scholarly journals Killer immunoglobulin-like receptor (KIR) genes are associated with the risk of episodes of high-level and detectable viremia among HIV controllers

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 546
Author(s):  
Nathalia Beatriz Ramos De Sá ◽  
Karina dos S. Silva ◽  
Marcelo Ribeiro-Alves ◽  
Diogo Gama Caetano ◽  
Fernanda Heloise Côrtes ◽  
...  
Keyword(s):  
Viral Load ◽  
Viral Replication ◽  
Human Leukocyte ◽  
Nucleotide Polymorphisms ◽  
Elite Controllers ◽  
Viral Control ◽  
Kir Genes ◽  
Specific Amplification ◽  
Hiv Controllers ◽  
High Level

Background: HIV controllers (HICs) constitute a heterogeneous group of HIV-1 individuals able to suppress plasma viremia to low or undetectable levels in the absence of antiretroviral therapy. Host genetic factors may be involved in the sustained control of viral replication observed. We investigated the distribution and the potential impact of human leukocyte antigens (HLA)-B and -C alleles, killer immunoglobulin-like receptor (KIR) genes, single nucleotide polymorphisms (SNPs) of the NLRP3, CARD8 and IL-1β inflammasome genes, and CCR5Δ32 mutation on the viral control among HICs. Methods: In total, 28 HICs were categorized as persistent elite controllers (PECs, n = 7), ebbing elite controllers (EECs, n = 7), and viremic controllers (VCs, n = 14) according to the level of natural suppression of viremia. HLA alleles were assigned by sequencing-based typing, KIR alleles by polymerase chain reaction (PCR) sequence-specific amplification, SNPs by real-time PCR, and the CCR5Δ32 mutation by PCR. Results: Significant differences were observed in the pairwise comparisons of protective HLA-B alleles, KIR Bx genotype, KIR2DL3 + C1 pair, KIR2DL5, and KIR2DS5 allelic carrier frequencies among the HIC groups. Multivariate models showed that HICs without the KIR2DL3 allele or without KIR2DL3 + C1/C2 pair, with the HLA-C*08 allele or with the NLRP3 rs10754558-G SNP had a higher mean hazard of a viral load above 2,000 copies/mL, while a lower mean hazard of this event was observed for HICs with KIR2DL5, KIR2DS1, KIR2DS5, and KIR3DS1 alleles. Moreover, HICs with the KIR2DS5 allele had less risk of undergoing viral load (VL) blips within the same normalized period than those participants without this allele, while HICs without the KIR2DL3 allele had a mean higher risk of experiencing VL blips. Conclusions: These results indicate that innate immune mechanisms may play an essential role in modulating the sustained control of viral replication in HICs.

BISTABILITY ANALYSIS OF AN HIV MODEL WITH IMMUNE RESPONSE

2017 ◽  
Vol 25 (04) ◽  
pp. 677-695 ◽  
Author(s):  
SHAOLI WANG ◽  
FEI XU ◽  
LIBIN RONG
Keyword(s):  
Immune Response ◽  
Steady State ◽  
Viral Load ◽  
Immune Cell ◽  
Post Treatment ◽  
Proliferation Rate ◽  
Virus Dynamics ◽  
Elite Controllers ◽  
Viral Control ◽  
Hiv Model

Some HIV-infected patients (the so-called post-treatment controllers) can control the virus after cessation of antiretroviral therapy. A small fraction of patients can even naturally maintain undetectable viral load without therapy (they are called elite controllers). The immune response may play an important role in viral control in these patients. In this paper, we analyze a within-host model including immune response to study the virus dynamics in HIV-infected patients. We derived two threshold values for the immune cell proliferation parameter. Below the lower immune proliferation rate, the model has a stable immune-free steady state, which predicts that patients have a high viral load. Above the higher immune proliferation rate, the model has a stable low infected steady state, which indicates that patients are under elite control. Between the two immune thresholds, the model exhibits the dynamic behavior of bistability, which suggests that patients either undergo viral rebound after treatment termination or achieve the post-treatment control. These results may explain the different virus dynamics in HIV-infected patients.

scholarly journals Viral adaptation to immune selection pressure by HLA class I–restricted CTL responses targeting epitopes in HIV frameshift sequences

2010 ◽  
Vol 207 (1) ◽  
pp. 61-75 ◽  
Author(s):  
Christoph T. Berger ◽  
Jonathan M. Carlson ◽  
Chanson J. Brumme ◽  
Kari L. Hartman ◽  
Zabrina L. Brumme ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Ex Vivo ◽  
Natural Infection ◽  
Human Leukocyte ◽  
Population Level ◽  
Sequence Information ◽  
Viral Control

CD8+ cytotoxic T lymphocyte (CTL)–mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q < 0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03–restricted +2 frame–encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level.

scholarly journals HLA-C*18:01 and KIR2DL2+C1 genetic variants are associated with low viral load in cART naïve HIV-infected adult Zimbabweans

2018 ◽  
Vol 12 (12) ◽  
pp. 1105-1111
Author(s):  
Kudakwashe Mhandire ◽  
Mqondisi Tshabalala ◽  
Lynn Sodai Zijenah ◽  
Tommy Mlambo ◽  
Doreen Zvipo Mhandire ◽  
...  
Keyword(s):  
Viral Load ◽  
Hiv Infection ◽  
T Lymphocyte ◽  
Genetic Variants ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Gene Families ◽  
Cd4 Count ◽  
Kir Genes ◽  
Differential Outcomes

Introduction: Polymorphisms in killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) gene families are implicated in differential outcomes of HIV infection. However, research findings on the influence of KIR and HLA-C polymorphism on HIV disease progression remain inconclusive. We thus investigated the association of KIR and HLA-C gene polymorphisms with plasma HIV load (VL) and CD4+ T lymphocyte (CD4) count in 183 chronically HIV-infected, combination antiretroviral therapy (cART) naïve Zimbabweans of Bantu origin. Methodology: The presence or absence of 15 KIR genes were determined using sequence specific primer polymerase chain reaction while HLA-C typing was performed using chain termination DNA sequencing. Plasma VL was determined using the Cavidi Exavir viral load version 3 assay while CD4+ T lymphocytes were enumerated using flow cytometry. VLs and CD4 counts were compared between gene/genotype carriers and non-carriers using Mann-Whitney ranksum test. Results: HLA-C*18:01 allele carriers had a significantly lower median log10 VL (2.87copies/mL [IQR;2.3-3.2]) than the non-C*18:01 carriers (3.33copies/mL [IQR; 2.74-3.9]), p = 0.018. Further, median log10 VL was significantly lower in KIR2DL2+C1 carriers (2.745 [IQR; 2.590-2.745]) than non-KIR2DL2+C1 carriers (3.4 [IQR; 2.746-3.412]), p = 0.041. Comparison of CD4 + T lymphocyte counts between C*08:02 allele carriers and non-C*08:02 carriers showed a significantly higher median CD4 count in C*08:02 carriers (548cells/µL [IQR;410-684]) than in non-carriers (428cells/µL [IQR;388-537]), p = 0.034. Conclusion: We conclude that the HLA-C*18:01 and KIR2DL2+C1 genetic variants are associated with low VL while the C*08:02 is associated with high CD4+ T lymphocyte count among cART naïve Zimbabwean adults with chronic HIV infection.

scholarly journals Understanding the CD8 T-cell response in natural HIV control

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 985 ◽  
Author(s):  
Sushma Boppana ◽  
Paul Goepfert
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Viral Replication ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Elite Controllers ◽  
Natural Control ◽  
Functional Cure ◽  
Hiv Controllers

HIV-infected individuals who maintain control of virus without antiretroviral therapy (ART) are called HIV controllers. The immune responses of these individuals suppress HIV viral replication to low levels or, in the case of elite controllers, to undetectable levels. Although some research indicates a role for inferior virulence of the infecting viral strain in natural control, perhaps by way of defective Nef protein function, we find that the majority of research in HIV controllers highlights CD8 T cells as the main suppressor of viral replication. The most convincing evidence for this argument lies in the strong correlation between certain HLA-I alleles, especially B*57, and HIV control status, a finding that has been replicated by many groups. However, natural control can also occur in individuals lacking these specific HLA alleles, and our understanding of what constitutes an effective CD8 T-cell response remains an incomplete picture. Recent research has broadened our understanding of natural HIV control by illustrating the interactions between different immune cells, including innate immune effectors and antigen-presenting cells. For many years, the immune responses of the natural HIV controllers have been studied for clues on how to achieve functional cure in the rest of the HIV-infected population. The goal of a future functional cure to HIV is one where HIV-infected individuals’ immune responses are able to suppress virus long-term without requiring ART. This review highlights recent advances in our understanding of how HIV controllers’ natural immune responses are able to suppress virus.

scholarly journals HIV Antibody Profiles in HIV Controllers and Persons With Treatment-Induced Viral Suppression

2021 ◽  
Vol 12 ◽  
Author(s):  
Kai Kammers ◽  
Athena Chen ◽  
Daniel R. Monaco ◽  
Sarah E. Hudelson ◽  
Wendy Grant-McAuley ◽  
...  
Keyword(s):  
Viral Load ◽  
Viral Suppression ◽  
Validation Cohort ◽  
Elite Controllers ◽  
Discovery Cohort ◽  
Hiv Viral Load ◽  
Antibody Reactivity ◽  
Viral Load Set Point ◽  
Hiv Controllers ◽  
Independent Cohort

IntroductionLow HIV viral load is associated with delayed disease progression and reduced HIV transmission. HIV controllers suppress viral load to low levels in the absence of antiretroviral treatment (ART). We used an antibody profiling system, VirScan, to compare antibody reactivity and specificity in HIV controllers, non-controllers with treatment-induced viral suppression, and viremic non-controllers.MethodsThe VirScan library contains 3,384 phage-displayed peptides spanning the HIV proteome. Antibody reactivity to these peptides was measured in plasma from a Discovery Cohort that included 13 elite controllers, 27 viremic controllers, 12 viremic non-controllers, and 21 non-controllers who were virally suppressed on ART. Antibody reactivity to selected peptides was also assessed in an independent cohort of 29 elite controllers and 37 non-controllers who were virally suppressed on ART (Validation Cohort) and in a longitudinal cohort of non-controllers.ResultsIn the Discovery Cohort, 62 peptides were preferentially targeted in HIV controllers compared to non-controllers who were virally suppressed on ART. These specificities were not significantly different when comparing controllers versus viremic non-controllers. Aggregate reactivity to these peptides was also high in elite controllers from the independent Validation Cohort. The 62 peptides formed seven clusters of homologous epitopes in env, gag, integrase, and vpu. Reactivity to one of these clusters located in gag p17 was inversely correlated with viral load set point in an independent cohort of non-controllers.ConclusionsAntibody reactivity was low in non-controllers suppressed on ART, but remained high in viremic controllers despite viral suppression. Antibodies in controllers and viremic non-controllers were directed against epitopes in diverse HIV proteins; higher reactivity against p17 peptides was associated with lower viral load set point. Further studies are needed to determine if these antibodies play a role in regulation of HIV viral load.

Virus-specific antibodies allow viral replication in the marginal zone, thereby promoting CD8+ T-cell priming and viral control

2016 ◽  
Vol 54 (12) ◽  
pp. 1343-1404
Author(s):  
V Duhan ◽  
V Khairnar ◽  
SK Friedrich ◽  
C Hardt ◽  
PA Lang ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Marginal Zone ◽  
Cd8 T Cell ◽  
Viral Control ◽  
Specific Antibodies ◽  
T Cell Priming

scholarly journals Synergistic In Vitro Antiretroviral Activity of a Humanized Monoclonal Anti-CD4 Antibody (TNX-355) and Enfuvirtide (T-20)

2006 ◽  
Vol 50 (6) ◽  
pp. 2231-2233 ◽  
Author(s):  
Xing-Quan Zhang ◽  
Meredith Sorensen ◽  
Michael Fung ◽  
Robert T. Schooley
Keyword(s):  
Viral Replication ◽  
Viral Entry ◽  
Antiretroviral Agents ◽  
Entry Inhibitors ◽  
High Level ◽  
Antiretroviral Activity

ABSTRACT Recently, antiretroviral agents directed at several steps involved in viral entry have been shown to reduce viral replication in vitro and in vivo. We have demonstrated a high level of in vitro synergistic antiretroviral activity for two entry inhibitors that are directed at sequential steps in the entry process.

Multiple sclerosis risk genotypes correlate with an elevated cerebrospinal fluid level of the suggested prognostic marker CXCL13

2012 ◽  
Vol 19 (7) ◽  
pp. 863-870 ◽  
Author(s):  
M Lindén ◽  
M Khademi ◽  
I Lima Bomfim ◽  
F Piehl ◽  
M Jagodic ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Neurological Diseases ◽  
Severe Disease ◽  
Human Leukocyte ◽  
Disease Course ◽  
Nucleotide Polymorphisms ◽  
Treatment Protocols ◽  
Tnfaip3 Gene ◽  
Cerebrospinal Fluid Level

Background: The mechanisms of multiple sclerosis (MS) pathogenesis are still largely unknown. The heterogeneity of disease manifestations make the prediction of prognosis and choice of appropriate treatment protocols challenging. Recently, increased cerebrospinal fluid (CSF) levels of the B-cell chemokine CXCL13 was proposed as a possible marker for a more severe disease course and conversion from clinically isolated syndrome (CIS) to relapsing–remitting MS (RRMS). Objective: To investigate whether there are genetic susceptibility variants in MS that correlate with the levels of CXCL13 present in the CSF of MS patients. Methods: We genotyped the human leukocyte antigens HLA-DRB1 and HLA-A, plus a panel of single nucleotide polymorphisms (SNPs) that have been associated with susceptibility to MS and then correlated the genotypes with the levels of CXCL13, as measured with ELISA in the CSF of a total of 663 patients with MS, CIS, other neurological diseases (OND) or OND with an inflammatory component (iOND). Results: Presence of the HLA-DRB1*15 and the MS risk genotypes for SNPs in the RGS1, IRF5 and OLIG3/TNFAIP3 gene regions correlated significantly with increased levels of CXCL13. Conclusion: Our results pointed towards a genetic predisposition for increased CXCL13 levels, which in MS patients correlates with the severity of the disease course. These findings encourage further investigation and replication, in an independent patient cohort.

