Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross River virus (RRV) infections highlight the need for robust intervention strategies. Alphaviral arthritis can persist for months after the initial acute disease, and is mediated by cellular immune responses. A common strategy to limit inflammation and pathology is to dampen the overwhelming inflammatory responses by modulating proinflammatory cytokine pathways. Here, we investigate the contribution of interleukin-17 (IL-17), a cytokine involved in arthropathies such as rheumatoid arthritis, in the development RRV-induced arthritis and myositis. IL-17 was quantified in serum from RRV-infected patients, and mice were infected with RRV and joints and muscle tissues collected to analyse cellular infiltrates, tissue mRNA, cytokine expression, and joint and muscle histopathology. IL-17 expression was increased in musculoskeletal tissues and serum of RRV-infected mice and humans, respectively. IL-17-producing T cells and neutrophils contributed to the cellular infiltrate in the joint and muscle tissue during acute RRV disease in mice. Blockade of IL-17A/F using a monoclonal antibody (mAb) reduced disease severity in RRV-infected mice and led to decreased proinflammatory proteins, cellular infiltration in synovial tissues and cartilage damage, without affecting viral titers in inflamed tissues. IL-17A/F blockade triggered a shift in transcriptional profile of both leukocyte infiltrates and musculoskeletal stromal cells by downregulating proinflammatory genes. This study highlights a previously uncharacterized role for an effector cytokine in alphaviral pathology and points towards potential therapeutic benefit in targeting IL-17 to treat patients presenting with RRV-induced arthropathy.

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.

While targeted therapies have resulted in the surge of personalized medicine strategies for cancer treatment, many patients ultimately still receive radiation therapy. We hypothesized that patients with non-small cell lung cancer (NSCLC) mutations who received radiation treatment would have increased progression free survival and overall survival. Upon diagnosis, many NCSLC patients at our institution undergo mutation testing for oncogenic drivers to create the best treatment plan. The mutation test included ALK gene rearrangements and single nucleotide polymorphisms in EGFR, KRAS, ERBB2, BRAF, PIK3CA, NRAS, MEK1, AKT, and PTEN. We retrospectively analyzed radiation-treated patients with mutation testing from 2001 to 2015. All Stage I-III patients received radiation for local disease, while we selected Stage IV patients with brain metastases that received radiation with or without surgery. We analyzed the progression free survival, progression location (local, regional, distant), radiation type and parameters, brain metastasis location, ECOG status, smoking status, and overall survival. We identified 103 Stage I-III patients (50 male, 53 female, mean age 65.6 + 11.7 years). Sixty-one patients had mutations (34 KRAS, 16 EGFR, 5 ALK, 5 ERBB2, 4 PIK3CA, 3 BRAF, 1 NRAS, and 2 MEK1). Stage I-III patients with a mutation had a median survival of 39.1 months and wild type patients was 31.8 months. Median progression free survival for mutation patients was 36.8 months and wild type was 13.7 months, which represented a significant increase (p = 0.003) in progression free survival for mutation patients. When analyzing subsets of mutation patients, KRAS (40.7 months, p = 0.009) and EGFR (42.2 months, p = 0.032) patients had significantly longer progression free survival compared to wild type patients. In the Stage IV patient cohort, we had 90 patients (47 male, 43 female, mean age 60.7 + 9.6 years) where 70 patients had mutations (32 KRAS, 26 EGFR, 8 ALK, 4 PIK3CA, 1 ERBB2, 1 NRAS, 1 MEK1, 1 AKT1). Stage IV mutation patients had significantly higher overall survival (median 11.6 months, p = 0.044) compared to overall survival in wild type patients (4.7 months). In mutation subsets, only EGFR mutation patients had significantly higher overall survival (12.5 months, p = 0.032) compared to wild type patients. Stage I-III patients with oncogene mutations have increased progression free survival, and Stage IV patients with oncogene mutations have increased overall survival compared to wild type patients. These data have implications for tailoring radiotherapy and other management approaches for patients with oncogene mutations in NSCLC tumors.

