Biology subjects

Maness, N. J.

Publications and source records attributed to Maness, N. J..

17 recordsLinked to original sources

bioRxiv2025

Depletion and recovery of IgG following treatment with Rozanoliximab and Imlifidase in pigtail macaques

Antibodies are central players in adaptive immunity, providing protection against a wide array of pathogens through mechanisms such as neutralization, opsonization, recruitment of effector immune cells, complement activation and engagement. However, in other contexts, these same effector functions can contribute to immunopathology, particularly when antibodies are developed against self-antigens, resulting in autoimmunity. Understanding the role antibodies play in preventing or causing disease is often supported by studies in model systems wherein manipulation of IgG levels can be used as an experimental tool. Here, we report in simian immunodeficiency virus (SIV) infected pigtail macaques (Macaca nemestrina) the capacity of two orthogonal strategies to systemically deplete IgG - treatment with a neonatal Fc receptor blocking antibody (Rozanolixizumab) that restricts IgG rescue and recycling, and administration of the IgG protease Imlifidase (IdeS) that cleaves the Fc domain. Under the conditions evaluated, we observed more rapid and effective, although not necessarily more durable, IgG depletion mediated by IdeS, reducing levels by 74.1-95.1%, compared to a lesser reduction of 31.3-66.9% with anti-FcRn treatment. We observed a similar degree of depletion, comparable kinetics of rebound among SIV antigen-specific fractions as total IgG, but differential balance among IgG subclasses following treatment in some cases. In sum, this study in a nonhuman primate model describes the efficacy and downstream impacts of new tools to modify humoral immune states providing insight into the balance between protective and pathological effects of IgG antibodies.

immunology↗

bioRxiv2024

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses ({beta}-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other {beta}-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n=6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-{beta}-CoV vaccines. AUTHOR SUMMARYIn this study, we explore the development of a broadly protective vaccine against betacoronaviruses ({beta}-CoVs), including SARS-CoV-2. We focused on monoclonal antibodies (mAbs) from individuals who recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other {beta}-CoVs. Unlike current vaccines that target the S1 region of the virus, these mAbs target a highly conserved S2 region of the spike protein. One antibody, CC40.8, showed promising results in small animal models. To further test its effectiveness, we infused CC40.8 into rhesus macaques at different doses and then challenged them with SARS-CoV-2. We found that higher doses of CC40.8 significantly reduced viral loads and inflammation in the lower airway. Additionally, there were no escape mutations in the targeted region, suggesting that the virus could not easily evade the antibody. Our findings highlight the potential of S2-targeting antibodies to protect against SARS-CoV-2 and support the development of vaccines that can broadly protect against various {beta}-CoVs. Conflicting InterestsRA, TFR, and DRB are listed as inventors on pending patent applications describing the SARS-CoV-2 and HCoV-HKU1 S cross-reactive antibodies. DRB and RA are listed as inventors on a pending patent application describing the S2 stem epitope immunogens identified in this study. DRB is a consultant for IAVI. All other authors declare that they have no competing interests. ONE SENTENCE SUMMARYPan-beta-coronavirus neutralizing mAb CC40.8 reduces SARS-CoV-2 viral loads and inflammation within the lower airway of infected rhesus macaques and provides pre-clinical support for S2-directed immunization strategies.

immunology↗

bioRxiv2023

The Impact of SIV-Induced Immunodeficiency on Clinical Manifestation, Immune Response, and Viral Dynamics in SARS-CoV-2 Coinfection

