venditti

et al. IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features. J Leukoc Biol, 2006; 80:1500–1511.

40.

Piacentini

, Fenizia

, Naddeo

, Clerici

. Not just sheer luck! Immune correlates of protection against HIV-1 infection. Vaccine, 2008; 26:3002–3007.

41.

Samarajiwa

, Forster

, Auchettl

, Hertzog

. INTERFEROME: The database of interferon regulated genes. Nucleic Acids Res, 2009; 37:D852–857.

42.

Hou

, Wang

, Ye

, Zhou

, Yang

Z-Q

, Riedel

et al. Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol, 2009; 83:3834–3842.

43.

Shirazi

, Pitha

. Interferon alpha-mediated inhibition of human immunodeficiency virus type 1 provirus synthesis in T-cells. Virology, 1993; 193:303–312.

44.

Michaelis

, Levy

. HIV replication can be blocked by recombinant human interferon beta. AIDS, 1989; 3:27–31.

45.

Haase

. Targeting early infection to prevent HIV-1 mucosal transmission. Nature, 2010; 464:217–223.

46.

McMichael

, Borrow

, Tomaras

, Goonetilleke

, Haynes

. The immune response during acute HIV-1 infection: Clues for vaccine development. Nat Rev Immunol, 2009; 10:11–23.

47.

Boasso

, Shearer

. Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin Immunol, 2008; 126:235–242.

48.

Huigen

, Kamp

, Nottet

. Multiple effects of HIV-1 trans-activator protein on the pathogenesis of HIV-1 infection. Eur J Clin Invest, 2004; 34:57–66.

49.

Remoli

, Marsili

, Perrotti

, Gallerani

, Ilari

, Nappi

et al. Intracellular HIV-1 Tat protein represses constitutive LMP2 transcription increasing proteasome activity by interfering with the binding of IRF-1 to STAT1. Biochem J, 2006; 396:371–380.

50.

Badley

, Pilon

, Landay

, Lynch

. Mechanisms of HIV-associated lymphocyte apoptosis. Blood, 2000; 96:2951–2964.

51.

Chow

, Fang

, Yee

J-K

. The IFN regulatory factor family participates in regulation of Fas ligand gene expression in T cells. J Immunol, 2000; 164:3512–3518.

52.

Castaldello

, Sgarbanti

, Marsili

. Interferon regulatory factor-1 acts as a powerful adjuvant in tat DNA based vaccination. J Cell Physiol, 2010; 224:702–709.