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1.  Sex-Based Differences in HIV Type 1 Pathogenesis 
The Journal of Infectious Diseases  2014;209(Suppl 3):S86-S92.
Human immunodeficiency virus (HIV) remains a global infectious diseases threat that disproportionally affects women. Beyond social and political factors, biological and genetic differences have been identified that lead to differential disease courses and outcomes in men and women. Following HIV type 1 (HIV-1) seroconversion, women have up to 40% lower HIV loads and higher CD4+ T-cell counts than men. However, at the same level of viremia, progression to AIDS is faster in women. After adjustment for viral load, HIV-positive women also display increased levels of generalized immune activation and experience the consequences of elevated inflammatory activity more frequently than men. Part of these observations are linked to sex-based differences in innate immunity, in which the differential ability of plasmacytoid dendritic cells to produce interferon α following stimulation of Toll-like receptor 7 and upregulation of interferon-stimulated genes play a central role. Here, we review the current knowledge and remaining gaps therein regarding sex-based differences in HIV-1 pathogenesis.
doi:10.1093/infdis/jiu175
PMCID: PMC4157516  PMID: 24966195
HIV-1; sex; Immune activation; interferon-alpha; ISG
2.  Sequence variations in HIV-1 p24 Gag-derived epitopes can alter binding of KIR2DL2 to HLA- C*03:04 and modulate primary NK cell function 
AIDS (London, England)  2014;28(10):1399-1408.
OBJECTIVE
The aim of this study was to assess the consequence of sequence variations in HLA-C*03:04-presented HIV-1 p24 Gag epitopes on binding of the inhibitory NK cell receptor KIR2DL2 to HLA-C*03:04.
DESIGN
HIV-1 may possibly evade recognition by KIR+ NK cells through selection of sequence variants that interfere with the interactions of inhibitory KIRs and their target ligands on HIV-1-infected cells. KIR2DL2 is an inhibitory NK cell receptor that binds to a family of HLA-C ligands. Here, we investigated whether HIV-1 encodes for HLA-C*03:04-restricted epitopes that alter KIR2DL2 binding.
METHODS
Tapasin-deficient 721.220 cells expressing HLA-C*03:04 were pulsed with overlapping peptides (10mers overlapping by 9 amino acids, spanning the entire HIV-1 p24 Gag sequence) to identify peptides that stabilized HLA-C expression. Then, the impact that sequence variation in HLA-C*03:04-binding HIV-1 epitopes has on KIR2DL2 binding and KIR2DL2+ NK cell function was determined using KIR2DL2-Fc constructs and NK cell degranulation assays.
RESULTS
Several novel HLA-C*03:04 binding epitopes were identified within the HIV-1 p24 Gag consensus sequence. Three of these consensus sequence peptides (Gag144-152, Gag163-171, and Gag295-304) enabled binding of KIR2DL2 to HLA-C*03:04 and resulted in inhibition of KIR2DL2+ primary NK cells. Furthermore, naturally occurring minor variants of epitope Gag295-304 enhanced KIR2DL2 binding to HLA-C*03:04.
CONCLUSIONS
Our data show that naturally occurring sequence variations within HLA-C*03:04-restricted HIV-1 p24 Gag epitopes can have a significant impact on the binding of inhibitory KIR receptors and primary NK cell function.
doi:10.1097/QAD.0000000000000284
PMCID: PMC4453925  PMID: 24785948
Innate Immunity; HIV-1 epitopes; Natural Killer cell; Killer cell immunoglobulin-like receptor
3.  Emergence of Individual HIV-Specific CD8 T Cell Responses during Primary HIV-1 Infection Can Determine Long-Term Disease Outcome 
Journal of Virology  2014;88(21):12793-12801.
