AIDS/HIV
Abstract
Type I IFN (IFN-I) production by plasmacytoid DCs (pDCs) occurs during acute HIV-1 infection in response to TLR7 stimulation, but the role of pDC-derived IFN-I in controlling or promoting HIV-1 infection is ambiguous. We report here a sex-biased interferogenic phenotype for a frequent single-nucleotide polymorphism of human TLR7, rs179008, displaying an impact on key parameters of acute HIV-1 infection. We show allele rs179008 T to determine lower TLR7 protein abundance in cells from women, specifically — likely by diminishing TLR7 mRNA translation efficiency through codon usage. The hypomorphic TLR7 phenotype is mirrored by decreased TLR7-driven IFN-I production by female pDCs. Among women from the French ANRS PRIMO cohort of acute HIV-1 patients, carriage of allele rs179008 T associated with lower viremia, cell-associated HIV-1 DNA, and CXCL10 (IP-10) plasma concentrations. RNA viral load was decreased by 0.85 log10 (95% CI, −1.51 to −0.18) among T/T homozygotes, who also exhibited a lower frequency of acute symptoms. TLR7 emerges as an important control locus for acute HIV-1 viremia, and the clinical phenotype for allele rs179008 T, carried by 30%–50% of European women, supports a beneficial effect of toning down TLR7-driven IFN-I production by pDCs during acute HIV-1 infection.
Authors
Pascal Azar, José Enrique Mejía, Claire Cenac, Arnoo Shaiykova, Ali Youness, Sophie Laffont, Asma Essat, Jacques Izopet, Caroline Passaes, Michaela Müller-Trutwin, Pierre Delobel, Laurence Meyer, Jean-Charles Guéry
Abstract
The RV144 HIV-1 vaccine trial results showed moderate reduction in viral infections among vaccinees as well as induction of antibody-dependent cellular cytotoxicity and vaccine-specific IgG and IgG3 responses directed at variable loop regions 1 and 2 of the HIV envelope protein. However, with the recent failure of the HVTN 702 clinical trial, comprehensive profiling of humoral immune responses may provide insight for these disappointing results. One of the changes included in the HVTN 702 study was the addition of a late boost, aimed at augmenting peak immunity and durability. The companion vaccine trial RV305 was designed to permit the evaluation of the immunologic impact of late boosting with either the boosting protein antigen alone, the canarypox viral vector ALVAC alone, or a combination of both. Although previous data showed elevated levels of IgG antibodies in both boosting arms, regardless of ALVAC-HIV vector incorporation, the effect on shaping antibody effector function remains unclear. Thus, here we analyzed the antibody and functional profile induced by RV305 boosting regimens and found that although IgG1 levels increased in both arms that included protein boosting, IgG3 levels were reduced compared with the original RV144 vaccine strategy. Most functional responses increased upon protein boosting, regardless of the viral vector-priming agent incorporation. These data suggest that the addition of a late protein boost alone is sufficient to increase functionally potent vaccine-specific antibodies previously associated with reduced risk of infection with HIV.
Authors
Stephanie Fischinger, Sally Shin, Carolyn M. Boudreau, Margaret Ackerman, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayaphan, Jerome H. Kim, Merlin L. Robb, Nelson L. Michael, Robert J. O’Connell, Sandhya Vasan, Hendrik Streeck, Galit Alter
Abstract
HIV-1 remains incurable due to the persistence of proviral DNA integrated into host cells, providing a reservoir for viral rebound upon cessation of antiretroviral therapy (ART). There is evidence for sex-based differences in HIV-1 immune responses and pathogenesis, but little is known about differences in HIV-1 persistence. To address this knowledge gap, we quantified persistent HIV-1 in 90 adults on suppressive ART in Rakai, Uganda (57 females). Total HIV-1 DNA was quantified by PCR and replication competent provirus by the quantitative viral outgrowth assay (QVOA). Immune phenotyping of T cell subsets and plasma biomarkers was also performed. We found that while both sexes had similar levels of total HIV DNA, females had significantly fewer cells harboring replication-competent virus, as measured by viral outgrowth in the QVOA. Predictors of viral outgrowth differed by sex; notably, frequency of PD-1+ CD4 T cells correlated with reservoir size in males, but not females. The sex-based differences in HIV-1 persistence observed in this cohort warrant additional research, especially given the widespread use of the QVOA to assess reservoir size and current explorations of PD-1 agonists in cure protocols. Efforts should be made to power future cure studies to assess outcomes in both males and females.