Introduction: Despite an effective vaccine, hepatitis B virus (HBV) infection continues to impose a large burden of disease globally. Until childhood immunisation achieves high adult population coverage, people who inject drugs (PWID), including prison inmates remain at risk. PWID have a higher prevalence of HBV than the wider population, and lower rates of vaccine-conferred immunity. This study sought to identify the incidence and predictors of HBV transmission and uptake of immunisation in PWID prisoners in Australia. Methods: Longitudinally collected, stored sera from subjects previously enrolled in a prospective study of hepatitis C in recently incarcerated PWID prisoners (n = 590) were serologically tested for HBV. Interviews recording demographic and behavioural risks were analysed. Multivariate statistical analyses were applied to identify associations of incident infection or immunisation. Results: Upon imprisonment there were n = 373 (63%) individuals who were HBV susceptible, of whom 140 remained susceptible at the subsequent enrolment into the cohort, and had one or more follow-up visits (a total of 406.73 person years [p.y.]), and so were included in this analysis. There were 7 incident cases of HBV infection (1.7 per 100 p.y.) in this group, with transmission being associated with injecting drug use daily or more often. There were 48 individuals who were successfully immunised (11.8 per 100 p.y.) with younger age and continuous imprisonment predicting this outcome. Conclusions: The Australian prison environment poses a high risk for HBV infection, and also provides an opportunity for immunisation for PWID. Further efforts are required to improve coverage and prevent ongoing transmissions. (C) 2020 Elsevier Ltd. All rights reserved.

BACKGROUND:In hepatitis C virus (HCV) infection, virus-specific CD8+ T cells are recruited to the liver for antiviral activity. Multiple chemokine ligands are induced by the infection, notably interferon-inducible chemokine, CXCL10. In HCV, intrahepatic T cells express chemokine receptors (CCRs), including CXCR3, CXCR6, CCR1, and CCR5, but CCR expression on antigen-specific effector and memory T cells has not been investigated.METHODS:Paired blood and liver samples were collected from subjects with chronic HCV for flow cytometric analysis of CCR expression on CD8+ T cells. Expression of these CCRs was then examined on HCV-specific CD8+ T-cell subpopulations in the blood from subjects with acute or chronic HCV.RESULTS:Relative to peripheral blood, the liver was enriched with CD8+ T cells expressing CCR2, CCR5, CXCR3, and CXCR6 either singly or in combinations. CXCR3 was preferentially expressed on HCV-specific CD8+ T cells in both acute and chronic phases of infection in blood. Both CXCR3 and CCR2 were overexpressed on HCV-specific CD8+CCR7+CD45RO+ (central memory) cells, whereas effector memory (CD8+CCR7-CD45RO+) cells expressed more CXCR6.CONCLUSIONS:CXCR3-mediated signals support the accumulation of HCV-specific CD8+ memory T cells in the infected liver, and emphasize the importance of the CXCL10/CXCR3 trafficking pathway during acute and chronic HCV infection.

The literature describing the prognosis of patients with gastrointestinal (GI) cancers and brain metastases (BM) is sparse. Our group previously published a prognostic index, the Graded Prognostic Assessment (GPA) for GI cancer patients with BM, based on 209 patients diagnosed from 1985-2005. The purpose of this analysis is to identify prognostic factors for GI cancer patients with newly diagnosed BM in a larger contemporary cohort. A multi-institutional retrospective IRB-approved database of 792 GI cancer patients with new BM diagnosed from 1/1/2006 to 12/31/2016 was created. Demographic data, clinical parameters, and treatment were correlated with survival and time from primary diagnosis to BM (TPDBM). Kaplan-Meier median survival (MS) estimates were calculated and compared with log-rank tests. The MS from time of first treatment for BM for the prior and current cohorts were 5 and 8 months, respectively (P < 0.001). Eight prognostic factors (age, stage, primary site, resection of primary tumor, Karnofsky Performance Status (KPS), extracranial metastases, number of BM and Hgb were found to be significant for survival, in contrast to only one (KPS) in the prior cohort. In this cohort, the most common primary sites were rectum (24%) and esophagus (23%). Median TPDBM was 22 months. Notably, 37% (267/716) presented with poor prognosis (GPA 0-1.0). Although little improvement in overall survival in this cohort has been achieved in recent decades, survival varies widely and multiple new prognostic factors were identified. Future work will translate these factors into a prognostic index to facilitate clinical decision-making and stratification of future clinical trials.