ABSTRACT
Events during primary HIV-1 infection have been shown to be critical for the subsequent rate of disease progression. Early control of viral replication, resolution of clinical symptoms and development of a viral set point have been associated with the emergence of HIV-specific CD8 T cell responses. Here we assessed which particular HIV-specific CD8 T cell responses contribute to long-term control of HIV-1. A total of 620 individuals with primary HIV-1 infection were screened by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay for HLA class I-restricted, epitope-specific CD8 T cell responses using optimally defined epitopes approximately 2 months after initial presentation. The cohort was predominantly male (97%) and Caucasian (83%) (Fiebig stages II/III [n = 157], IV [n = 64], V [n = 286], and VI [n = 88] and Fiebig stage not determined [n = 25]). Longitudinal viral loads, CD4 count, and time to ART were collected for all patients. We observed strong associations between viral load at baseline (initial viremia) and the established early viral set points (P < 0.0001). Both were significantly associated with HLA class I genotypes (P = 0.0009). While neither the breadth nor the magnitude of HIV-specific CD8 T cell responses showed an influence on the early viral set point, a broader HIV-specific CD8 T cell response targeting epitopes within HIV-1 Gag during primary HIV-1 infection was associated with slower disease progression. Moreover, the induction of certain HIV-specific CD8 T cell responses—but not others—significantly influenced the time to ART initiation. Individual epitope-specific CD8 T cell responses contribute significantly to HIV-1 disease control, demonstrating that the specificity of the initial HIV-specific CD8 T cell response rather than the restricting HLA class I molecule alone is a critical determinant of antiviral function.
IMPORTANCE Understanding which factors are involved in the control of HIV-1 infection is critical for the design of therapeutic strategies for patients living with HIV/AIDS. Here, using a cohort of over 600 individuals with acute and early HIV-1 infection, we assessed in unprecedented detail the individual contribution of epitope-specific CD8 T cell responses directed against HIV-1 to control of viremia and their impact on the overall course of disease progression.
doi:10.1128/JVI.02016-14
PMCID: PMC4248916  PMID: 25165102
4.  Early Preservation of CXCR5+ PD-1+ Helper T Cells and B Cell Activation Predict the Breadth of Neutralizing Antibody Responses in Chronic HIV-1 Infection 
Journal of Virology  2014;88(22):13310-13321.
ABSTRACT
Much is known about the characteristics of broadly neutralizing antibodies (bNAbs) generated during HIV-1 infection, but little is known about immunological mechanisms responsible for their development in only a minority of those infected by HIV-1. By monitoring longitudinally a cohort of HIV-1-infected subjects, we observed that the preservation of CXCR5+ CD4+ T helper cell frequencies and activation status of B cells during the first year of infection correlates with the maximum breadth of plasma neutralizing antibody responses during chronic infection independently of viral load. Although, during the first year of infection, no differences were observed in the abilities of peripheral CXCR5+ CD4+ T helper cells to induce antibody secretion by autologous naive B cells, higher frequencies of class-switched antibodies were detected in cocultures of CXCR5+ CD4+ T and B cells from the subjects who later developed broadly neutralizing antibody responses than those who did not. Furthermore, B cells from the former subjects had higher expression of AICDA than B cells from the latter subjects, and transcript levels correlated with the frequency of CXCR5+ CD4+ T cells. Thus, the early preservation of CXCR5+ CD4+ T cells and B cell function are central to the development of bNAbs. Our study provides a possible explanation for their infrequent generation during HIV-1 infection.
IMPORTANCE Broadly neutralizing antibodies are developed by HIV-1-infected subjects, but so far (and despite intensive efforts over the past 3 decades) they have not been elicited by immunization. Understanding how bNAbs are generated during natural HIV-1 infection and why only some HIV-1-infected subjects generate such antibodies will assist our efforts to elicit bNAbs by immunization. CXCR5+ PD-1+ CD4+ T cells are critical for the development of high-affinity antigen-specific antibody responses. In our study, we found that the HIV-1-infected subjects who develop bNAbs have a higher frequency of peripheral CXCR5+ PD-1+ CD4+ T cells in early infection and also that this frequency mirrored what was observed in uninfected subjects and correlated with the level of B cell activation across subjects. Our study highlights the critical role helper T cell function has in the elicitation of broadly neutralizing antibody responses in the context of HIV infection.
doi:10.1128/JVI.02186-14
PMCID: PMC4249103  PMID: 25210168
5.  CD4+ T-Cell Help Enhances NK Cell Function following Therapeutic HIV-1 Vaccination 
Journal of Virology  2014;88(15):8349-8354.