Persistent and uncontrolled SARS-CoV-2 replication in immunocompromised individuals has been observed and may be a contributing source of novel viral variants that continue to drive the pandemic. Importantly, the effects of immunodeficiency associated with chronic HIV infection on COVID-19 disease and viral persistence have not been directly addressed in a controlled setting. Here we conducted a pilot study wherein two pigtail macaques (PTM) chronically infected with SIVmac239 were exposed to SARS-CoV-2 and monitored for six weeks for clinical disease, viral replication, and viral evolution, and compared to our previously published cohort of SIV-naive PTM infected with SARS-CoV-2. At the time of SARS-CoV-2 infection, one PTM had minimal to no detectable CD4+ T cells in gut, blood, or bronchoalveolar lavage (BAL), while the other PTM harbored a small population of CD4+ T cells in all compartments. Clinical signs were not observed in either PTM; however, the more immunocompromised PTM exhibited a progressive increase in pulmonary infiltrating monocytes throughout SARS-CoV-2 infection. Single-cell RNA sequencing (scRNAseq) of the infiltrating monocytes revealed a less activated/inert phenotype. Neither SIV-infected PTM mounted detectable anti-SARS-CoV-2 T cell responses in blood or BAL, nor anti-SARS-CoV-2 neutralizing antibodies. Interestingly, despite the diminished cellular and humoral immune responses, SARS-CoV-2 viral kinetics and evolution were indistinguishable from SIV-naive PTM in all sampled mucosal sites (nasal, oral, and rectal), with clearance of virus by 3-4 weeks post infection. SIV-induced immunodeficiency significantly impacted immune responses to SARS-CoV-2 but did not alter disease progression, viral kinetics or evolution in the PTM model. SIV-induced immunodeficiency alone may not be sufficient to drive the emergence of novel viral variants.

immunology↗

bioRxiv2023

Real time analysis of SARS-CoV-2 induced cytolysis reveals distinct variant-specific replication profiles

The continuous evolution of new SARS-CoV-2 variants with enhanced immune evasion capacity suggests the entire population is and will continue to be potentially vulnerable to infection despite pre-existing immunity. The ability of each new variant to evade host humoral immunity is the focus of intense research across the globe. Each variant may also harbor unique replication capabilities relevant for disease and transmission. Here we demonstrate the utility of a new approach to assessing viral replication kinetics using Real Time Cell Analysis (RTCA). Virus induced cell death is measured in real time by the detection of electrical impedance through cell monolayers. Using this system, we quantified replication kinetics of five clinically important viral variants; USA WA1/2020 (an A1 ancestral lineage isolate), Delta, and Omicron subvariants BA.1, BA.4, and BA.5. We identified multiple kinetic measures that proved useful in variant replication comparisons including time (in hours) to the maximum rate of cell death at each log10 viral dilution and the slope at the maximum rate of cell death. We found that WA1/2020 and Delta were the most rapid but in distinct ways. While WA1/2020 induced cell death most rapidly after inoculation, Delta was slightly slower to reach cell death, it appeared to kill cells faster once cytotoxic effects began. Interestingly, BA.1, showed substantially reduced replication kinetics relative to all other variants. Together, these data show that real time analysis of cell death is a robust method to assess replicative capacity of any given SARS-CoV-2 variant rapidly and quantitatively, which may be useful in assessment of newly emerging variants.

microbiology↗

bioRxiv2022

Durable protection against SARS-CoV-2 Omicron induced by an adjuvanted subunit vaccine

Despite the remarkable efficacy of COVID-19 vaccines, waning immunity, and the emergence of SARS-CoV-2 variants such as Omicron represents a major global health challenge. Here we present data from a study in non-human primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine, consisting of RBD (receptor binding domain) on the I53-50 nanoparticle, adjuvanted with AS03, currently in Phase 3 clinical trial (NCT05007951). Vaccination induced robust neutralizing antibody (nAb) titers that were maintained at high levels for at least one year after two doses (Pseudovirus nAb GMT: 2207, Live-virus nAb GMT: 1964) against the ancestral strain, but not against Omicron. However, a booster dose at 6-12 months with RBD-Wu or RBD-{beta} (RBD from the Beta variant) displayed on I53-50 elicited equivalent and remarkably high neutralizing titers against the ancestral as well as the Omicron variant. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Importantly, vaccination resulted in protection against Omicron infection in the lung (no detectable virus in any animal) and profound suppression of viral burden in the nares (median peak viral load of 7567 as opposed to 1.3x107 copies in unvaccinated animals) at 6 weeks post final booster. Even at 6 months post vaccination, there was significant protection in the lung (with 7 out of 11 animals showing no viral load, 3 out of 11 animals showing ~20-fold lower viral load than unvaccinated controls) and rapid control of virus in the nares. These results highlight the durable cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine platform.

immunology↗

bioRxiv2021

Myeloid cell-driven nonregenerative pulmonary scarring is conserved in multiple nonhuman primate species regardless of SARS-CoV-2 infection modality

