HIV Controllers Research Articles

Short Communication: Low Expression of Activation and Inhibitory Molecules on NK Cells and CD4(+) T Cells Is Associated with Viral Control.

Chronic HIV-1 infection induces severe immune alterations, including hyperactivation, exhaustion, and apoptosis. In fact, viral control has been associated with low frequencies of these processes. Here, we evaluated the expression of activation and inhibitory molecules on natural killer (NK) and CD4(+) T cells and plasma levels of proinflammatory cytokines in individuals exhibiting viral control: a cohort of HIV-1-exposed-seronegative individuals (HESN) and a cohort of HIV controllers. There was lower expression of CD69, LAG-3, PD-1, and TIM-3 in both cohorts when compared to a low-risk population or HIV progressors. In addition, HIV controllers exhibited lower plasma levels of proinflamatory molecules TNF-α and IP-10. These findings suggest that individuals exhibiting viral control have lower basal expression of markers associated with cellular activation and particularly immune exhaustion.

A Human Immunodeficiency Virus Controller With a Large Population of CD4(+)CD8(+) Double-Positive T Cells.

Human immunodeficiency virus (HIV) controllers are patients who control viral replication without antiretroviral therapy. We present the case of an HIV controller who had CD4 and CD8 coexpressed on 40% of his T cells. Although a recent study found that double-positive T cells had superior antiviral capacity in HIV-1 controllers, in this case, the CD4+CD8+ T cells did not have strong antiviral activity.

Long-term control of simian immunodeficiency virus (SIV) in cynomolgus macaques not associated with efficient SIV-specific CD8+ T-cell responses.

The spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8(+) T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8(+) T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8(+) T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8(+) T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8(+) T cells that lacked efficient SIV suppression capacity ex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4(+) T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8(+) cell depletion and inducible SIV replication from its CD4(+) T cells in vitro. Altogether, our results suggest that CD8(+) T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control. Spontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8(+) T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8(+) T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8(+) cells induced a rise in the viral load. However, viremia was correlated with CD4(+) T-cell activation subsequent to CD8(+) cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8(+) T cells. Our results suggest that CD8(+) T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.

Higher frequency of NK and CD4+ T-cells in mucosa and potent cytotoxic response in HIV controllers

Event Abstract Back to Event Higher frequency of NK and CD4+ T-cells in mucosa and potent cytotoxic response in HIV controllers NATALIA A. TABORDA1, SANDRA M. GONZALEZ1, CRISTIAM M. ALVAREZ2, LUIS A. CORREA3, 4, CARLOS J. MONTOYA1 and MARÍA T. RUGELES1* 1 Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia, UdeA, Colombia 2 Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia, Colombia 3 Sección de Dermatología, Departamento de Medicina interna, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellín, Colombia, Colombia 4 Coordinador Laboratorio de Patología, Laboratorio Clínico VID, Obra de la Congregación Mariana, Medellín, Colombia, Colombia HIV infection induces immune alterations, mainly in gut mucosa, where the main target cells reside. However, the evolution of the infection is variable among infected individuals, as evidenced by HIV controllers who exhibit low or undetectable viral load in the absence of treatment. The aim of this study was to evaluate the frequency and activity of T and NK cells in peripheral blood and gut mucosa, as well as the level of microbial translocation, in a cohort of Colombian HIV controllers. The frequency and the cytotoxic activity of Gag-stimulated CD8+ T-cells and cytokine-stimulated NK cells were tested by flow cytometry in blood and gut biopsies. Finally, microbial translocation was measured by plasma lipopolysaccharide quantification. Compared with HIV-progressors, HIV controllers exhibited higher frequency of CD4+ T and NK cells and lower microbial translocation. An increased production of molecules associated with cytotoxic activity of CD8+ T-cells in blood and mucosa and a higher percentage of polyfunctional cells in blood were also observed in HIV controllers. In addition, an increased activity of NK cells was observed in blood from HIV controllers. These findings suggest that HIV controllers have a potent immune response, mainly mediated by cytotoxic cells that control HIV replication, reducing alterations at the gut mucosa. Acknowledgements This investigation was supported by CODI-Universidad de Antioquia “convocatoria mediana cuantía 2011”; “Estrategia para Sostenibilidad de Grupos 2014-2015 Universidad de Antioquia”; Natalia Taborda received a scholarship from Colciencias. Keywords: HIV, disease progression, Intestinal Mucosa, T-Lymphocytes, NK cells, Immunologic cytotoxicity Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Oral Presentation Topic: Mucosal Immunity and the microbiome Citation: TABORDA NA, GONZALEZ SM, ALVAREZ CM, CORREA LA, MONTOYA CJ and RUGELES MT (2015). Higher frequency of NK and CD4+ T-cells in mucosa and potent cytotoxic response in HIV controllers. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00310 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 16 Apr 2015; Published Online: 15 Sep 2015. * Correspondence: Dr. MARÍA T RUGELES, Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellín, Colombia, maria.rugeles@udea.edu.co Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers NATALIA A TABORDA SANDRA M GONZALEZ CRISTIAM M ALVAREZ LUIS A CORREA CARLOS J MONTOYA MARÍA T RUGELES Google NATALIA A TABORDA SANDRA M GONZALEZ CRISTIAM M ALVAREZ LUIS A CORREA CARLOS J MONTOYA MARÍA T RUGELES Google Scholar NATALIA A TABORDA SANDRA M GONZALEZ CRISTIAM M ALVAREZ LUIS A CORREA CARLOS J MONTOYA MARÍA T RUGELES PubMed NATALIA A TABORDA SANDRA M GONZALEZ CRISTIAM M ALVAREZ LUIS A CORREA CARLOS J MONTOYA MARÍA T RUGELES Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Posttreatment controllers: what do they tell us?

