Marcus Altfeld

Publications of Marcus Altfeld

• Frequent and Strong Antibody-Mediated Natural Killer Cell Activation to HIV-1 Env in Individuals with Chronic HIV-1 Infection.

  Authors: Christina F Thobakgale, Lena Fadda, Kimberly Lane, Ildiko Toth, Florencia Pereyra, Suzane Bazner, Thumbi Ndung'u, Bruce D Walker, Eric Rosenberg, Galit Alter, Mary Carrington, Todd Allen, Marcus Altfeld

  Journal of virology. 04/2012;

  Natural killers (NK) cells play a critical role in the control of HIV-1 infection, and NK cells that respond to HIV-1 peptides have been recently described. However, the mechanisms by which NK cellsNatural killers (NK) cells play a critical role in the control of HIV-1 infection, and NK cells that respond to HIV-1 peptides have been recently described. However, the mechanisms by which NK cells recognize HIV-1 antigen are not fully understood. We investigated NK cell activation to HIV-1 peptides during early and chronic HIV-1 clade B infection using a whole blood assay and multiparameter flow cytometry. Antibody mediated NK cell activation to HIV-1 peptides was not detected in HIV-1 uninfected individuals. In contrast, 79% of individuals with chronic infection and 22% of individuals with early infection had detectable IFN-γ+ NK cell responses to HIV-1 antigen (P<0.00001). IFN-γ and TNF-α-producing NK cells most frequently targeted Env-gp120 (median 4%, range 0-31% of all NK cells). NK cells rarely targeted other HIV-1 proteins such as Gag, Pol and Nef. Antibody-mediated NK cell responses to peptides mapped predominantly to Env protein, required the presence of plasma or plasma IgG, and resulted in lower CD16 expression on NK cells, suggesting an antibody-mediated activation of NK cells. Further studies are needed to assess the consequences of these antibody-mediated NK cell responses for HIV-1 disease progression and vaccine-induced protection from infection.

• Preserved function of regulatory T cells in chronic HIV-1 infection despite decreased numbers in blood and tissue.

  Authors: Mathieu Angin, Douglas S Kwon, Hendrik Streeck, Fang Wen, Melanie King, Ashley Rezai, Kenneth Law, Tomoyuki C Hongo, Augustine Pyo, Alicja Piechocka-Trocha, Ildiko Toth, Florencia Pereyra, Musie Ghebremichael, Scott J Rodig, Danny A Milner, James M Richter, Marcus Altfeld, Daniel E Kaufmann, Bruce D Walker, Marylyn M Addo

  The Journal of infectious diseases. 03/2012;

  Regulatory T cells (Tregs) are potent immune modulators, but their role in HIV-1 pathogenesis remains poorly understood. We performed a detailed analysis of the frequency and function of Tregs in aRegulatory T cells (Tregs) are potent immune modulators, but their role in 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" had similar Treg numbers and frequencies as uninfected individuals, absolute numbers of Tregs declined in blood and gut-associated lymphoid tissue (GALT) in 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.

• Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection.

  Authors: Matthew R Henn, Christian L Boutwell, Patrick Charlebois, Niall J Lennon, Karen A Power, Alexander R Macalalad, Aaron M Berlin, Christine M Malboeuf, Elizabeth M Ryan, Sante Gnerre [......] Ken H Mayer, Eric Rosenberg, Florencia Pereyra, Joshua Z Levin, Sarah K Young, Heiko Jessen, Marcus Altfeld, Bruce W Birren, Bruce D Walker, Todd M Allen

  PLoS pathogens. 03/2012; 8(3):e1002529.

  Deep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolvingDeep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more highly constrained regions of the virus in order to ensure the maintenance of immunodominant CD8 responses and the sustained decline of early viremia.

• Preservation HIV-1-specific IFNγ+ CD4+ T cell responses in breakthrough infections following exposure to Tenofovir Gel in the CAPRISA 004 microbicide trial.