scholarly journals The Major Histocompatibility Complex Class II Alleles Mamu-DRB1*1003 and -DRB1*0306 Are Enriched in a Cohort of Simian Immunodeficiency Virus-Infected Rhesus Macaque Elite Controllers

2007 ◽  
Vol 82 (2) ◽  
pp. 859-870 ◽  
Author(s):  
Juan P. Giraldo-Vela ◽  
Richard Rudersdorf ◽  
Chungwon Chung ◽  
Ying Qi ◽  
Lyle T. Wallace ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Viral Replication ◽  
Rhesus Macaques ◽  
Complex Class ◽  
Elite Controllers ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus

ABSTRACT The role of CD4+ T cells in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication is not well understood. Even though strong HIV- and SIV-specific CD4+ T-cell responses have been detected in individuals that control viral replication, major histocompatibility complex class II (MHC-II) molecules have not been definitively linked with slow disease progression. In a cohort of 196 SIVmac239-infected Indian rhesus macaques, a group of macaques controlled viral replication to less than 1,000 viral RNA copies/ml. These elite controllers (ECs) mounted a broad SIV-specific CD4+ T-cell response. Here, we describe five macaque MHC-II alleles (Mamu-DRB*w606, -DRB*w2104, -DRB1*0306, -DRB1*1003, and -DPB1*06) that restricted six SIV-specific CD4+ T-cell epitopes in ECs and report the first association between specific MHC-II alleles and elite control. Interestingly, the macaque MHC-II alleles, Mamu-DRB1*1003 and -DRB1*0306, were enriched in this EC group (P values of 0.02 and 0.05, respectively). Additionally, Mamu-B*17-positive SIV-infected rhesus macaques that also expressed these two MHC-II alleles had significantly lower viral loads than Mamu-B*17-positive animals that did not express Mamu-DRB1*1003 and -DRB1*0306 (P value of <0.0001). The study of MHC-II alleles in macaques that control viral replication could improve our understanding of the role of CD4+ T cells in suppressing HIV/SIV replication and further our understanding of HIV vaccine design.

Interferon resistance of cutaneous T-cell lymphoma–derived clonal T-helper 2 cells allows selective viral replication

Blood ◽  
2001 ◽  
Vol 97 (2) ◽  
pp. 523-527 ◽  
Author(s):  
Reinhard Dummer ◽  
Udo Döbbeling ◽  
Ralf Geertsen ◽  
Jörg Willers ◽  
Günter Burg ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Human Leukocyte ◽  
T Helper ◽  
Cd4 Cells ◽  
Efficient Treatment ◽  
T Helper 2 ◽  
Ifn Γ ◽  
The Impact

Abstract Cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of lymphoproliferative disorders that are characterized by an accumulation of T-lymphocytes in the skin and occasionally in blood known as Sézary syndrome (SS). In most cases the dominant clone displays T-helper 2 cytokines. Because IFN-γ is a natural inhibitor of T-helper 2 cells and IFN-α is frequently used in CTCL, the impact of IFNs on SS-derived purified clonal T-helper 2 cells was studied using anti-Vβ antibodies. Moreover, IFNs are known to mediate virus resistance in normal cells. The isolated clonal CD4+ cells, but not the nonclonal CD4+ cells, appeared resistant to IFN-γ and IFN-α stimulation in terms of human leukocyte antigen up-regulation and MxA induction caused in part by alterations in Stat-1 molecule mRNA and IFNγR1 mRNA transcription. The IFN resistance of the patient-derived clonal cells was then targeted by vesicular stomatitis virus infection after IFN-α priming, resulting in selective viral replication in clonal cells. In contrast, nonclonal cells of the same patient showed IFN-dependent MxA expression, which is a major mediator protein of viral protection. The IFN resistance of the dominant T-helper 2 cells might be important for lymphomagenesis. Interferon signaling deficiencies can be targeted for purging patients' cells in vitro. Furthermore, this approach may allow specific molecular interventions, resulting in the efficient treatment of CTCL and other IFN-resistant neoplasms such as lung cancer.

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