The posttreatment controllers (PTCs), as described for the Viro-Immunological Sustained COntrol after Treatment Interruption patients, are able to maintain durable HIV control after interruption of early antiretroviral therapy (ART). They are different from spontaneous HIV controllers who achieve HIV control without prior ART. PTCs provide proof-of-concept that prolonged ART-free remission is possible. PTCs support the idea that early treatment could be especially beneficial. They show that a stable equilibrium between a small HIV reservoir and HIV-1-specific immune responses can be achieved. PTCs occur at a frequency of 5 and 15% of patients with early combination ART interruption, which might be considered too infrequent to support early combination ART in all individuals. However, it will be necessary to use more potent ART, with good penetration into lymphoid tissues, initiated earlier and maintained for at least 4 years to see if this frequency might be increased. Understanding the mechanisms underlying durable HIV control among PTCs will provide critical insights into how this might be achieved in others. PTCs give hope that the objective of durable HIV remission is a realistic goal in the medium term.

Characterization of Asymptomatic Children Infected with the Human Immunodeficiency Virus at Birth

Background: Mother-to-child HIV transmission remains very high in Cameroon. Therefore follow-up of numerous HIV-infected infants is a critical issue in the country. Here, we investigated the file of HIV-infected infants remaining asymptomatic in the absence of anti-retroviral therapy (ART). The first goal was to obtain an estimate of the prevalence of infants with an HIV controller like status. Method: HIV-infected infants, aged 6 months to 17 years presenting at CIRCB for biological examinations were enrolled upon signed a proxy-consent. The enrollment took place from April 2011 to February 2013. From the medical file of 359 HIV vertically-infected infants, 41 were found naive of anti-retroviral therapy and free of clinical symptoms. Diseases related to HIV infection (oral candidosis, zona, chronic diarrhea, pulmonary tuberculosis, dermatitis) were more particularly checked and corresponding infants not included in the study. From the selected infants, CD4 counts and viral load were recorded. Non-exposed children were enrolled as control group. Results: Of the 359 infants, 41 were ARV-naive and free from HIV clinical symptoms. Five of them (12%) exhibit a viral load 10%). Conclusion: Our preliminary cross-sectional study highly suggests the existence of pediatric HIV controllers like in Cameroon despite all disfavoring living conditions. However, a longitudinal study would be required to confirm this hypothesis. The development of an HIV vaccine applicable to infants of countries with high incidence of HIV-infected people should benefit from the immunological analysis explaining the HIV controller (HIC) status.

Preserved immune parameters in peripheral blood and gastrointestinal mucosa is a characteristic of spontaneous HIV controllers

Preserved immune parameters in peripheral blood and gastrointestinal mucosa is a characteristic of spontaneous HIV controllers

Differential partial activation phenotype and production of tumour necrosis factor-α by conventional dendritic cells in response to lipopolysaccharide in HIV+ viraemic subjects and HIV+ controllers.