  Authors: Marianne W Mureithi, Danielle Poole, Vivek Naranbhai, Shabashini Reddy, Nompumelelo P Mkhwanazi, Sengeziwe Sibeko, Lise Werner, Quarraisha Abdool Karim, Salim Abdool Karim, Thumbi Ndungʼu, Marcus Altfeld

  Journal of acquired immune deficiency syndromes (1999). 02/2012;

  ABSTRACT: The CAPRISA004 trial demonstrated reduction of sexual HIV-1 acquisition in women using a vaginal microbicide containing tenofovir. A better understanding of the consequences ofABSTRACT: 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.

• Preferential CTL targeting of Gag is associated with relative viral control in long-term surviving HIV-1 infected former plasma donors from China.

  Authors: Mingming Jia, Kunxue Hong, Jianping Chen, Yuhua Ruan, Zhe Wang, Bing Su, Guoliang Ren, Xiaoqing Zhang, Zhen Liu, Quanbi Zhao, Dan Li, Hong Peng, Marcus Altfeld, Bruce D Walker, Xu G Yu, Yiming Shao

  Cell research. 01/2012;

  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 ofIt 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.Cell Research advance online publication 31 January 2012; doi:10.1038/cr.2012.19.

• Regulatory T cell frequencies do not correlate with breadth or magnitude of HIV-1-specific T cell responses.

  Authors: Mathieu Angin, Hendrik Streeck, Fang Wen, Melanie King, Florencia Pereyra, Marcus Altfeld, Bruce Walker, Marylyn Martina Addo

  AIDS research and human retroviruses. 01/2012;

  Regulatory T cells (Tregs) are potent immunoregulatory cells capable of suppressing antigen-specific immune responses against pathogens including HIV-1. We hypothesized that regulatory T cells impactRegulatory T cells (Tregs) are potent immunoregulatory cells capable of suppressing antigen-specific immune responses against pathogens including HIV-1. We hypothesized that regulatory T cells impact breadth and magnitude of HIV-1-specific T cell responses in HIV-1 infected individuals. To assess the relationship between Tregs and HIV-1-specific T cell immunity we performed a detailed analysis of regulatory T cells and HIV-1 epitope-specific T cell responses in peripheral blood in untreated HIV-1-positive individuals including elite controllers, chronic progressors and individuals with acute HIV-1 infection. Our data show that Treg numbers and frequencies do not correlate with breadth and magnitude of HIV-1-specific T cell responses measured in PBMC of untreated HIV-1 positive individuals as measured by IFN-γ Elispot.

• Factors predicting discordant virological and immunological responses to antiretroviral therapy in HIV-1 clade C infected Zulu/Xhosa in South Africa.

  Authors: Boris Julg, Danielle Poole, Musie Ghebremichael, Carmen Castilla, Marcus Altfeld, Henry Sunpath, Richard A Murphy, Bruce D Walker

  PloS one. 01/2012; 7(2):e31161.

  Factors predicting suboptimal CD4 cell recovery have been studied in HIV clade-B infected US and European populations. It is, however, uncertain to what extent these results are applicable to HIVFactors predicting suboptimal CD4 cell recovery have been studied in HIV clade-B infected US and European populations. It is, however, uncertain to what extent these results are applicable to HIV clade-C infected African populations. Multivariate analysis using logistic regression and longitudinal analyses using mixed models were employed to assess the impact of age, gender, baseline CD4 cell count, hemoglobin, body mass index (BMI), tuberculosis and other opportunistic co-infections, and frequencies of regimen change on CD4 cell recovery at 12 and 30 months and on overtime change in CD4 cells among 442 virologically suppressed South Africans. Despite adequate virological response 37% (95% CI:32%-42%) and 83% (95% CI:79%-86%) of patients on antiretroviral therapy failed to restore CD4 cell counts ≥ 200 cells/mm(3) after 12 and ≥ 500 cells/mm(3) after 30 months, respectively, in this South African cohort. Critical risk factors for inadequate recovery were older age (p = 0.001) and nadir CD4 cell count at ART initiation (p<0.0001), while concurrent TB co-infection, BMI, baseline hemoglobin, gender and antiretroviral regimen were not significant risk factors. These data suggest that greater efforts are needed to identify and treat HAART-eligible patients prior to severe CD4 cell decline or achievement of advanced age.