Neural stem cells (NSCs) in the adult brain reside in niches termed the V-SVZ and SGZ. Emerging research suggests that adult V-SVZ NSCs can transform into malignant astrocytomas that are highly resistant to therapy. Additionally, clinical evidence suggests that glioblastoma contacting the V-SVZ is highly resistant to chemoradiation. An important question is the origin of this resistance. The majority of NSCs (GFAP+/SOX2+ B cells) that populate the V-SVZ are quiescent. We hypothesized that malignant astrocytoma therapeutic resistance is based, in part, on an intrinsic resistance of quiescent NSC B cells. Cohorts of 10-12 week old C57Bl6 male and female mice were injected with 0 or 50 mg/kg temozolomide ip 1 hr prior to administration of 0 or 2 Gy (300 kVp/10mA X-rays) whole brain radiation daily for five days. Mice were sacrificed 24 hours after the 5th dose of radiation or 14 days later injected with 0 or 100 mg/kg TMZ for another 5 days and then sacrificed after 60 days. At sacrifice mice were transcardially perfused and brains fixed. Serial 10 μm sections were collected throughout the SVZ. Sections were stained for stem cells markers including GFAP and SOX-2. Immunofluorescent Jpeg images were capture using an Apiro Versa 200 or an Olympus FV-1000 inverted confocal microscope and analyzed using Image J (NIH). Because preclinical literature is sparse regarding the effects of combined daily, fractionated radiation and temozolomide (TMZ) on quiescent NSC B cells, we began by quantifying their response to combined therapy. Ventricles were identified histologically and by SDF1 immunofluorescent ependymal cells that line the ventricles. NSC B cells located along the dorsal and dorsolateral walls of a ventricle were identified by co-expressed SOX2 and GFAP. The number of NSC B cells in female mice present 24 hrs after the last fraction of TMZ and irradiation was not significantly different from sham treated (P =0.54, N= 6 mice, 18 fields). In contrast, there was a 60% increase in NSC B cells in treated male mice (P = 0.0012, N= 6 mice, 17 fields). The ability of quiescent NSC B cells to survive 5-daily TMZ and irradiation treatments suggests that these cells may be intrinsically resistant. We will report on whether B cells are resistant 80 days after treatment.

In the era of personalized medicine and targeted therapies, routine identification of oncogene mutation status is becoming common and may assist in prognostication and therapeutic decision-making. We hypothesized that mutation status in non-small cell lung cancer would be predictive of survival and number of brain metastases diagnosed at initial presentation. At our institution, patients with non-small cell lung cancers undergo mutational testing for a panel of known oncogenic drivers at time of presentation, including ALK gene rearrangements and single nucleotide polymorphisms in EGFR, KRAS, ERBB2, BRAF, PIK3CA, NRAS, MEK1, AKT, and PTEN. We retrospectively identified 2 groups of patients from 2001 to 2015 within these mutational classes. Group 1 presented with brain metastases at initial diagnosis, whereas Group 2 presented with stage I-III, then subsequently developed brain metastases. All patients received radiotherapy for their brain metastases. We evaluated clinical characteristics based on tumor mutation status, which included median survival, median time to intracranial progression, number of brain metastases at presentation, ECOG status, and smoking status. In Group 1, we identified 91 patients (51 male, 40 female, mean age 61.3 years; KRAS, N=44; ALK, N=12; EGFR, N=32; PIK3CA, N=3). 52% of EGFR, 27% of KRAS, 33% PIK3CA, 42% of ALK patients presented with >4 brain metastases. Median survival for EGFR, KRAS, ALK, and PIK3CA patients was 12.7, 11.0, 9.7, and 12.7 months, respectively. In Group 2, we identified 13 patients (7 male, 6 female, mean age 66.5 years; KRAS, N=7; ALK, N=1; EGFR, N=3; PIK3CA, N=2). Median time to intracranial progression for KRAS, EGFR, ALK, and PIK3CA mutants was 26.7, 23.3, 108.0, and 12.5 months, respectively. At diagnosis, one KRAS, all EGFR, and all PIK3CA patients presented with >4 metastases. The ALK patient presented with a single metastasis and remains alive at time of analysis. After developing brain metastasis, median survival for KRAS and PIK3CA patients was 7.0 and 3.5 months. Of the patients with an EGFR mutation, 1 patient is alive at time of analysis, 1 patient passed away within 17 days of developing brain metastases due to extracranial progression and the other patient passed away 10 days after developing leptomeningeal carcinomatosis. Oncogene driver mutations correlate with a greater number of brain metastases without decreased median survival compared to historical controls. Stage I-III patients with oncogene driver mutations showed a worse prognosis after developing brain metastases. This should be studied further in a prospective fashion to determine the best treatment algorithm for these patients.