ABSTRACT
Increasing data suggest that NK cells can mediate antiviral activity in HIV-1-infected humans, and as such, novel approaches harnessing the anti-HIV-1 function of both T cells and NK cells represent attractive options to improve future HIV-1 immunotherapies. Chronic progressive HIV-1 infection has been associated with a loss of CD4+ T helper cell function and with the accumulation of anergic NK cells. As several studies have suggested that cytokines produced by CD4+ T cells are required to enhance NK cell function in various infection models, we hypothesized that reconstitution of HIV-1-specific CD4+ T-cell responses by therapeutic immunization would restore NK cell activity in infected individuals. Using flow cytometry, we examined the function of CD4+ T cells and NK cells in response to HIV-1 in subjects with treated chronic HIV-1 infection before and after immunization with an adjuvanted HIV-1 Gp120/NefTat subunit protein vaccine candidate provided by GlaxoSmithKline. Vaccination induced an increased expression of interleukin-2 (IL-2) by Gp120-specific CD4+ T cells in response to HIV-1 peptides ex vivo, which was associated with enhanced production of gamma interferon (IFN-γ) by NK cells. Our data show that reconstitution of HIV-1-specific CD4+ T-cell function by therapeutic immunization can enhance NK cell activity in HIV-1-infected individuals.
IMPORTANCE NK cells are effector cells of the innate immune system and are important in the control of viral infection. Recent studies have demonstrated the crucial role played by NK cells in controlling and/or limiting acquisition of HIV-1 infection. However, NK cell function is impaired during progressive HIV-1 infection. We recently showed that therapeutic immunization of treated HIV-1-infected individuals reconstituted strong T-cell responses, measured notably by their production of IL-2, a cytokine that can activate NK cells. The current study suggests that reconstitution of T-cell function by therapeutic vaccination can enhance NK cell activity in individuals with chronic HIV-1 infection. Our findings provide new insights into the interplay between adaptive and innate immune mechanisms involved in HIV-1 immunity and unveil opportunities to harness NK cell function in future therapeutic vaccine strategies to target HIV-1.
doi:10.1128/JVI.00924-14
PMCID: PMC4135926  PMID: 24829350
6.  HIV-1 infection induces strong production of IP-10 through TLR7/9-dependent pathways 
AIDS (London, England)  2013;27(16):2505-2517.
Objective
To study the cytokine/chemokine profiles in response to HIV-1 viremia, and elucidate the pathways leading to HIV-1-induced inflammation.
Design/Methods
Plasma levels of 19 cytokines in individuals with early HIV-1 infection and individuals undergoing treatment interruptions were evaluated via multiplex assay. To investigate the cellular sources of relevant cytokines, sorted cells from HIV-1 infected individuals were assessed for mRNA expression. Relevant signaling pathways were assessed by comparing cytokine production patterns of PBMCs stimulated with intact HIV-1 or specific TLR stimulants with and without a TLR7/9 antagonist.
Results
IP-10 plasma concentration was most significantly associated with HIV-1 viral load and was the most significant contributor in a multivariate model. IP-10 mRNA was highly expressed in monocytes and mDCs and these cells were the dominant producers after in vitro stimulation with TLR7/8 ligands (CL097 and ssRNAGag1166), AT-2 HIV-1, and HIV-1NL43 virus. Partial least square discriminant analysis of culture supernatants revealed distinct cytokine/chemokine secretion profiles associated with intact viruses compared to TLR7/8 ligands alone, with IP-10 production linked to the former. A TLR7/9 antagonist blocked IP-10 production following whole virus stimulation, suggesting the involvement of TLR7/9 in the recognition of HIV-1 by these cells.
Conclusions
Monocytes and mDCs produce significant amounts of IP-10 in response to HIV-1 viremia and after in vitro stimulation with HIV-1. Stimulation with HIV-1-derived TLR7/8-ligands versus HIV-1 resulted in distinct cytokine/chemokine profiles, indicating additional pathways other than TLR7/8 that lead to the activation of innate immune cells by HIV-1.
doi:10.1097/01.aids.0000432455.06476.bc
PMCID: PMC4288813  PMID: 24096630
IP-10; immune activation; TLR; monocytes; mDCs
7.  Immune Activation and the Role of TLRs and TLR Agonists in the Pathogenesis of HIV-1 Infection in the Humanized Mouse Model 
The Journal of Infectious Diseases  2013;208(Suppl 2):S145-S149.