Authors
Jessica L. Prodger, Adam A. Capoferri, Katherine Yu, Jun Lai, Steven J. Reynolds, Jingo Kasule, Taddeo Kityamuweesi, Paul Buule, David Serwadda, Kyungyoon J. Kwon, Katherine Schlusser, Craig Martens, Eileen P. Scully, Yun-Hee Choi, Andrew D. Redd, Thomas C. Quinn
Abstract
Depletion of CD4+ T cells during HIV-1 infection is mostly mediated by inflammatory cells via indirect but not clearly defined mechanisms. In this report we employed the single-cell RNA sequencing (scRNA-seq) technology to study HIV-induced transcriptomic change in innate immune cells in lymphoid organs. We performed scRNA-seq on hCD45+hCD3-hCD19- human leukocytes isolated from spleens of humanized NOD/Rag2-/-/γc-/- (NRG) mice transplanted with human CD34+ hematopoietic stem-progenitor cells (NRG-hu HSC mice). We identified major populations of innate immune cells including plasmacytoid dendritic cells (pDC), myeloid dendritic cells (mDC), macrophage, nature killer (NK) cells and innate lymphoid cells (ILC). HIV-1 infection significantly upregulated genes involved in type-I interferon inflammatory pathways in each of the innate immune subsets. Interestingly, we found that the TNF-related apoptosis-inducing ligand (TRAIL) was upregulated in the innate immune populations including pDC, mDC, macrophage, NK and ILC. We further demonstrated that blockade of TRAIL signaling pathway in NRG-hu HSC mice prevented HIV-1 induced CD4+ T cell depletion in vivo. In summary, we characterized HIV-induced transcriptomic changes of innate immune cells in the spleen at single-cell levels, identified the TRAIL+ innate immune cells and defined an important role of TRAIL signaling pathway in HIV-1 induced CD4+ T cell depletion in vivo.
Authors
Liang Cheng, Haisheng Yu, John A. Wrobel, Guangming Li, Peng Liu, Zhiyuan Hu, Xiao-Ning Xu, Lishan Su
Abstract
HIV infection is associated with an increase in the proportion of activated CD8 memory T cells (Tmem) that express CX3CR1, but how these cells are generated and maintained in vivo is unclear. We demonstrate that increased CX3CR1 expression on CD8 Tmem in people living with HIV (PLWH) is dependent on coinfection with human cytomegalovirus (CMV), and CX3CR1+ CD8 Tmem are enriched for a putatively immunosenescent CD57+CD28– phenotype. The cytokine IL-15 promotes the phenotype, survival, and proliferation of CX3CR1+CD57+ CD8 Tmem in vitro, whereas TCR stimulation leads to their death. IL-15-driven survival is dependent on STAT5 and Bcl-2 activity, and IL-15-induced proliferation requires STAT5 and mTORC1. Thus, we identify mechanistic pathways that could explain how “inflammescent” CX3CR1+CD57+ CD8 Tmem dominate the overall memory T cell pool in CMV-seropositive PLWH and that support reevaluation of immune senescence as a nonproliferative dead-end.