Peripheral immunity plays a key role in maintaining homeostasis and conferring crucial neuroprotective effects on the injured nervous system, while at the same time may contribute to increased vulnerability to neuropathic pain. Little is known about the reciprocal relationship between entrapment neuropathy and peripheral immunity. This study investigated immune profile in patients with carpal tunnel syndrome (CTS), the most prevalent entrapment neuropathy. All patients exhibited neurophysiological abnormalities in the median nerve, with the majority reporting neuropathic pain symptoms. We found a significant increase in serum CCL5, CXCL8, CXCL10 and VEGF, and in CD4+ central and effector memory T cells in CTS patients, as compared to healthy controls. CCL5 and VEGF were identified as having the highest power to discriminate between patients and controls. Interestingly, and contrary to the prevailing view of CCL5 as a pro-nociceptive factor, the level of circulating CCL5 was inversely correlated with neuropathic pain intensity and median nerve motor latency. In contrast, the level of central memory T cells was positively associated with abnormal neurophysiological findings. These results suggest that entrapment neuropathy is associated with adaptive changes in the homeostasis of memory T cells and an increase in systemic inflammatory modulating cytokines/chemokines, which potentially regulate neuropathic symptoms.

Tremor is the most common movement disorder. Medical management is first-line treatment, but when ineffective patients have limited options other than surgical thalamotomy (ST) or deep brain stimulator placement (DBS). Stereotactic radiation to the ventral intermediate nucleus (VIM) of the thalamus is a standard treatment alternative to surgical option. We hypothesized that Linac-based stereotactic radiosurgery (SRS) would provide effective tremor control and improve quality of life on this prospective, observational study.

Background: A detailed description of the natural history of acute Q fever, caused by infection with Coxiella burnetii,Aim: To significantly increase understanding of the illness.Design: Subjects with provisional acute Q fever (n = 115) were recruited from primary care in rural Australia, and followed prospectively by interview and blood collection including for serological confirmation. A nested series of subjects with prolonged illness (cases), and those without (controls), were investigated in detail.Methods: Total phase I and phase II anti-C. burnetii antibodies were detected by complement fixation test; and IgG, IgM and IgA phase I and phase II titres by immunofluorescence. Flow cytometric analysis was conducted to enumerate circulating T cells subsets, B cells, monocytes and natural killer cells.Results: Serological testing confirmed acute Q fever in 73 subjects (63%). The acute illness featured fever, headache, sweats, fatigue and anorexia; and varied widely in severity, causing an average of 8 days in bed and 15 days out of work or other role in the first month of illness. The illness course varied from 2 days to greater than a year. No cases of chronic, localized Q fever infection, such as endocarditis, were identified. Neither severe nor prolonged illness were associated with persistence of C. burnetii DNA, altered patterns of C. burnetii-specific IgG, IgM or IgA antibody production, or altered leucocyte subsets.Conclusions: The severity of acute Q fever alone predicted prolonged duration. Further studies are warranted to better understand the pathophysiology of prolonged illness after acute Q fever.

SummaryInjecting drug use remains the major risk factor for hepatitis C (HCV) transmission. A minority of long‐term injecting drug users remain seronegative and aviraemic, despite prolonged exposure to HCV – termed highly exposed seronegative subjects. Natural killer (NK) cells have been implicated in this apparent protection. A longitudinal nested, three group case–control series of subjects was selected from a prospective cohort of seronegative injecting drug users who became incident cases (n = 11), remained seronegative (n = 11) or reported transient high‐risk behaviour and remained uninfected (n = 11). The groups were matched by age, sex and initial risk behaviour characteristics. Stored peripheral blood mononuclear cells were assayed in multicolour flow cytometry to enumerate natural killer cell subpopulations and to assess functional activity using Toll‐like receptor ligands before measurement of activation, cytokine production and natural cytotoxicity receptor expression. Principal components were derived to describe the detailed phenotypic characteristics of the major NK subpopulations (based on CD56 and CD16 co‐expression), before logistic regression analysis to identify associations with exposed, seronegative individuals. The CD56dimCD16+ (P = 0.05, OR 6.92) and CD56dimCD16− (P = 0.05, OR 6.07) principal components differed between exposed, seronegative individuals and pre‐infection samples of the other two groups. These included CD56dimCD16+ and CD56dimCD16− subsets with CD56dimCD16+ IFN‐γ and TNF‐α on unstimulated cells, and CD56dimCD16− CD69+, CD107a+, IFN‐γ and TNF‐α following TLR stimulation. The cytotoxic CD56dim NK subset thus distinguished highly exposed, seronegative subjects, suggesting NK cytotoxicity may contribute to protection from HCV acquisition. Further investigation of the determinants of this association and prospective assessment of protection against HCV infection are warranted.