Immune activation plays a critical role in HIV-1 pathogenesis, but the pathways that are responsible for HIV-1-associated immune activation are not well understood. Recent advances in the development of a humanized mouse model for HIV-1 infection might provide new approaches to study the mechanisms of HIV-1 associated immune activation, and to test interventions aimed at reducing HIV-1 pathogenesis.
doi:10.1093/infdis/jit402
PMCID: PMC3807976  PMID: 24151321
TLR; innate immunity; HIV-1; humanized mouse; pathogenesis
8.  TRIM5α and TRIM22 Are Differentially Regulated According to HIV-1 Infection Phase and Compartment 
Journal of Virology  2014;88(8):4291-4303.
ABSTRACT
The antiviral role of TRIM E3 ligases in vivo is not fully understood. To test the hypothesis that TRIM5α and TRIM22 have differential transcriptional regulation and distinct anti-HIV roles according to infection phase and compartment, we measured TRIM5α, TRIM22, and type I interferon (IFN-I)-inducible myxovirus resistance protein A (MxA) levels in peripheral blood mononuclear cells (PBMCs) during primary and chronic HIV-1 infection, with chronic infection samples being matched PBMCs and central nervous system (CNS)-derived cells. Associations with biomarkers of disease progression were explored. The impact of IFN-I, select proinflammatory cytokines, and HIV on TRIM E3 ligase-specific expression was investigated. PBMCs from individuals with primary and chronic HIV-1 infection had significantly higher levels of MxA and TRIM22 than did PBMCs from HIV-1-negative individuals (P < 0.05 for all comparisons). PBMCs from chronic infection had lower levels of TRIM5α than did PBMCs from primary infection or HIV-1-uninfected PBMCs (P = 0.0001 for both). In matched CNS-derived samples and PBMCs, higher levels of MxA (P = 0.001) and TRIM5α (P = 0.0001) in the CNS were noted. There was a negative correlation between TRIM22 levels in PBMCs and plasma viral load (r = −0.40; P = 0.04). In vitro, IFN-I and, rarely, proinflammatory cytokines induced TRIM5α and TRIM22 in a cell type-dependent manner, and the knockdown of either protein in CD4+ lymphocytes resulted in increased HIV-1 infection. These data suggest that there are infection-phase-specific and anatomically compartmentalized differences in TRIM5α and TRIM22 regulation involving primarily IFN-I and specific cell types and indicate subtle differences in the antiviral roles and transcriptional regulation of TRIM E3 ligases in vivo.
IMPORTANCE Type I interferon-inducible TRIM E3 ligases are a family of intracellular proteins with potent antiviral activities mediated through diverse mechanisms. However, little is known about the contribution of these proteins to antiviral immunity in vivo and how their expression is regulated. We show here that TRIM5α and TRIM22, two prominent members of the family, have different expression patterns in vivo and that the expression pattern depends on HIV-1 infection status and phase. Furthermore, expression differs in peripheral blood versus central nervous system anatomical sites of infection. Only TRIM22 expression correlated negatively with HIV-1 viral load, but gene silencing of both proteins enhances HIV-1 infection of target cells. We report subtle differences in TRIM5α and TRIM22 gene induction by IFN-I and proinflammatory cytokines in CD4+ lymphocytes, monocytes, and neuronal cells. This study enhances our understanding of antiviral immunity by intrinsic antiviral factors and how their expression is determined.
doi:10.1128/JVI.03603-13
PMCID: PMC3993776  PMID: 24478420
9.  Higher Expression of Several Interferon-Stimulated Genes in HIV-1-Infected Females After Adjusting for the Level of Viral Replication 
The Journal of Infectious Diseases  2013;208(5):830-838.
Background. Clinical studies have shown faster disease progression and stronger immune activation in human immunodeficiency virus (HIV)-1–infected females when compared with males for the same level of HIV-1 replication. Here we determine whether the elevated levels of HIV-1–induced interferon-alpha (IFN-α) production observed in females are associated with higher interferon-stimulated gene (ISG) expression levels in T cells, hence suggesting type-I IFN as a mechanism for the higher HIV-1–associated immune activation observed.
Methods. T-cell and dendritic cell populations were isolated from treatment-naive chronically HIV-1–infected individuals enrolled in the Adult Clinical Trials Group 384 by fluorescence-activated cell sorting. The expression of 98 genes involved in Toll-like receptor and type I IFN signaling pathways were quantified using Nanostring technology.
Results. Several ISGs were significantly correlated with HIV-1 viral load and/or CD4+ T-cell count. Higher expression levels of a subset of these ISGs were observed in cells derived from females as compared to males after adjusting for viral load and were correlated to higher levels of T-cell activation.
Conclusion. These data show that higher IFN-α production is associated with higher ex vivo expression of several ISGs in females. This might contribute to higher levels of immune activation and the observed faster HIV-1 disease progression in females for a given level of viral replication.
doi:10.1093/infdis/jit262
PMCID: PMC3733517  PMID: 23757341
HIV-1; innate immunity; type I Interferon; Toll-like receptors; T cells; sex differences; immune activation; dendritic cells; pathogenesis
10.  Neither microbial translocation nor TLR responsiveness are likely explanations for pre-existing immune activation in women who subsequently acquired HIV in CAPRISA004 
Journal of acquired immune deficiency syndromes (1999)  2013;63(3):10.1097/QAI.0b013e31828e604b.
Innate immune activation was a strong predictor of HIV acquisition in women at risk for HIV in CAPRISA004. Identifying the cause/s of activation could enable targeted prevention interventions. In this study, plasma concentrations of lipopolysaccharide, soluble CD14 and intestinal fatty-acid binding protein did not differ between subjects who did or did not subsequently acquire HIV, nor were these levels correlated with plasma cytokines or natural killer cell activation. There was no difference between HIV-acquirers and non-acquirers in the chemokine and cytokine responses of peripheral blood mononuclear cells stimulated with TLR2, 4 or 7/8 agonists. Further studies are required.
doi:10.1097/QAI.0b013e31828e604b
PMCID: PMC3683111  PMID: 23481666
HIV; microbial translocation; LPS; sCD14; I-FABP; TLR2; TLR4; TLR7/8; immune activation
11.  Natural Killer Cells: Tolerance to Self and Innate Immunity to Viral Infection and Malignancy 
Natural killer (NK) cells are lymphocytes whose ability to identify and kill virally infected and malignant cells while sparing normal cells was poorly understood until the late 1980’s and the introduction of the “missing self’ hypothesis. According to this hypothesis, downregulation of major histocompatibility complex (MHC) class I molecules during viral infection or malignant transformation triggers NK activation (1). Since this hypothesis was first proposed, much has been learned about NK cell surface receptors, their role in the molecular basis of missing-self recognition, and the mechanisms underlying NK cell tolerance. In this review, we will discuss these mechanisms, as well as their relevance to viral infection and tumor immunity and stem cell transplantation.
doi:10.1016/j.bbmt.2009.10.009
PMCID: PMC3900292  PMID: 19835969
12.  Temporal effect of HLA-B*57 on viral control during primary HIV-1 infection 
Retrovirology  2013;10:139.
Background
HLA-B alleles are associated with viral control in chronic HIV-1 infection, however, their role in primary HIV-1 disease is unclear. This study sought to determine the role of HLA-B alleles in viral control during the acute phase of HIV-1 infection and establishment of the early viral load set point (VLSP).
Findings
Individuals identified during primary HIV-1 infection were HLA class I typed and followed longitudinally. Associations between HLA-B alleles and HIV-1 viral replication during acute infection and VLSP were analyzed in untreated subjects. The results showed that neither HLA-B*57 nor HLA-B*27 were significantly associated with viral control during acute HIV-1 infection (Fiebig stage I-IV, n=171). HLA-B*57 was however significantly associated with a subsequent lower VLSP (p<0.001, n=135) with nearly 1 log10 less median viral load. Analysis of a known polymorphism at position 97 of HLA-B showed significant associations with both lower initial viral load (p<0.01) and lower VLSP (p<0.05). However, this association was dependent on different amino acids at this position for each endpoint.