Authors
Stephen R. Morris, Bonnie Chen, Joseph C. Mudd, Soumya Panigrahi, Carey L. Shive, Scott F. Sieg, Cheryl M. Cameron, David A. Zidar, Nicholas T. Funderburg, Souheil-Antoine Younes, Benigno Rodriguez, Sara Gianella, Michael M. Lederman, Michael L. Freeman
Abstract
Plasma viral load (VL) and CD4+ T-cell count are widely used as biomarkers of HIV-1 replication, pathogenesis, and response to antiretroviral therapy (ART). However, the clinical potential of cell-associated (CA) HIV-1 molecular markers is much less understood. Here, we measured CA HIV-1 RNA and DNA in HIV-infected individuals treated with temporary ART initiated during primary HIV-1 infection. We demonstrate significant predictive value of CA RNA for: (a) the virological and immunological response to early ART, (b) the magnitude and time to viral rebound after discontinuation of early ART, and (c) the disease progression in the absence of treatment. Remarkably, when adjusted for CA RNA, plasma VL no longer appeared as an independent predictor of any clinical endpoint in this cohort. The potential of CA RNA as an HIV-1 clinical marker, in particular as a predictive biomarker of virological control after stopping ART, should be explored in the context of HIV-1 curative interventions.
Authors
Alexander O. Pasternak, Marlous L. Grijsen, Ferdinand W. Wit, Margreet Bakker, Suzanne Jurriaans, Jan M. Prins, Ben Berkhout
Abstract
BACKGROUND. The relative stabilities of the intact and defective HIV genomes over time during effective antiretroviral therapy (ART) have not been fully characterized. METHODS. We used the intact proviral DNA assay (IPDA) to estimate the rate of change of intact and defective proviruses in HIV-infected adults on ART over several years. We used linear spline models with a knot at seven years; these included a random intercept and slope up to the knot. We also estimated the influence of covariates on starting levels and rates of change. RESULTS. We studied 81 individuals for a median of 7.3 (IQR 5.9–9.6) years. In a model allowing for a change in the rate of decline, we found evidence for a more rapid rate of decline in intact genomes from initial suppression through seven years (15.7% per year decline; CI –22.8%, –8.0%) followed by a slower rate of decline after seven years (3.6% per year; CI –8.1%, +1.1%). The estimated half-life of the reservoir was 4.0 years (CI 2.7–8.3) until year seven and 18.7 years (CI 8.2–infinite) thereafter. There was substantial variability between individuals in the rate of decline until year seven. Intact provirus declined at a faster rate than defective provirus (P < 0.001). Individuals with higher CD4+ T cell nadir values had a faster rate of decline in intact provirus. CONCLUSIONS. These findings provide evidence that the biology of the replication-competent (intact) reservoir differs from that of the replication-incompetent (non-intact) pool of proviruses. The IPDA will likely be informative when investigating the impact of interventions targeting the reservoir. FUNDING. This work was supported the Delaney AIDS Research Enterprise (DARE; AI096109, A127966). The SCOPE cohort receives additional support from the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763), the CFAR Network of Integrated Systems (R24 AI067039) and the amfAR Institute for HIV Cure Research (amfAR 109301). Additional support was provided by the I4C and Beat-HIV Collaboratories, the Howard Hughes Medical Institute, Gilead, and the Bill and Melinda Gates Foundation.
Authors
Michael J. Peluso, Peter Bacchetti, Kristen D. Ritter, Subul A. Beg, Jun Lai, Jeffrey N. Martin, Peter W. Hunt, Timothy J. Henrich, Janet D. Siliciano, Robert F. Siliciano, Gregory M. Laird, Steven G. Deeks
Abstract
The HIV latent reservoir in resting memory CD4+ T cells prevents cure. Therapeutics to reactivate and eliminate this reservoir are in clinical trials in adults, but not in pediatric populations. We determined, ex vivo, the inducibility and size of the latent reservoir in perinatal compared with adult infections using the Tat/rev Induced Limiting Dilution Assay (TILDA), in which a single-round (12hr) of CD4+ T cell stimulation with PMA/ionomycin maximally activates T cells and leads to proviral expression with multiply-spliced HIV RNA production. Markers of immune activation and exhaustion were measured to assess interactions with inducibility. Despite similar rates of T cell activation with PMA/ionomycin, the latent reservoir in perinatal infection is slower to reactivate and of lower magnitude compared to adult infection, independent of proviral load. An enhanced TILDA with the addition of phytohemagglutin and for 18 hours augmented proviral expression in perinatal but not adult infection. Baseline HLA–DR+ CD4+ T cells was significantly lower in perinatal compared with adult infections, but not correlated with induced reservoir size. These data support differences in baseline immune activation and kinetics of latency reversal in perinatal compared with adult infections, with implications for latency reversal strategies towards reservoir clearance and remission.