HIV(+) subjects are reported to have increased soluble CD14 (sCD14) in plasma, an indicator of microbial translocation. We evaluated if microbial translocation has a differential impact on the activation and function of conventional dendritic cells (cDC) from viraemic HIV(+) subjects and HIV(+) controllers (CTs). The HIV(+) subjects were classified into two groups according to their plasma viral load (pVL): CT and viraemic. Subjects without HIV were included as controls (HIV(-) ). The frequencies and phenotypes of cDC from these subjects were evaluated by multi-parameter flow cytometry. In addition, peripheral blood mononuclear cells (PBMCs) were stimulated with lipopolysaccharide (LPS) or single-stranded RNA40 (ssRNA40), the phenotype of the cDC and the intracellular production of tumour necrosis factor (TNF)-α by the cDC were evaluated by flow cytometry. We observed a partial activation phenotype for the cDC in the viraemic subjects and CTs ex vivo and after LPS activation, which showed differences in the expression of CD40 and CD86. Furthermore, in response to LPS the cDC from the viraemic subjects produced more TNF-α compared to the cDC from CTs. Interestingly, the percentage of TNF-α(+) cDC was found to be correlated positively with the pVL. The partial activation of cDC and the over-production of TNF-α in response to LPS in viraemic HIV(+) subjects might be related to the increased chronic activation observed in these subjects. In contrast, cDC from CTs seem to have a regulated response to LPS, indicating that they respond differently to chronic immune activation. These results may have implications in the development of HIV therapies and vaccines using DC.

Lymphoid fibrosis occurs in long-term nonprogressors and persists with antiretroviral therapy but may be reversible with curative interventions.

Human immunodeficiency virus (HIV) replication causes lymphoid tissue (LT) fibrosis, which causes CD4(+) T-cell depletion. It is unknown whether people who spontaneously control HIV replication have LT fibrosis. We measured LT fibrosis and CD4(+) T cells in 25 HIV controllers, 10 noncontrollers, 45 HIV-positive individuals receiving therapy, and 10 HIV-negative individuals. Controllers had significant LT fibrosis and CD4(+) T-cell depletion, similar to noncontrollers, but the so-called Berlin patient (in whom HIV infection was cured) had near normal LT. Thus, LT fibrosis occurs in all HIV-infected subjects, and current therapy does not reverse it. Reversal of fibrosis during a curative intervention suggests that ongoing low-level virus production may maintain LT fibrosis.

Alternative Effector-Function Profiling Identifies Broad HIV-Specific T-Cell Responses in Highly HIV-Exposed Individuals Who Remain Uninfected

The characterization of host immune responses to human immunodeficiency virus (HIV) in HIV controllers and individuals with high exposure but seronegativity to HIV (HESN) is needed to guide the development of effective preventive and therapeutic vaccine candidates. However, several technical hurdles severely limit the definition of an effective virus-specific T-cell response. By using a toggle-peptide approach, which takes HIV sequence diversity into account, and a novel, boosted cytokine staining/flow cytometry strategy, we here describe new patterns of T-cell responses to HIV that would be missed by standard assays. Importantly, this approach also allows detection of broad and strong virus-specific T-cell responses in HESN individuals that are characterized by a T-helper type 1 cytokine-like effector profile and produce cytokines that have been associated with potential control of HIV infection, including interleukin 10, interleukin 13, and interleukin 22. These results establish a novel approach to improve the current understanding of HIV-specific T-cell immunity and identify cellular immune responses and individual cytokines as potential markers of relative HIV resistance. As such, the findings also help develop similar strategies for more-comprehensive assessments of host immune responses to other human infections and immune-mediated disorders.

Correction: Functional Characterization of Two scFv-Fc Antibodies from an HIV Controller Selected on Soluble HIV-1 Env Complexes: A Neutralizing V3- and a Trimer-Specific gp41 Antibody

Correction: Functional Characterization of Two scFv-Fc Antibodies from an HIV Controller Selected on Soluble HIV-1 Env Complexes: A Neutralizing V3- and a Trimer-Specific gp41 Antibody

Breadth of HIV-1 Env-specific antibody-dependent cellular cytotoxicity: relevance to global HIV vaccine design.