• Differential regulation of toll-like receptor pathways in acute and chronic HIV-1 infection.

  Authors: J Judy Chang, Aurore Lacas, Robert J Lindsay, Erin H Doyle, Karen L Axten, Florencia Pereyra, Eric S Rosenberg, Bruce D Walker, Todd M Allen, Marcus Altfeld

  AIDS (London, England). 12/2011; 26(5):533-41.

  : The objective of this study was to determine changes in toll-like receptor (TLR) responses of monocytes, myeloid dendritic cells and plasmacytoid dendritic cells during primary and chronic HIV-1: The objective of this study was to determine changes in toll-like receptor (TLR) responses of monocytes, myeloid dendritic cells and plasmacytoid dendritic cells during primary and chronic HIV-1 infection. 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. : Using intracellular flow cytometry, cytokine production by cryopreserved peripheral blood mononuclear cells from healthy controls and HIV-1-infected individuals were examined after TLR stimulation. : 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 myeloid dendritic cell responses to TLR8 stimulation were associated with HIV-1 viral load and CD4 T-cell count, whereas plasmacytoid dendritic cell responses to TLR7 stimulation were not. Responses to TLR2 stimulation were not affected by HIV-1 infection, whereas responses to TLR9 stimulation were universally decreased in all HIV-1-infected individuals examined regardless of treatment or clinical parameters. : 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.

• Induction of strong HIV-1-specific CD4+ T-cell responses using an HIV-1 gp120/NefTat vaccine adjuvanted with AS02A in antiretroviral-treated HIV-1-infected individuals.

  Authors: Mathias Lichterfeld, Rajesh T Gandhi, Rachel P Simmons, Theresa Flynn, Amy Sbrolla, Xu G Yu, Nesli Basgoz, Stanley Mui, Katie Williams, Hendrik Streeck [......] Gilbert Roy, Michel Janssens, Louise Pedneault, Pierre Vandepapelière, Marguerite Koutsoukos, Marie-Ange Demoitié, Patricia Bourguignon, Lisa McNally, Gerald Voss, Marcus Altfeld

  Journal of acquired immune deficiency syndromes (1999). 09/2011; 59(1):1-9.

  Induction of HIV-1-specific CD4(+) T-cell responses by therapeutic vaccination represents an attractive intervention to potentially increase immune control of HIV-1. We performed a double-blinded,Induction of HIV-1-specific CD4(+) T-cell responses by therapeutic vaccination represents an attractive intervention to potentially increase immune control of HIV-1. We performed a double-blinded, randomized, placebo-controlled clinical trial to determine the safety and immunogenicity of GlaxoSmithKline Biologicals' HIV-1 gp120/NefTat subunit protein vaccine formulated with the AS02(A) Adjuvant System in subjects with well-controlled chronic HIV-1 infection on highly active antiretroviral therapy. Ten individuals received the vaccine; whereas adjuvant alone or placebo was given to 5 subjects each. Immunogenicity was monitored by intracellular cytokine flow cytometry and carboxyfluorescein succinimidyl ester-based proliferation assays. The vaccine was well tolerated with no related serious adverse events. Vaccine recipients had significantly stronger gp120-specific CD4(+) T-cell responses which persisted until week 48 and greater gp120-specific CD4(+) T-cell proliferation activity as compared with controls. In the vaccine group, the number of participants who demonstrated positive responses for both gp120-specific CD4(+) T-cell interleukin-2 production and gp120-specific CD8(+) T-cell proliferation were significantly higher at week 6. The gp120/NefTat/AS02(A) vaccine induced strong gp120-specific CD4(+) T-cell responses and a higher number of vaccinees developed both HIV-1-specific CD4(+) T-cell responses and CD8(+) T-cell proliferation. The induction of these responses may be important in enhancing immune-mediated viral control.