SummaryClearance of primary hepatitis C virus (HCV) infection has been associated with strong and broadly targeted cellular immune responses. This study aimed to characterize HCV‐specific CD4+ effector and regulatory T‐cell numbers and cytokine production during primary infection. Antigen‐specific CD4+ T‐cell responses were investigated in a longitudinal cohort of subjects from pre‐infection to postoutcome, including subjects who cleared [n=12] or became chronically infected [n=17]. A cross‐sectional cohort with previously cleared, or chronic infection [n=15 for each], was also studied. Peripheral blood mononuclear cells were incubated with HCV antigens and surface stained for T‐effector (CD4+CD25highCD134+CD39‐) and T‐regulatory (CD4+CD25highCD134+CD39+) markers, and culture supernatants assayed for cytokine production. Contrary to expectations, the breadth and magnitude of the HCV‐specific CD4+ T‐cell responses were higher in subjects who became chronically infected. Subjects who cleared the virus had HCV‐specific CD4+ T‐cell responses dominated by effector T cells and produced higher levels of IFN‐γ, in contrast to HCV‐specific CD4+ T‐cell responses dominated by regulatory T cells and more IL‐10 production in those who became chronically infected. Better understanding of the role of antigen‐specific CD4+ T‐cell responses in primary HCV will further define pathogenesis and help guide development of a preventative vaccine.

ABSTRACT The interaction between hepatitis C virus (HCV) and cellular immune responses during very early infection is critical for disease outcome. To date, the impact of antigen-specific cellular immune responses on the evolution of the viral population establishing infection and on potential escape has not been studied. Understanding these early host-virus dynamics is important for the development of a preventative vaccine. Three subjects who were followed longitudinally from the detection of viremia preseroconversion until disease outcome were analyzed. The evolution of transmitted/founder (T/F) viruses was undertaken using deep sequencing. CD8 + T cell responses were measured via enzyme-linked immunosorbent spot (ELISpot) assay using HLA class I-restricted T/F epitopes. T/F viruses were rapidly extinguished in all subjects associated with either viral clearance ( n = 1) or replacement with viral variants leading to establishment of chronic infection ( n = 2). CD8 + T cell responses against 11 T/F epitopes were detectable by 33 to 44 days postinfection, and 5 of these epitopes had not previously been reported. These responses declined rapidly in those who became chronically infected and were maintained in the subject who cleared infection. Higher-magnitude CD8 + T cell responses were associated with rapid development of immune escape variants at a rate of up to 0.1 per day. Rapid escape from CD8 + T cell responses has been quantified for the first time in the early phase of primary HCV infection. These rapid escape dynamics were associated with higher-magnitude CD8 + T cell responses. These findings raise questions regarding optimal selection of immunogens for HCV vaccine development and suggest that detailed analysis of individual epitopes may be required. IMPORTANCE A major limitation in our detailed understanding of the role of immune response in HCV clearance has been the lack of data on very early primary infection when the transmitted viral variants successfully establish the acute infection. This study was made possible through the availability of specimens from a unique cohort of asymptomatic primary infection cases in whom the first available viremic samples were collected approximately 3 weeks postinfection and at regular intervals thereafter. The study included detailed examination of both the evolution of the viral population and the host cellular immune responses against the T/F viruses. The findings here provide the first evidence of host cellular responses targeting T/F variants and imposing a strong selective force toward viral escape. The results of this study provide useful insight on how virus escapes the host response and consequently on future analysis of vaccine-induced immunity.