Conclusions
The effect of HLA-B*57 on viral control is more pronounced during the later stages of primary HIV-1 infection, which suggests the underlying mechanism of control occurs at a critical period in the first several months after HIV-1 acquisition. The risk profile of polymorphisms at position 97 of HLA-B are more broadly associated with HIV-1 viral load during primary infection and may serve as a focal point in further studies of HLA-B function.
doi:10.1186/1742-4690-10-139
PMCID: PMC3874665  PMID: 24245727
HLA-B*57; HLA-B; Acute HIV-1 infection; Primary HIV-1 infection; Viral load set point; MHC class I
13.  Identification of HIV-1-specific regulatory T-cells using HLA class II tetramers 
AIDS (London, England)  2012;26(16):10.1097/QAD.0b013e328358cc75.
Regulatory T cells (Tregs) are potent immune modulators, but their precise role in HIV pathogenesis remains incompletely understood. Most studies to date have focused on frequencies or phenotypes of “bulk” Treg populations. However, although antigen-specific Tregs have been reported in other diseases, HIV-1-epitope specific Tregs have not been described to date. We here report the first identification of functional HIV-1-Gag-specific regulatory T cells using human leukocyte antigen class II tetramer staining in HIV-1-infected individuals.
doi:10.1097/QAD.0b013e328358cc75
PMCID: PMC3825094  PMID: 22874519
14.  Innate Immune Activation Enhances HIV Acquisition in Women, Diminishing the Effectiveness of Tenofovir Microbicide Gel 
The Journal of Infectious Diseases  2012;206(7):993-1001.
The antiretroviral agent, tenofovir, formulated as a vaginal microbicide gel, reduces human immunodeficiency virus (HIV) acquisition by 39% in women. This study assessed the role of preexisting immune activation in HIV acquisition in women from the CAPRISA 004 trial, to identify potential strategies to increase the effectiveness of tenofovir gel. Systemic cytokine and cellular immune mediators (platelets and natural killer [NK] cells) were assessed in women at high risk for HIV assigned to either tenofovir or placebo gel in the CAPRISA 004 trial. Notwithstanding tenofovir gel use, women who acquired HIV had significantly higher systemic innate immune activation prior to infection than women who remained uninfected. Activation of both soluble (cytokine) and cellular (NK cells) immune mediators were associated with HIV acquisition, individually or in combination. Hence, an innate immune activation suppressant could be added to tenofovir gel as a potential combination gel strategy in developing the next generation of higher efficacy antiretroviral microbicides.
doi:10.1093/infdis/jis465
PMCID: PMC3501691  PMID: 22829639
15.  Harnessing Innate and Adaptive Immunity for Viral Vaccine Design 
Expert review of vaccines  2012;11(7):775-777.
doi:10.1586/erv.12.48
PMCID: PMC3760238  PMID: 22913253
16.  Evasion from NK cell-mediated immune responses by HIV-1 
Human immunodeficiency virus type 1 (HIV-1) mostly owes its success to its ability to evade host immune responses. Understanding viral immune escape mechanisms is prerequisite to improve future HIV-1 vaccine design. This review focuses on the strategies that HIV-1 has evolved to evade recognition by natural killer (NK) cells.
doi:10.1016/j.micinf.2012.05.001
PMCID: PMC3432664  PMID: 22626930
HIV-1; NK cells; escape; innate immunity; vaccine
17.  Differential regulation of TLR pathways in acute and chronic HIV-1 infection 
AIDS (London, England)  2012;26(5):533-541.
Objective and design
The objective of this study was to determine changes in TLR responses of monocytes, myeloid dendritic cells and plasmacytoid dendritic cells during primary and chronic HIV-1 infection. Toll-like receptors (TLRs) serve as important innate receptors to sense pathogens, and have been implicated in mediating immune activation in HIV-1 infection. Studies assessing the consequences of HIV-1 infection on the ability of innate immune cells to respond to TLR stimulation have come to varying conclusions.
Methods
Using intracellular flow cytometry, cytokine production by cryopreserved PBMCs from healthy controls and HIV-1 infected individuals were examined after TLR stimulation.
Results
We observed that the effect of HIV-1 infection on TLR responses not only depended on the stage of HIV-1 infection, but was also dependent on the individual receptor and cell type examined. Monocyte and mDC responses to TLR8 stimulation were associated with HIV-1 viral load and CD4+ T cell count, while pDC responses to TLR7 stimulation were not. Responses to TLR2 stimulation were not affected by HIV-1 infection while responses to TLR9 stimulation were universally decreased in all HIV-1 infected individuals examined regardless of treatment or clinical parameters.