• Limited immunogenicity of HIV CD8+ T-cell epitopes in acute Clade C virus infection.

  Authors: Mopo Radebe, Kriebashnie Nair, Fundisiwe Chonco, Karen Bishop, Jaclyn K Wright, Mary van der Stok, Ingrid V Bassett, Zenele Mncube, Marcus Altfeld, Bruce D Walker, Thumbi Ndung'u

  The Journal of infectious diseases. 09/2011; 204(5):768-76.

  Human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) responses contribute to the decline in acute peak viremia following infection. However, data on the relative immunogenicity of CD8(+)Human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) responses contribute to the decline in acute peak viremia following infection. However, data on the relative immunogenicity of CD8(+) T-cell epitopes during and after acute viremia are lacking. We characterized CD8(+) T-cell responses in 20 acutely infected, antiretroviral-naive individuals with HIV-1 subtype C infection using the interferon-γ enzyme-linked immunosorbent spot assay. Eleven of these had not fully seroconverted at the time of analysis. Viruses from plasma were sequenced within defined cytotoxic T-lymphocyte (CTL) cell epitopes for selected subjects. At approximately 28 days after estimated initial infection, CD8(+) T-cell responses were directed against an average of 3 of the 410 peptides tested (range, 0-6); 2 individuals had no detectable responses at this time. At 18 weeks, the average number of peptides targeted had increased to 5 (range 0-11). Of the 56 optimal Gag CTL epitopes sequenced, 31 were wild-type in the infecting viruses, but only 11 of 31 elicited measurable CD8(+) T-cell responses. These data demonstrate that the majority of CD8(+) responses are not elicited during acute HIV infection despite the presence of the cognate epitope in the infecting strain. There is a need to define factors that influence lack of induction of effective immune responses and the parameters that dictate immunodominance in acute infection.

• HIV-1 adaptation to NK-cell-mediated immune pressure.

  Authors: Galit Alter, David Heckerman, Arne Schneidewind, Lena Fadda, Carl M Kadie, Jonathan M Carlson, Cesar Oniangue-Ndza, Maureen Martin, Bin Li, Salim I Khakoo, Mary Carrington, Todd M Allen, Marcus Altfeld

  Nature. 08/2011; 476(7358):96-100.

  Natural killer (NK) cells have an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors. Epidemiological andNatural killer (NK) cells have an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors. Epidemiological and functional studies have recently suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory killer immunoglobulin-like receptors (KIRs). However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. Here we describe KIR-associated amino-acid polymorphisms in the HIV-1 sequence of chronically infected individuals, on a population level. We show that these KIR-associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected CD4(+) T cells, and reduce the antiviral activity of KIR-positive NK cells. These data demonstrate that KIR-positive NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK-cell-mediated immune pressure by selecting for sequence polymorphisms, as was previously described for virus-specific T cells and neutralizing antibodies. NK cells might therefore have a previously underappreciated role in contributing to viral evolution.

• Coordinate linkage of HIV evolution reveals regions of immunological vulnerability.

  Authors: Vincent Dahirel, Karthik Shekhar, Florencia Pereyra, Toshiyuki Miura, Mikita Artyomov, Shiv Talsania, Todd M Allen, Marcus Altfeld, Mary Carrington, Darrell J Irvine, Bruce D Walker, Arup K Chakraborty

  Proceedings of the National Academy of Sciences of the United States of America. 06/2011; 108(28):11530-5.

  Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determineCellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated ("HIV sectors"). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses.

• Early viral replication in lymph nodes provides HIV with a means by which to escape NK-cell-mediated control.