Background T cells have been implicated in neuropathic pain that is caused by peripheral nerve injury. Immunogenic myelin basic protein (MBP) peptides have been shown to initiate mechanical allodynia in a T cell-dependent manner. Antagonistic altered peptide ligands (APLs) are peptides with substitutions in amino acid residues at T cell receptor contact sites and can inhibit T cell function and modulate inflammatory responses. In the present study, we studied the effects of immunization with MBP-derived APL on pain behavior and neuroinflammation in an animal model of peripheral nerve injury. Methods Lewis rats were immunized subcutaneously at the base of the tail with either a weakly encephalitogenic peptide of MBP (cyclo-MBP 87-99 ) or APL (cyclo-(87-99)[A 91 ,A 96 ]MBP 87-99 ) in complete Freund’s adjuvant (CFA) or CFA only (control), following chronic constriction injury (CCI) of the left sciatic nerve. Pain hypersensitivity was tested by measurements of paw withdrawal threshold to mechanical stimuli, regulatory T cells in spleen and lymph nodes were analyzed by flow cytometry, and immune cell infiltration into the nervous system was assessed by immunohistochemistry (days 10 and 30 post-CCI). Cytokines were measured in serum and nervous tissue of nerve-injured rats (day 10 post-CCI). Results Rats immunized with the APL cyclo-(87-99)[A 91 ,A 96 ]MBP 87-99 had significantly reduced mechanical pain hypersensitivity in the ipsilateral hindpaw compared to cyclo-MBP 87-99 -treated and control rats. This was associated with significantly decreased infiltration of T cells and ED1+ macrophages in the injured nerve of APL-treated animals. The percentage of anti-inflammatory (M2) macrophages was significantly upregulated in the APL-treated rats on day 30 post-CCI. Compared to the control rats, microglial activation in the ipsilateral lumbar spinal cord was significantly increased in the MBP-treated rats, but was not altered in the rats immunized with the MBP-derived APL. In addition, immunization with the APL significantly increased splenic regulatory T cells. Several cytokines were significantly altered after CCI, but no significant difference was observed between the APL-treated and control rats. Conclusions These results suggest that immune deviation by active immunization with a non-encephalitogenic MBP-derived APL mediates an analgesic effect in animals with peripheral nerve injury. Thus, T cell immunomodulation warrants further investigation as a possible therapeutic strategy for the treatment of peripheral neuropathic pain.

Studies of individuals who were highly exposed but seronegative (HESN) for HIV infection led to the discovery that homozygosity for the Δ32 deletion mutation in the CCR5 gene prevents viral entry into target cells, and is associated with resistance to infection. Additionally, evidence for protective immunity has been noted in some HESN groups, such as sex workers in The Gambia. Population studies of individuals at high risk for hepatitis C virus infection suggest that an HESN phenotype exists. The body of evidence, which suggests that protective immunity allows clearance of hepatitis C virus without seroconversion is growing. Furthermore, proof-of-principle evidence from in-vitro studies shows that genetic polymorphisms can confer resistance to establishment of infection. This Review discusses the possibility that genetic mutations confer resistance against hepatitis C virus, and also explores evidence for protective immunity, including via genetically programmed variations in host responses. The data generally strengthens the notion that investigations of naturally arising polymorphisms within the hepatitis C virus interactome, and genetic association studies of well characterised HESN individuals, could identify potential targets for vaccine design and inform novel therapies.

Genetic resistance to specific infections is well recognized. In hepatitis C virus (HCV) infection, genetic polymorphisms in IL-28B and the killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands have been shown to affect clearance of the virus following infection. There are limited data regarding resistance to established HCV infection. Reliable quantification of repeated exposure in high-risk populations, such as injecting drug users (IDU), is a key limitation of previous studies of resistance. Behavioural data and DNA from IDU (n = 210) in the Hepatitis C Incidence and Transmission Study in prisons (HITS-p) cohort were genotyped for polymorphisms in: IL-28B, peptidyl-prolyl isomerase A (PPIA), HLA-C and KIR2. To quantify risk, a composite risk index based on factors predictive of incident HCV infection was derived. Logistic regression analysis revealed the risk index was strongly associated with incident HCV infection (P < 0.0001). The upper tertile of the uninfected individuals had risk indices comparable to the incident cases, but remained uninfected. There were no significant differences in the frequencies of IL-28B or PPIA polymorphisms between these exposed-uninfected cases, or in the frequencies of KIR2-DL3, HLA-C1, or their combination. A framework for the investigation of genetic determinants of resistance to HCV infection has been developed. Several candidate gene associations were investigated and excluded. Further investigation of genetic determinants of resistance to HCV infection is warranted.