The novel coronavirus SARS-CoV-2 has caused a worldwide pandemic resulting in widespread efforts in development of animal models that recapitulate human disease for evaluation of medical countermeasures, and to dissect COVID-19 immunopathogenesis. We tested whether route of experimental infection substantially changes COVID-19 disease characteristics in two species (Macaca mulatta; rhesus macaques; RM, Chlorocebus atheiops; African green monkeys; AGM) of nonhuman primates. Species-specific cohorts of RM and AGM Rhesus macaques (Macaca mulatta, RMs) and African green monkeys (Chlorocebus aethiops, AGMs) were experimentally infected with homologous SARS-CoV-2 by either direct mucosal instillation or small particle aerosol in route-discrete subcohorts. Both species demonstrated equivalent infection initially by either exposure route although the magnitude and duration of viral loading was greater in AGMs than that of the RM. Clinical onset was nearly immediate (+1dpi) in mucosally-exposed cohorts whereas aerosol-infected animals began to show signs +7dpi. Myeloid cell responses indicative of the development of pulmonary scarring and extended lack of regenerative capacity in the pulmonary compartment was a conserved pathologic response in both species by either exposure modality. This pathological commonality may be useful in future anti-fibrosis therapeutic evaluations and expands our understanding of how SARS-CoV-2 infection leads to ARDS and functional lung damage.

microbiology↗

bioRxiv2021

The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over four million people worldwide as of July 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.

immunology↗

bioRxiv2021

Intra-host SARS-CoV-2 evolution in the gut of mucosally-infected Chlorocebus aethiops (African green monkeys)

In recent months, several SARS-CoV-2 variants have emerged that enhance transmissibility and escape host humoral immunity. Hence, the tracking of viral evolutionary trajectories is clearly of great importance. Little is known about SARS-CoV-2 evolution in nonhuman primate models used to test vaccines and therapies and to model human disease. Viral RNA was sequenced from rectal swabs from Chlorocebus aethiops (African green monkeys) after experimental respiratory SARS-CoV-2 infection. Two distinct patterns of viral evolution were identified that were shared between all collected samples. First, mutations in the furin cleavage site that were initially present in the virus as a consequence of VeroE6 cell culture adaptation were subsequently lost in virus recovered in rectal swabs, confirming the necessity of this motif for viral infection in vivo. Three amino acid changes were also identified; ORF 1a S2103F, and spike D215G and H655Y, that were detected in rectal swabs from all sampled animals. These findings are demonstrative of intra-host SARS-CoV-2 evolution unique to this nonhuman primate species and may identify a host-adapted variant of SARS-CoV-2 that would be useful in future development of primate disease models.

microbiology↗

bioRxiv2021

Effective prophylaxis of COVID-19 in rhesus macaques using a combination of two parentally-administered SARS-CoV-2 neutralizing antibodies

SARS-CoV-2 is a respiratory borne pathogenic beta coronavirus that is the source of a worldwide pandemic and the cause of multiple pathologies in man. The rhesus macaque model of COVID-19 was utilized to test the added benefit of combinatory parenteral administration of two high-affinity anti-SARS-CoV-2 monoclonal antibodies (mAbs; C144-LS and C135-LS) expressly developed to neutralize the virus and modified to extend their pharmacokinetics. After completion of kinetics study of mAbs in the primate, combination treatment was administered prophylactically to mucosal viral challenge. Results showed near complete virus neutralization evidenced by no measurable titer in mucosal tissue swabs, muting of cytokine/chemokine response, and lack of any discernable pathologic sequalae. Blocking infection was a dose-related effect, cohorts receiving lower doses (6, 2 mg/kg) resulted in low grade viral infection in various mucosal sites compared to that of a fully protective dose (20 mg/kg). A subset of animals within this cohort whose infectious challenge was delayed 75 days later after mAb administration were still protected from disease. Results indicate this combination mAb effectively blocks development of COVID-19 in the rhesus disease model and accelerates the prospect of clinical studies with this effective antibody combination.

microbiology↗

bioRxiv2021

A tyrosine-based trafficking signal in the simian immunodeficiency virus envelope cytoplasmic domain is strongly selected for in pathogenic SIV infection

The HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-dependent trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting of Env. Despite extensive characterization, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which the Tyr-based signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239{Delta}GY) replicates to high levels acutely in pigtail macaques (PTM) but is rapidly controlled. We previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239{Delta}GY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the {Delta}GY deletion and a nine nucleotide deletion that encodes amino acids 734-736 ({Delta}QTH) and overlaps with the rev and tat open reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected, which generated a new signal for polarized sorting but not endocytosis. This mutation by itself was sufficient to maintain high viral loads for several months when introduced into naive PTMs. These findings reveal, for the first time, strong selection pressure for Env endocytosis and, in particular, for polarized sorting during pathogenic SIV infection in vivo.

cell biology↗

bioRxiv2021

Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates

The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.

immunology↗

bioRxiv2020

Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates

We investigated the immune events following SARS-CoV-2 infection, from the acute inflammatory state up to four weeks post infection, in non-human primates (NHP) with heterogeneous pulmonary pathology. The acute phase was characterized by a robust and rapid migration of monocytes expressing CD16 from the blood and concomitant increase in CD16+ macrophages in the lungs. We identified two subsets of interstitial macrophages (HLA-DR+ CD206-), a transitional CD11c+ CD16+ cell population that was directly associated with IL-6 levels in plasma, and one long lasting CD11b+ CD16+ cell population. Strikingly, levels of monocytes were a correlate of viral replication in bronchial brushes and we discovered TARC (CCL17) as a new potential mediator of myeloid recruitment to the lungs. Worse disease outcomes were associated with high levels of cell infiltration in lungs including CD11b+ CD16hi macrophages and CD11b+ neutrophils. Accumulation of macrophages was long-lasting and detectable even in animals with mild or no signs of disease. Interestingly, animals with anti-inflammatory responses including high IL-10:IL-6 and kynurenine to tryptophan ratios had less signs of disease. Our results unravel cellular mechanisms of COVID-19 and suggest that NHP may be appropriate models to test immune therapies.

immunology↗

bioRxiv2020

ARDS and Cytokine Storm in SARS-CoV-2 Infected Caribbean Vervets

SARS-CoV-2 induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. Among those persons with serious COVID-19 disease, acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. Animal models of SARS-CoV-2 infection that manifest severe disease are needed to investigate the pathogenesis of COVID-19 induced ARDS and evaluate therapeutic strategies. Here we report ARDS in two aged African green monkeys (AGMs) infected with SARS-CoV-2 that demonstrated pathological lesions and disease similar to severe COVID-19 in humans. We also report a comparatively mild COVID-19 phenotype characterized by minor clinical, radiographic and histopathologic changes in the two surviving, aged AGMs and four rhesus macaques (RMs) infected with SARS-CoV-2. We found dramatic increases in circulating cytokines in three of four infected, aged AGMs but not in infected RMs. All of the AGMs showed increased levels of plasma IL-6 compared to baseline, a predictive marker and presumptive therapeutic target in humans infected with SARS-CoV-2 infection. Together, our results show that both RM and AGM are capable of modeling SARS-CoV-2 infection and suggest that aged AGMs may be useful for modeling severe disease manifestations including ARDS.

pathology↗

bioRxiv2020

Zika virus infection during pregnancy protects against secondary infection in the absence of CD8+ cells

While T cell immunity is an important component of the immune response to Zika virus (ZIKV) infection generally, the efficacy of these responses during pregnancy remains unknown. Here, we tested the capacity of CD8 lymphocytes to protect from secondary challenge in four macaques, two of which were depleted of CD8+ cells prior to rechallenge with a heterologous ZIKV isolate. The initial challenge during pregnancy produced transcriptional signatures suggesting complex patterns of immune modulation, but all animals efficiently controlled the rechallenge virus, implying that the primary infection conferred adequate protection. The secondary challenge promoted humoral responses and activation of innate and adaptive immune cells, suggesting a brief period of infection prior to clearance. These data confirm that ZIKV infection during pregnancy induces sufficient immunity to protect from a secondary challenge and suggest that this protection is not solely dependent on CD8 T cells but entails multiple arms of the immune system.