  Authors: Rutger Luteijn, Gaia Sciaranghella, Jan van Lunzen, Anne Nolting, Anne-Sophie Dugast, Musie S Ghebremichael, Marcus Altfeld, Galit Alter

  European journal of immunology. 06/2011; 41(9):2729-40.

  Acute HIV infection is marked by dramatic viral replication associated with preferential replication within secondary lymphoid tissues, such as lymph nodes (LNs), that is rapidly but incompletelyAcute HIV infection is marked by dramatic viral replication associated with preferential replication within secondary lymphoid tissues, such as lymph nodes (LNs), that is rapidly but incompletely contained to a viral setpoint. Accumulating evidence supports a role for natural killer (NK) cells in the early control of HIV infection; however, little is known about the location of their antiviral control. Given that HIV replicates profusely in LNs during early infection, we sought to define whether changes occurred in the NK cell infiltrate within these sites during the first year of HIV infection. Surprisingly, NK cell numbers and distribution were unaltered during early HIV infection. LN NK cells expressed decreased inhibitory receptors, were more highly activated, and expressed elevated TRAIL, potentially conferring a superior capacity for NK cells to become activated and control infection. Most noticeably, KIR(+) NK cells were rarely detected in the LN during HIV infection, associated with diminished migratory capacity in the setting of reduced expression of CX3CR1 and CXCR1. Thus, incomplete control of HIV viral replication during early disease may be due to the inefficient recruitment of KIR(+) NK cells to this vulnerable site, providing HIV a niche where it can replicate unabated by early NK-cell-mediated innate pressure.

• Common HIV-1 peptide variants mediate differential binding of KIR3DL1 to HLA-Bw4 molecules.

  Authors: Lena Fadda, Geraldine M O'Connor, Swati Kumar, Alicja Piechocka-Trocha, Clair M Gardiner, Mary Carrington, Daniel W McVicar, Marcus Altfeld

  Journal of virology. 04/2011; 85(12):5970-4.

  Epidemiological studies have shown the protective effect of KIR3DL1/HLA-Bw4 genotypes in human immunodeficiency virus type 1 (HIV-1) infection; however, the functional correlates for the protectiveEpidemiological studies have shown the protective effect of KIR3DL1/HLA-Bw4 genotypes in human immunodeficiency virus type 1 (HIV-1) infection; however, the functional correlates for the protective effect remain unknown. We investigated whether human leukocyte antigen (HLA)-Bw4-presented HIV-1 peptides could affect the interaction between the inhibitory natural killer (NK) cell receptor KIR3DL1 and its ligand HLA-Bw4. Distinct HIV-1 epitopes differentially modulated the binding of KIR3DL1 to HLA-Bw4. Furthermore, cytotoxic T lymphocyte (CTL) escape mutations within the immunodominant HLA-B57 (Bw4)-restricted Gag epitope TSTLQEQIGW abrogated KIR3DL1 binding to HLA-B57, suggesting that sensing of CTL escape variants by NK cells can contribute to the protective effect of the KIR3DL1/HLA-Bw4 compound genotype.

• Correction: Characteristics of the Earliest Cross-Neutralizing Antibody Response to HIV-1.

  Authors: Iliyana Mikell, D Noah Sather, Spyros A Kalams, Marcus Altfeld, Galit Alter, Leonidas Stamatatos

  PLoS pathogens. 03/2011; 7(3).

  [This corrects the article on p. e1001251 in vol. 7.].

• The STEP study provides a hint that vaccine induction of the right CD8+ T cell responses can facilitate immune control of HIV.

  Authors: Marcus Altfeld, Philip J Goulder

  The Journal of infectious diseases. 03/2011; 203(6):753-5.

• Mutiny or scrutiny: NK cell modulation of DC function in HIV-1 infection.

  Authors: Galit Alter, Marcus Altfeld

  Trends in immunology. 03/2011; 32(5):219-24.