The objective of this study is to determine the breadth of HIV-1 Env-specific antibody-dependent cellular cytotoxicity (ADCC) in HIV controllers and HIV progressors with a view to design globally relevant HIV vaccines. The breadth of ADCC towards four major HIV-1 Env subtypes was measured in vitro for 11 HIV controllers and 11 HIV progressors. Plasma from 11 HIV controllers (including long-term slow progressors, viremic controllers, elite controller and posttreatment controller) and 11 HIV progressors, mostly infected with HIV-1 subtype B, was analysed for ADCC responses. ADCC assays were performed against 10 HIV-1 gp120 and 8 gp140 proteins from four major HIV-1 subtypes (A, B, C and E) and 3 glycosylation-mutant gp140 proteins. ADCC-mediated natural killer cell activation was significantly broader (P = 0.02) and of higher magnitude (P < 0.001) in HIV controllers than in HIV progressors. HIV controllers also showed significantly higher magnitude of ADCC-mediated killing of Env-coated target cells than HIV progressors to both HIV-1 subtype B and the heterologous subtype E gp140 (P = 0.001). We found good ADCC reactivity to subtype B and E Envs, less cross-reactivity to subtype A and minimal cross-reactivity to subtype C Envs. Glycosylation-dependent ADCC epitopes comprise a significant proportion of the total Env-specific ADCC response, as evident from the reduction in ADCC to nonglycosylated form of HIV-1 gp140 (P = 0.004). HIV controllers have robust ADCC responses that recognize a broad range of HIV-1 Env. Glycosylation of Env was found to be important for recognition of ADCC epitopes. Identifying conserved ADCC epitopes will assist in designing globally relevant ADCC-based HIV vaccines.

Hepatitis B vaccine responsiveness and clinical outcomes in HIV controllers.

BackgroundHepatitis B virus (HBV) vaccine responsiveness is associated with reduced risk of AIDS or death in HIV-infected individuals. Although HIV controllers (HIC) typically have favorable immunologic and clinical characteristics compared to non-controllers, vaccine responsiveness has not been studied.Methods and FindingsIn the U.S. Military HIV Natural History Study, HBV vaccine response was defined as antibody to hepatitis B surface antigen (anti-HBs) ≥10 IU/L after last vaccination. For determination of vaccine responsiveness, HIC (n = 44) and treatment-naïve non-controllers (n = 476) were not on highly active antiretroviral therapy (HAART) when vaccinated while treated non-controllers (n = 284) received all HBV vaccine doses during viral load (VL)-suppressive HAART. Progression to AIDS or death was also compared for all HIC (n = 143) and non-controllers (n = 1566) with documented anti-HBs regardless of the timing of HBV vaccination. Positive vaccine responses were more common in HIC (65.9%) compared to HAART-naïve non-controllers (36.6%; P<0.001), but similar to non-controllers on HAART (59.9%; P = 0.549). Factors associated with vaccine response for HIC compared to HAART-naïve non-controllers include HIC status (OR 2.65, 95% CI 1.23–5.89; P = 0.014), CD4 count at last vaccination (OR 1.28, 1.15–1.45 for every 100 cells/uL; P<0.001), and number of vaccine doses administered (OR 0.56, 0.35–0.88; P = 0.011). When HIC were compared to non-controllers on HAART, only CD4 count at last vaccination was significant (OR 1.23, 1.1–1.38 for every 100 cells/uL; P<0.001). The rate of AIDS or death per 100 person/years for HIC compared to non-controllers was 0.14 (95% CI 0–0.76) versus 0.98 (95% CI 0.74–1.28) for vaccine responders and 0 (95% CI 0–2.22) versus 4.11 (95% CI 3.38–4.96) for non-responders, respectively.ConclusionsHIC have improved HBV vaccine responsiveness compared to treatment-naïve non-controllers, but similar to those on VL-suppressive HAART. Progression to AIDS or death can be predicted by HBV vaccine responder status for non-controllers, however these events are rarely observed in HIC.

Reduction of death receptor 5 expression and apoptosis of CD4 + T cells from HIV controllers

TNF-related apoptosis ligand (TRAIL) induces apoptosis of HIV-1-exposed CD4 T cells expressing the death receptor 5 (DR5) in vitro and has been associated with reduced CD4 T cell number in viremic HIV-1-infected patients. Alterations of the TRAIL/DR5 apoptotic pathway could be involved in the absence of massive CD4 T cell depletion in HIV-1-infected controllers (HIC). We studied here apoptosis of CD4 T cells from HIV-infected progressors and controllers. Reduced apoptosis of CD4 T cells from HIC was observed upon HIV stimulation. This lower apoptosis correlated with a deficiency of DR5 cell surface expression by CD4 T cells upon HIV-1 stimulation. The significant lower apoptosis observed in CD4 T cells after HIV exposure, associated with lower expression of membrane DR5 could explain the better survival of HIV-specific CD4 T cells from HIV controllers. The levels of DR5 cell surface expression on CD4 T cells could represent a new prognostic marker.