Conclusion
Responsiveness to TLR7/8 stimulation, which have been shown to recognize HIV-1 ssRNA, did not decrease in chronic infection, and may represent a contributing factor to ongoing T cell immune activation in the setting of chronic viremic HIV-1 infection.
doi:10.1097/QAD.0b013e32834f3167
PMCID: PMC3738004  PMID: 22210629
HIV-1; Toll-like receptor; Innate immunity; Pathogenesis; Dendritic Cells; Monocytes
19.  Reduced frequencies of NKp30+ NKp46+, CD161+, and NKG2D+ NK cells in acute HCV infection may predict viral clearance 
Journal of hepatology  2010;55(2):278-288.
Background & Aims
While the majority of HCV-infected patients progress to chronic hepatitis, a small fraction of individuals are able to clear the virus. Resolution of infection occurs within the first few weeks to months of infection, suggesting that innate immune functions may be critical for early control. Epidemiologic data support a role for particular NK cell receptor bearing populations in this control, yet the mechanism by which NK cells respond to HCV early in infection is unknown.
Methods
Changes in the phenotype and function of NK cells were investigated in a cohort of 43 individuals identified during various stages of HCV infection with different clinical outcomes.
Results
Acute, chronic, and resolved HCV infections were characterized by an expansion of CD56neg NK cells. Furthermore, increased levels of HLA-C-binding KIR+ NK cells were observed in HCV resolvers, while all stages of HCV infection were associated with reduced percentages of NKG2D+, NKp30+, and NKp46+ NK cells, and a slight increase in the ability of NK cells to respond to target cells bearing the ligands for these receptors. In contrast, NKG2A+ and CD94+ NK cells were elevated in acute and chronic HCV infection, but not in resolved infection. Most importantly, in acute infection, lower frequencies of NKp30+, NKp46+, CD161+, and NKG2D+ NK cells were observed in patients who were subsequently able to clear HCV infection than in those becoming chronically infected.
Conclusions
These data implicate particular populations of NK cells in the early control and clearance of HCV infection.
doi:10.1016/j.jhep.2010.11.030
PMCID: PMC3729214  PMID: 21168454
Hepatitis C virus; Natural killer cells; Innate immunity; CD161; NK-p30; NKp46; Resolution of HCV infection; Acute infection
20.  Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection 
Retrovirology  2013;10:74.
Background
Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood.
Results
We analyzed Tim-3 and Gal-9 expression in a cohort of 85 individuals with early and chronic HIV-1 infection, and in 13 HIV-1 seronegative control subjects. HIV-1 infection was associated with reduced expression of Tim-3 on NK cells, which was normalized by HAART. Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals. Interestingly, Gal-9 expression in immune cells was significantly elevated in early infection, with monocytes and dendritic cells displaying the highest expression levels, which correlated with HIV-1 viral loads. In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.
Conclusions
Our data suggest that high expression levels of Gal-9 during early HIV-1 infection can lead to enhanced NK cell activity, possibly allowing for improved early control of HIV-1. In contrast, persistent Gal-9 production might impair Tim-3 activity and contribute to NK cell dysfunction in chronic HIV-1 infection.
doi:10.1186/1742-4690-10-74
PMCID: PMC3750478  PMID: 23866914
Tim-3; Gal-9; HIV-1; Innate immunity; NK cells
21.  Rapid Evolution of HIV-1 to Functional CD8+ T-Cell Responses in Humanized BLT Mice 
Science translational medicine  2012;4(143):143ra98.
Important advancements in the development of novel mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exists regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. As a model pathogen we infected humanized BLT mice with HIV-1 and characterized HIV-1-specific immune responses and viral evolution during the acute phase of infection. HIV-1-specific CD8+ T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication, and restricted the same CD8+ T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen-specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the utility of a small animal model for human pathogens.
doi:10.1126/scitranslmed.3003984
PMCID: PMC3685142  PMID: 22814851
22.  Preservation HIV-1-specific IFNγ+ CD4+ T cell responses in breakthrough infections following exposure to Tenofovir Gel in the CAPRISA 004 microbicide trial 
The CAPRISA004 trial demonstrated reduction of sexual HIV-1 acquisition in women using a vaginal microbicide containing tenofovir. A better understanding of the consequences of antiretroviral-containing microbicides for immune responses in individuals with intercurrent HIV-1 infection is needed for future trials combining the use of microbicides with HIV-1 vaccines. Investigation of immune responses in women who acquired HIV-1 whilst using tenofovir gel showed significantly higher (p=0.01) Gag-specific IFNγ+ CD4+ T-cell responses. The use of tenofovir containing gel around the time of infection can modulate HIV-1 immunity, and these immunological changes need to be considered in future trials combining vaccines and microbicides.
doi:10.1097/QAI.0b013e31824f53a9
PMCID: PMC3381429  PMID: 22362152
HIV-1; vaginal microbicide; tenofovir; HIV-1-specific CD4+ T cell help
23.  Preserved Function of Regulatory T Cells in Chronic HIV-1 Infection Despite Decreased Numbers in Blood and Tissue 
The Journal of Infectious Diseases  2012;205(10):1495-1500.
Regulatory T cells (Tregs) are potent immune modulators, but their role in human immunodeficiency virus type 1 (HIV-1) pathogenesis remains poorly understood. We performed a detailed analysis of the frequency and function of Tregs in a large cohort of HIV-1–infected individuals and HIV-1 negative controls. While HIV “elite controllers” and uninfected individuals had similar Treg numbers and frequencies, the absolute numbers of Tregs declined in blood and gut-associated lymphoid tissue in patients with chronic progressive HIV-1 infection. Despite quantitative changes in Tregs, HIV-1 infection was not associated with an impairment of ex vivo suppressive function of flow-sorted Tregs in both HIV controllers and untreated chronic progressors.
doi:10.1093/infdis/jis236
PMCID: PMC3415814  PMID: 22427677
24.  Preferential CTL targeting of Gag is associated with relative viral control in long-term surviving HIV-1 infected former plasma donors from China 
Cell Research  2012;22(5):903-914.
It is generally believed that CD8+ cytotoxic T lymphocytes (CTLs) play a critical role in limiting the replication of human immunodeficiency virus type 1 (HIV-1) and in determining the outcome of the infection, and this effect may partly depend on which HIV product is preferentially targeted. To address the correlation between HIV-1-specific CTL responses and virus replication in a cohort of former plasma donors (FPDs), 143 antiretroviral therapy naive FPDs infected with HIV-1 clade B' strains were assessed for HIV-1-specific CTL responses with an IFN-γ Elispot assay at single peptide level by using overlapping peptides (OLPs) covering the whole consensus clade B proteome. By using a Spearman's rank correlation analysis, we found that the proportion of Gag-specific CTL responses among the total virus-specific CTL activity was inversely correlated with viral loads while being positively correlated to CD4 counts, as opposed to Pol- and Env-specific responses that were associated with increased viral loads and decreased CD4 counts. In addition, Vpr-specifc CTL responses showed a similar protective effect with Gag responses, but with a much lower frequency of recognition. Significantly, we also observed an association between HLA-A*30/B*13/Cw*06 haplotype and lower viral loads that was probably due to restricted Gag-specific CTL responses. Thus, our data demonstrate the prominent role of Gag-specific CTL responses in disease control. The advantage of HLA-A*30/B*13/Cw*06 haplotype in viral control may be associated with the contribution of Gag-specific CTL responses in the studied individuals.
doi:10.1038/cr.2012.19
PMCID: PMC3343654  PMID: 22290423
human immunodeficiency virus type 1; cytotoxic T lymphocytes; human leukocyte antigen class I; Gag
25.  Changes in Natural Killer Cell Activation and Function during Primary HIV-1 Infection 
PLoS ONE  2013;8(1):e53251.
Background
Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection.
Methodology/Principal Findings
Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, α4β7). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p = 0.03 and p<0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r = 0.68;p<0.0001; post-infection, during primary infection r = 0.074;p = 0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r = 0.32'p = 0.04 and r = 0.35;p = 0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIRpos) NK cells increased following HIV acquisition (p = 0.006), and KIRpos NK cells were less activated than KIRneg NK cells amongst individuals sampled while seronegative or serodiscordant (p = 0.001;p<0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p = 0.006 and p = 0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p<0.0001).
Conclusions/Significance
Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.
doi:10.1371/journal.pone.0053251
PMCID: PMC3541400  PMID: 23326405

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