immunology↗

bioRxiv2019

A Zika Virus Primary Isolate Induces Neuroinflammation, Compromises the Blood-Brain Barrier, and Upregulates CXCL12 in Adult Macaques

Zika virus (ZIKV) is a neurotropic virus that can cause neuropathy in adults and fetal neurologic malformation following infection of pregnant women. We used a nonhuman primate model, the Indian-origin Rhesus macaque (IRM), to gain insight into virus-associated hallmarks of ZIKV-induced adult neuropathy. We find that the virus causes prevalent acute and chronic neuroinflammation and chronic disruption of the blood-brain barrier (BBB) in adult animals. Infection results in significant, targeted, and sustained upregulation of the chemokine, CXCL12, in the central nervous system (CNS). CXCL12 plays a key role both in regulating lymphocyte trafficking through the BBB to the CNS, and in mediating repair of damaged neural tissue including remyelination. Understanding how CXCL12 expression is controlled will likely be of central importance in the definition of ZIKV-associated neuropathy in adults. Author summaryZika virus (ZIKV) is a virus that can cause neurological problems in adults and damage to the fetal brain. Nonhuman primates (NHPs) are usually superior animal models for recapitulating human neurological disease because their brain, nervous system structure and immune response to virus infection are very similar to that of humans. We have studied the effect of ZIKV infection on the adult NHP brain and made several significant observations. Infection resulted in a high incidence of mild to moderate brain inflammation that persisted for a surprisingly long period of time. We also found that the virus disrupted the blood brain barrier, which is important for controlling transport of material from blood to the brain. It appears that the central nervous system expresses a specific substance in response to virus infection called a chemokine. This specific chemokine may be involved in virus-induced inflammation and/or in repair of virus-induced brain damage. Our data are significant since they help in understanding the mechanism of brain damage caused by ZIKV in adults.

microbiology↗

bioRxiv2019

Brief report: Mutations in SIV Nef that disrupt and restore tetherin downregulation

The H196 residue in SIVmac239 Nef is conserved across nearly all HIV and SIV isolates, lies immediately adjacent to the AP-2 (adaptor protein 2) interacting domain (ExxxLM195), and is critical for several described AP-2 dependent Nef functions, including the downregulation of tetherin (BST-2/CD317). Surprisingly, many stocks of the closely related SIVmac251 swarm virus harbor a nef allele encoding a Q196, which is associated with loss of multiple AP-2 dependent functions in SIVmac239. Publicly available sequences for SIVmac251 stocks were mined for variants linked to Q196 that might compensate for functional defects associated with this mutation. Variants were engineered into the SIVmac239 parental plasmid and mutant viruses were used to test tetherin downregulatory capacity in primary CD4 T cells using flow cytometry. SIVmac251 stocks that encode a Q196 residue in Nef uniformly also encode an upstream R191 residue. We show that R191 restores the ability of Nef to downregulate tetherin in the presence of Q196. However, a published report showed Q196 commonly evolves to H196 in vivo, suggesting a fitness cost. R191 may represent compensatory evolution to restore the ability to downregulate tetherin lost in viruses harboring Q196.

immunology↗

bioRxiv2018

CD8+ lymphocytes modulate acute ZIKV viremia, innate antiviral immunity and tissue dissemination in nonhuman primates

CD8+ lymphocytes are critically important in the control of viral infections, but their roles in acute Zika virus (ZIKV) infection remain incompletely explored in a model sufficiently similar to humans immunologically. Here, we use CD8+ lymphocyte depletion to dissect acute immune responses in adult male rhesus and cynomolgus macaques infected with ZIKV. CD8 depletion delayed serum viremia and dysregulated patterns of innate immune cell homing and monocyte-driven transcriptional responses in the blood. CD8-depleted macaques also showed evidence of compensatory adaptive immune responses, with elevated Th1 activity and persistence of neutralizing antibodies beyond the clearance of serum viremia. The absence of CD8+ lymphocytes increased viral burdens in lymphatic tissues, semen, and cerebrospinal fluid, and neural lesions were also evident in both CD8-depleted rhesus macaques. Together, these data support a role for CD8+ lymphocytes in the control of ZIKV dissemination and in maintaining immune regulation during acute infection of nonhuman primates.

immunology↗