Authors
Adit Dhummakupt, Jessica H. Rubens, Thuy Anderson, Laura Powell, Bareng A.S. Nonyane, Lilly V. Siems, Aleisha Collinson-Streng, Tricia L. Nilles, R. Brad Jones, Vicki Tepper, Allison Agwu, Deborah Persaud
Abstract
In the RV144 HIV-1 phase III trial, vaccine efficacy directly correlated with the magnitude of the variable region 2–specific (V2-specific) IgG antibody response, and in the presence of low plasma IgA levels, with the magnitude of plasma antibody-dependent cellular cytotoxicity. Reenrollment of RV144 vaccinees in the RV305 trial offered the opportunity to define the function, maturation, and persistence of vaccine-induced V2-specific and other mAb responses after boosting. We show that the RV144 vaccine regimen induced persistent V2 and other HIV-1 envelope–specific memory B cell clonal lineages that could be identified throughout the approximately 11-year vaccination period. Subsequent boosts increased somatic hypermutation, a critical requirement for antibody affinity maturation. Characterization of 22 vaccine-induced V2-specific mAbs with epitope specificities distinct from previously characterized RV144 V2-specific mAbs CH58 and CH59 found increased in vitro antibody-mediated effector functions. Thus, when inducing non-neutralizing antibodies, one method by which to improve HIV-1 vaccine efficacy may be through late boosting to diversify the V2-specific response to increase the breadth of antibody-mediated anti–HIV-1 effector functions.
Authors
David Easterhoff, Justin Pollara, Kan Luo, Benjamin Janus, Neelakshi Gohain, LaTonya D. Williams, Matthew Zirui Tay, Anthony Monroe, Kristina Peachman, Misook Choe, Susie Min, Paolo Lusso, Peng Zhang, Eden P. Go, Heather Desaire, Mattia Bonsignori, Kwan-Ki Hwang, Charles Beck, Matina Kakalis, Robert J. O’Connell, Sandhya Vasan, Jerome H. Kim, Nelson L. Michael, Jean-Louis Excler, Merlin L. Robb, Supachai Rerks-Ngarm, Jaranit Kaewkungwal, Punnee Pitisuttithum, Sorachai Nitayaphan, Faruk Sinangil, James Tartaglia, Sanjay Phogat, Kevin Wiehe, Kevin O. Saunders, David C. Montefiori, Georgia D. Tomaras, M. Anthony Moody, James Arthos, Mangala Rao, M. Gordon Joyce, Gilad A. Ofek, Guido Ferrari, Barton F. Haynes
Abstract
Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues yet its impact upon the heart is unknown. Here we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy and show that a novel mouse model of cardiac specific prelamin A accumulation exhibited a phenotype consistent with ‘inflammatory cardiomyopathy’ which we observed to be similar to HIV associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings: (1) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (2) have implications for the management of HIV patients with cardiac disease suggesting protease inhibitors should be replaced with alternative therapies i.e. non-nucleoside reverse transcriptase inhibitors; and (3) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy.
Authors
Daniel Brayson, Andrea Frustaci, Romina Verardo, Cristina Chimenti, Matteo Antonio Russo, Robert Hayward, Sadia Munir Ahmad, Gema Vizcay-Barrena, Andrea Protti, Peter S. Zammit, Cristobal G. dos Remedios, Elisabeth Ehler, Ajay M. Shah, Catherine M. Shanahan
No posts were found with this tag.