High eomesodermin expression among CD57+ CD8+ T cells identifies a CD8+ T cell subset associated with viral control during chronic human immunodeficiency virus infection.

During HIV infection, increased CD57 expression among CD8(+) T cells has been associated with immune senescence and defective immune responses. Interestingly, CD57-expressing CD8(+) T cells exhibit a dual profile, being simultaneously highly cytotoxic (terminally differentiated effectors) and poorly proliferative (replicative senescent). Recent publications point toward a positive role of CD57-expressing CD8(+) T cell subsets, presumably due to their high cytolytic activity. We further investigated the phenotype of CD57-expressing CD8(+) T cells in healthy donors and during HIV infection combining CD57 expression to Eomesodermin (EOMES), a T box transcription factor which determines, coordinately with T-bet, effector and memory CD8(+) T cell differentiation. We defined in healthy donors two functionally distinct CD57-expressing CD8(+) T cell subsets exhibiting different levels of EOMES expression: EOMES(hi) CD57(+) and EOMES(int) CD57(+) CD8(+) T cells. EOMES(hi) CD57(+) cells exhibited low cytotoxic activity but preserved proliferative capacity and interleukin 7 (IL-7) receptor expression, whereas EOMES(int) CD57(+) cells exhibited obvious cytotoxic functions and a more terminally differentiated phenotype. We next performed a similar analysis in different contexts of HIV infection: primary infected patients, long-term viremic patients, aviremic patients treated with antiretroviral therapy, and HIV controllers; we demonstrated a higher percentage of CD57-expressing cells in all HIV-infected patients regardless of virological status. When heterogeneity in EOMES expression among CD57 cells was taken into account, we detected significantly higher proportions of EOMES(hi) CD57(+) cells among HIV-specific and nonspecific CD8(+) T cells from HIV controllers than in aviremic antiretroviral-treated patients and viremic patients. Importantly, such a peculiar non-terminally differentiated EOMES(hi) CD57(+) phenotypic profile was associated with viral control. Importance: This study demonstrates that functional heterogeneity exists among CD57-expressing CD8 T cells, which include both terminally differentiated, highly cytotoxic EOMES(int) CD57(+) CD8(+) T cells and less differentiated EOMES(hi) CD57(+) CD8 T cells, which do not exhibit immediate cytotoxic functions but present high proliferative capacity. Interestingly, HIV controllers present a high proportion of EOMES(hi) CD57 cells among CD57-expressing HIV-specific CD8 T cells compared to both long-term viremic and aviremic antiretroviral therapy (ART)-treated patients, suggesting a beneficial role for this cell subset in viral control.

Spontaneous control of HIV replication, but not HAART-induced viral suppression, is associated with lower activation of immune cells.

HIV replication control is important to reduce AIDS progression. We determined frequency and activation status of immune cells in spontaneous HIV controllers vs. individuals with highly active antiretroviral therapy (HAART)-controlled viral load. HIV controllers exhibited significantly higher frequency of CD4 T cells and myeloid dendritic cells compared with HAART-controlled viral load. Additionally, HIV controllers have a significantly lower percentage of cells expressing activation markers on CD4 and CD8 T cells, myeloid dendritic cells, and natural killer cells. These findings suggest that during HIV infection, conservation of a normal frequency and physiological range of immune activation is associated with spontaneous, but not HAART-induced, control of viral replication.

Impaired Nef function is associated with early control of HIV-1 viremia.

Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P<0.01). HLA class I downregulation activity correlated inversely with days postinfection (Spearman's R=-0.85, P=0.004) and positively with baseline plasma viral load (Spearman's R=0.81, P=0.007) in acute controllers but not in acute progressors. Nef polymorphisms associated with functional changes over time were identified in follow-up samples from six controllers. For one such individual, mutational analyses indicated that four polymorphisms selected by HLA-A*31 and B*37 acted in combination to reduce Nef steady-state protein levels and HLA class I downregulation activity. Our results demonstrate that relative control of initial HIV-1 viremia is associated with Nef clones that display reduced function, which in turn may influence the course of HIV-1 infection. Transmission of impaired Nef sequences likely contributed in part to this observation; however, accumulation of HLA-associated polymorphisms in Nef that impair function also suggests that CD8+ T-cell pressures play a role in this phenomenon. Rare individuals can spontaneously control HIV-1 viremia in the absence of antiretroviral treatment. Understanding the host and viral factors that contribute to the controller phenotype may identify new strategies to design effective vaccines or therapeutics. The HIV-1 Nef protein enhances viral pathogenesis through multiple mechanisms. We examined the function of plasma HIV-1 RNA-derived Nef clones isolated from 10 recently infected individuals who subsequently controlled HIV viremia compared to the function of those from 50 individuals who failed to control viremia. Our results demonstrate that early Nef clones from HIV controllers displayed lower HLA class I and CD4 downregulation activity, as well as a reduced ability to enhance virion infectivity. The accumulation of HLA-associated polymorphisms in Nef during the first year postinfection was associated with impaired protein function in some controllers. This report highlights the potential for host immune responses to modulate HIV pathogenicity and disease outcome by targeting cytotoxic T lymphocyte (CTL) epitopes in Nef.

Genetic Variants of Fcγ (GM Allotypes) and the Fc-Mediated Effector Functions in HIV-1 Controllers

Genome-wide association studies (GWAS) have concluded that HLA class I alleles are the primary determinants of the outcome of HIV-1 infection. However, in a comprehensive analysis of the role of humoral immunity in HIV-1 control, Lai et al. (1) conclude that the “presence or absence of protective HLA alleles is not associated with strikingly divergent antibody responses” among HIV-1 controllers and that “understanding the specific features of IgGs with potentiated effector function may be critical to vaccine and therapeutic antibody development.” To explain the observed correlation between HIV-specific IgG1 antibodies and the total IgG1, the authors suggest that GM allotypes, hereditary antigenic variants of the immunoglobulin chains, may have influenced the baseline IgG subclass concentrations. I would like to add that GM allotypes, expressed primarily in the Fc region, may have contributed to all Fc-mediated effector functions listed by the authors: antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent complement-dependent cytotoxicity (ADCDC).

Functional characterization of two scFv-Fc antibodies from an HIV controller selected on soluble HIV-1 Env complexes: a neutralizing V3- and a trimer-specific gp41 antibody.

HIV neutralizing antibodies (nAbs) represent an important tool in view of prophylactic and therapeutic applications for HIV-1 infection. Patients chronically infected by HIV-1 represent a valuable source for nAbs. HIV controllers, including long-term non-progressors (LTNP) and elite controllers (EC), represent an interesting subgroup in this regard, as here nAbs can develop over time in a rather healthy immune system and in the absence of any therapeutic selection pressure. In this study, we characterized two particular antibodies that were selected as scFv antibody fragments from a phage immune library generated from an LTNP with HIV neutralizing antibodies in his plasma. The phage library was screened on recombinant soluble gp140 envelope (Env) proteins. Sequencing the selected peptide inserts revealed two major classes of antibody sequences. Binding analysis of the corresponding scFv-Fc derivatives to various trimeric and monomeric Env constructs as well as to peptide arrays showed that one class, represented by monoclonal antibody (mAb) A2, specifically recognizes an epitope localized in the pocket binding domain of the C heptad repeat (CHR) in the ectodomain of gp41, but only in the trimeric context. Thus, this antibody represents an interesting tool for trimer identification. MAb A7, representing the second class, binds to structural elements of the third variable loop V3 and neutralizes tier 1 and tier 2 HIV-1 isolates of different subtypes with matching critical amino acids in the linear epitope sequence. In conclusion, HIV controllers are a valuable source for the selection of functionally interesting antibodies that can be selected on soluble gp140 proteins with properties from the native envelope spike.

The potential role of HIV-specific CD38-/HLA-DR+ CD8+ T cells in viral suppressive activity and cytotoxicity in HIV controllers

In HIV-1 infection, some rare patients called HIV controllers (HICs) are capable to spontaneously control viral replication in vivo. Interestingly, HICs exhibit higher frequency of a particular activated phenotype CD38-HLA-DR+ HIV-specific CD8+ T cells. The aim of this study was to characterize this profile and evaluate its role in HICs.