  Accumulating data suggest that natural killer (NK) cells are involved not only in the innate antiviral response following infection, but also in shaping the quality of the adaptive immune response byAccumulating data suggest that natural killer (NK) cells are involved not only in the innate antiviral response following infection, but also in shaping the quality of the adaptive immune response by modulating the functional properties of myeloid dendritic cells (DC) during the acute immune response to infection. In this role, NK cells ensure that only fully mature, immunogenic DCs gain access to inductive sites, where they might prime effective antiviral adaptive immune responses. However, increasing evidence now suggests that several aspects of this cross-talk between NK cells and DCs are compromised during HIV infection, potentially contributing to immune dysfunction.

• DCs and NK cells: critical effectors in the immune response to HIV-1.

  Authors: Marcus Altfeld, Lena Fadda, Davor Frleta, Nina Bhardwaj

  Nature reviews. Immunology. 03/2011; 11(3):176-86.

  Dendritic cells (DCs) and natural killer (NK) cells have central roles in antiviral immunity by shaping the quality of the adaptive immune response to viruses and by mediating direct antiviralDendritic cells (DCs) and natural killer (NK) cells have central roles in antiviral immunity by shaping the quality of the adaptive immune response to viruses and by mediating direct antiviral activity. HIV-1 infection is characterized by a severe dysregulation of the antiviral immune response that starts during early infection. This Review describes recent insights into how HIV-1 infection affects DC and NK cell function, and the roles of these innate immune cells in HIV-1 pathogenesis. The importance of understanding DC and NK cell crosstalk during HIV infection for the development of effective antiviral strategies is also discussed.

• Epithelial adhesion molecules can inhibit HIV-1-specific CD8⁺ T-cell functions.

  Authors: Hendrik Streeck, Douglas S Kwon, Augustine Pyo, Michael Flanders, Mathieu F Chevalier, Kenneth Law, Boris Jülg, Kasper Trocha, Jonathan S Jolin, Melis N Anahtar [......] Ildiko Toth, Zabrina Brumme, J Judy Chang, Tyler Caron, Scott J Rodig, Danny A Milner, Alicja Piechoka-Trocha, Daniel E Kaufmann, Bruce D Walker, Marcus Altfeld

  Blood. 03/2011; 117(19):5112-22.

  Under persistent antigenic stimulation, virus-specific CD8⁺ T cells become increasingly dysfunctional and up-regulate several inhibitory molecules such as killer lectin-like receptor G1 (KLRG1).Under persistent antigenic stimulation, virus-specific CD8⁺ T cells become increasingly dysfunctional and up-regulate several inhibitory molecules such as killer lectin-like receptor G1 (KLRG1). Here, we demonstrate that HIV-1 antigen-specific T cells from subjects with chronic-progressive HIV-1 infection have significantly elevated KLRG1 expression (P < .001); show abnormal distribution of E-cadherin, the natural ligand of KLRG1, in the intestinal mucosa; and have elevated levels of systemic soluble E-cadherin (sE-cadherin) that significantly correlate with HIV-1 viral load (R = 0.7, P = .004). We furthermore demonstrate that in the presence of sE-cadherin, KLRG1(hi) HIV-1-specific CD8⁺ T cells are impaired in their ability to respond by cytokine secretion on antigenic stimulation (P = .002) and to inhibit viral replication (P = .03) in vitro. Thus, these data suggest a critical mechanism by which the disruption of the intestinal epithelium associated with HIV-1 leads to increased systemic levels of sE-cadherin, which inhibits the effector functions of KLRG1(hi)-expressing HIV-1-specific CD8⁺ T cells systemically.

• KIR polymorphisms modulate peptide-dependent binding to an MHC class I ligand with a Bw6 motif.

  Authors: Arnaud D Colantonio, Benjamin N Bimber, William J Neidermyer, R Keith Reeves, Galit Alter, Marcus Altfeld, R Paul Johnson, Mary Carrington, David H O'Connor, David T Evans

  PLoS pathogens. 03/2011; 7(3):e1001316.

  Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogensMolecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05(+) macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets.