Browsing by Subject "Antibodies, Viral"

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Open Access
A genetically engineered, stem-cell-derived cellular vaccine.
(Cell reports. Medicine, 2022-12) Cooper, Amanda; Sidaway, Adam; Chandrashekar, Abishek; Latta, Elizabeth; Chakraborty, Krishnendu; Yu, Jingyou; McMahan, Katherine; Giffin, Victoria; Manickam, Cordelia; Kroll, Kyle; Mosher, Matthew; Reeves, R Keith; Gam, Rihab; Arthofer, Elisa; Choudhry, Modassir; Henley, Tom; Barouch, Dan H
Despite rapid clinical translation of COVID-19 vaccines in response to the global pandemic, an opportunity remains for vaccine technology innovation to address current limitations and meet challenges of inevitable future pandemics. We describe a universal vaccine cell (UVC) genetically engineered to mimic natural physiological immunity induced upon viral infection of host cells. Cells engineered to express the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike as a representative viral antigen induce robust neutralizing antibodies in immunized non-human primates. Similar titers generated in this established non-human primate (NHP) model have translated into protective human neutralizing antibody levels in SARS-CoV-2-vaccinated individuals. Animals vaccinated with ancestral spike antigens and subsequently challenged with SARS-CoV-2 Delta variant in a heterologous challenge have an approximately 3 log decrease in viral subgenomic RNA in the lungs. This cellular vaccine is designed as a scalable cell line with a modular poly-antigenic payload, allowing for rapid, large-scale clinical manufacturing and use in an evolving viral variant environment.
Open Access
A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice.
(The Journal of clinical investigation, 2023-02) Kuraoka, Masayuki; Aschner, Clare Burn; Windsor, Ian W; Mahant, Aakash Mahant; Garforth, Scott J; Kong, Susan Luozheng; Achkar, Jacqueline M; Almo, Steven C; Kelsoe, Garnett; Herold, Betsy C
There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2-vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo-electron microscopic structure of the Fab-glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.
Open Access
A Prevalent Focused Human Antibody Response to the Influenza Virus Hemagglutinin Head Interface.
(mBio, 2021-06) McCarthy, Kevin R; Lee, Jiwon; Watanabe, Akiko; Kuraoka, Masayuki; Robinson-McCarthy, Lindsey R; Georgiou, George; Kelsoe, Garnett; Harrison, Stephen C
Novel animal influenza viruses emerge, initiate pandemics, and become endemic seasonal variants that have evolved to escape from prevalent herd immunity. These processes often outpace vaccine-elicited protection. Focusing immune responses on conserved epitopes may impart durable immunity. We describe a focused, protective antibody response, abundant in memory and serum repertoires, to a conserved region at the influenza virus hemagglutinin (HA) head interface. Structures of 11 examples, 8 reported here, from seven human donors demonstrate the convergence of responses on a single epitope. The 11 are genetically diverse, with one class having a common, IGκV1-39, light chain. All of the antibodies bind HAs from multiple serotypes. The lack of apparent genetic restriction and potential for elicitation by more than one serotype may explain their abundance. We define the head interface as a major target of broadly protective antibodies with the potential to influence the outcomes of influenza virus infection. IMPORTANCE The rapid appearance of mutations in circulating human influenza viruses and selection for escape from herd immunity require prediction of likely variants for an annual updating of influenza vaccines. The identification of human antibodies that recognize conserved surfaces on the influenza virus hemagglutinin (HA) has prompted efforts to design immunogens that might selectively elicit such antibodies. The recent discovery of a widely prevalent antibody response to the conserved interface between two HA "heads" (the globular, receptor-binding domains at the apex of the spike-like trimer) has added a new target for these efforts. We report structures of eight such antibodies, bound with HA heads, and compare them with each other and with three others previously described. Although genetically diverse, they all converge on a common binding site. The analysis here can guide immunogen design for preclinical trials.
Open Access
Chikungunya and dengue fever among hospitalized febrile patients in northern Tanzania.
(Am J Trop Med Hyg, 2012-01) Hertz, Julian T; Munishi, O Michael; Ooi, Eng Eong; Howe, Shiqin; Lim, Wen Yan; Chow, Angelia; Morrissey, Anne B; Bartlett, John A; Onyango, Jecinta J; Maro, Venance P; Kinabo, Grace D; Saganda, Wilbrod; Gubler, Duane J; Crump, John A
Consecutive febrile admissions were enrolled at two hospitals in Moshi, Tanzania. Confirmed acute Chikungunya virus (CHIKV), Dengue virus (DENV), and flavivirus infection were defined as a positive polymerase chain reaction (PCR) result. Presumptive acute DENV infection was defined as a positive anti-DENV immunoglobulin M (IgM) enzyme-linked immunsorbent assay (ELISA) result, and prior flavivirus exposure was defined as a positive anti-DENV IgG ELISA result. Among 870 participants, PCR testing was performed on 700 (80.5%). Of these, 55 (7.9%) had confirmed acute CHIKV infection, whereas no participants had confirmed acute DENV or flavivirus infection. Anti-DENV IgM serologic testing was performed for 747 (85.9%) participants, and of these 71 (9.5%) had presumptive acute DENV infection. Anti-DENV IgG serologic testing was performed for 751 (86.3%) participants, and of these 80 (10.7%) had prior flavivirus exposure. CHIKV infection was more common among infants and children than adults and adolescents (odds ratio [OR] 1.9, P = 0.026) and among HIV-infected patients with severe immunosuppression (OR 10.5, P = 0.007). CHIKV infection is an important but unrecognized cause of febrile illness in northern Tanzania. DENV or other closely related flaviviruses are likely also circulating.
Open Access
Cross-Reactive Dengue Virus Antibodies Augment Zika Virus Infection of Human Placental Macrophages.
(Cell host & microbe, 2018-11) Zimmerman, Matthew G; Quicke, Kendra M; O'Neal, Justin T; Arora, Nitin; Machiah, Deepa; Priyamvada, Lalita; Kauffman, Robert C; Register, Emery; Adekunle, Oluwaseyi; Swieboda, Dominika; Johnson, Erica L; Cordes, Sarah; Haddad, Lisa; Chakraborty, Rana; Coyne, Carolyn B; Wrammert, Jens; Suthar, Mehul S
Zika virus (ZIKV), which emerged in regions endemic to dengue virus (DENV), is vertically transmitted and results in adverse pregnancy outcomes. Antibodies to DENV can cross-react with ZIKV, but whether these antibodies influence ZIKV vertical transmission remains unclear. Here, we find that DENV antibodies increase ZIKV infection of placental macrophages (Hofbauer cells [HCs]) from 10% to over 80% and enhance infection of human placental explants. ZIKV-anti-DENV antibody complexes increase viral binding and entry into HCs but also result in blunted type I interferon, pro-inflammatory cytokine, and antiviral responses. Additionally, ZIKV infection of HCs and human placental explants is enhanced in an immunoglobulin G subclass-dependent manner, and targeting FcRn reduces ZIKV replication in human placental explants. Collectively, these findings support a role for pre-existing DENV antibodies in enhancement of ZIKV infection of select placental cell types and indicate that pre-existing immunity to DENV should be considered when addressing ZIKV vertical transmission.
Open Access
Evaluation of Commercially Available High-Throughput SARS-CoV-2 Serologic Assays for Serosurveillance and Related Applications.
(Emerging infectious diseases, 2022-03) Stone, Mars; Grebe, Eduard; Sulaeman, Hasan; Di Germanio, Clara; Dave, Honey; Kelly, Kathleen; Biggerstaff, Brad J; Crews, Bridgit O; Tran, Nam; Jerome, Keith R; Denny, Thomas N; Hogema, Boris; Destree, Mark; Jones, Jefferson M; Thornburg, Natalie; Simmons, Graham; Krajden, Mel; Kleinman, Steve; Dumont, Larry J; Busch, Michael P
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurveys can estimate cumulative incidence for monitoring epidemics, requiring assessment of serologic assays to inform testing algorithm development and interpretation of results. We conducted a multilaboratory evaluation of 21 commercial high-throughput SARS-CoV-2 serologic assays using blinded panels of 1,000 highly characterized specimens. Assays demonstrated a range of sensitivities (96%-63%), specificities (99%-96%), and precision (intraclass correlation coefficient 0.55-0.99). Durability of antibody detection was dependent on antigen and immunoglobulin targets; antispike and total Ig assays demonstrated more stable longitudinal reactivity than antinucleocapsid and IgG assays. Assays with high sensitivity, specificity, and durable antibody detection are ideal for serosurveillance, but assays demonstrating waning reactivity are appropriate for other applications, including correlation with neutralizing activity and detection of anamnestic boosting by reinfections. Assay performance must be evaluated in context of intended use, particularly in the context of widespread vaccination and circulation of SARS-CoV-2 variants.
Open Access
H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination.
(PloS one, 2011-01) Moody, M Anthony; Zhang, Ruijun; Walter, Emmanuel B; Woods, Christopher W; Ginsburg, Geoffrey S; McClain, Micah T; Denny, Thomas N; Chen, Xi; Munshaw, Supriya; Marshall, Dawn J; Whitesides, John F; Drinker, Mark S; Amos, Joshua D; Gurley, Thaddeus C; Eudailey, Joshua A; Foulger, Andrew; DeRosa, Katherine R; Parks, Robert; Meyerhoff, R Ryan; Yu, Jae-Sung; Kozink, Daniel M; Barefoot, Brice E; Ramsburg, Elizabeth A; Khurana, Surender; Golding, Hana; Vandergrift, Nathan A; Alam, S Munir; Tomaras, Georgia D; Kepler, Thomas B; Kelsoe, Garnett; Liao, Hua-Xin; Haynes, Barton F
During the recent H1N1 influenza pandemic, excess morbidity and mortality was seen in young but not older adults suggesting that prior infection with influenza strains may have protected older subjects. In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection.To study hemagglutinin (HA) antibody responses in influenza immunization and infection, we have studied the day 7 plasma cell repertoires of subjects immunized with seasonal trivalent inactivated influenza vaccine (TIV) and compared them to the plasma cell repertoires of subjects experimentally infected (EI) with influenza H3N2 A/Wisconsin/67/2005. The majority of circulating plasma cells after TIV produced influenza-specific antibodies, while most plasma cells after EI produced antibodies that did not react with influenza HA. While anti-HA antibodies from TIV subjects were primarily reactive with single or few HA strains, anti-HA antibodies from EI subjects were isolated that reacted with multiple HA strains. Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects. From an H3N2-infected subject, we isolated a 4-member clonal lineage of broadly cross-reactive antibodies that bound to multiple HA subtypes and neutralized both H1N1 and H3N2 viruses. This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject.The presence of broadly reactive subdominant antibody responses in some EI subjects suggests that improved vaccine designs that make broadly reactive antibody responses immunodominant could protect against novel influenza strains.
Open Access
Host range, transmissibility and antigenicity of a pangolin coronavirus.
(Nature microbiology, 2023-10) Hou, Yixuan J; Chiba, Shiho; Leist, Sarah R; Meganck, Rita M; Martinez, David R; Schäfer, Alexandra; Catanzaro, Nicholas J; Sontake, Vishwaraj; West, Ande; Edwards, Catlin E; Yount, Boyd; Lee, Rhianna E; Gallant, Samuel C; Zost, Seth J; Powers, John; Adams, Lily; Kong, Edgar F; Mattocks, Melissa; Tata, Aleksandra; Randell, Scott H; Tata, Purushothama R; Halfmann, Peter; Crowe, James E; Kawaoka, Yoshihiro; Baric, Ralph S
The pathogenic and cross-species transmission potential of SARS-CoV-2-related coronaviruses (CoVs) remain poorly characterized. Here we recovered a wild-type pangolin (Pg) CoV GD strain including derivatives encoding reporter genes using reverse genetics. In primary human cells, PgCoV replicated efficiently but with reduced fitness and showed less efficient transmission via airborne route compared with SARS-CoV-2 in hamsters. PgCoV was potently inhibited by US Food and Drug Administration approved drugs, and neutralized by COVID-19 patient sera and SARS-CoV-2 therapeutic antibodies in vitro. A pan-Sarbecovirus antibody and SARS-CoV-2 S2P recombinant protein vaccine protected BALB/c mice from PgCoV infection. In K18-hACE2 mice, PgCoV infection caused severe clinical disease, but mice were protected by a SARS-CoV-2 human antibody. Efficient PgCoV replication in primary human cells and hACE2 mice, coupled with a capacity for airborne spread, highlights an emergence potential. However, low competitive fitness, pre-immune humans and the benefit of COVID-19 countermeasures should impede its ability to spread globally in human populations.
Open Access
HPV16 antibodies as risk factors for oropharyngeal cancer and their association with tumor HPV and smoking status.
(Oral Oncol, 2015-07) Anderson, Karen S; Dahlstrom, Kristina R; Cheng, Julia N; Alam, Rizwan; Li, Guojun; Wei, Qingyi; Gross, Neil D; Chowell, Diego; Posner, Marshall; Sturgis, Erich M
BACKGROUND: Antibodies (Abs) to the HPV16 proteome increase risk for HPV-associated OPC (HPVOPC). The goal of this study was to investigate the association of a panel of HPV16 Abs with risk for OPC as well as the association of these Abs with tumor HPV and smoking status among patients with OPC. METHODS: IgG Abs to the HPV16 antigens E1, E2, E4, E5, E6, E7, L1, L2 were quantified using a programmable ELISA assay. Sera were obtained from 258 OPC patients at diagnosis and 250 healthy controls. HPV16 tumor status was measured by PCR for 137 cases. Multivariable logistic regression was used to calculate odds ratios for the association of HPV16 Abs with risk for OPC. RESULTS: HPV16 E1, E2, E4, E5, E6, E7 and L1-specific IgG levels were elevated in OPC patients compared to healthy controls (p<0.05). After multivariable adjustment, Ab positivity for NE2, CE2, E6, and/or E7 was associated with OPC risk (OR [95% CI], 249.1 [99.3-624.9]). Among patients with OPC, Ab positivity for these antigens was associated with tumor HPV status, especially among never or light smokers (OR [95% CI], 6.5 [2.1-20.1] and OR [95% CI], 17.5 [4.0-77.2], respectively). CONCLUSIONS: Antibodies to HPV16 proteins are associated with increased risk for HPVOPC. Among patients with OPC, HPV16 Abs are associated with tumor HPV status, in particular among HPV positive patients with no or little smoking history.
Open Access
Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques.
(PLoS Pathog, 2015-08) Santra, Sampa; Tomaras, Georgia D; Warrier, Ranjit; Nicely, Nathan I; Liao, Hua-Xin; Pollara, Justin; Liu, Pinghuang; Alam, S Munir; Zhang, Ruijun; Cocklin, Sarah L; Shen, Xiaoying; Duffy, Ryan; Xia, Shi-Mao; Schutte, Robert J; Pemble Iv, Charles W; Dennison, S Moses; Li, Hui; Chao, Andrew; Vidnovic, Kora; Evans, Abbey; Klein, Katja; Kumar, Amit; Robinson, James; Landucci, Gary; Forthal, Donald N; Montefiori, David C; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Rerks-Ngarm, Supachai; Robb, Merlin L; Michael, Nelson L; Kim, Jerome H; Soderberg, Kelly A; Giorgi, Elena E; Blair, Lily; Korber, Bette T; Moog, Christiane; Shattock, Robin J; Letvin, Norman L; Schmitz, Joern E; Moody, MA; Gao, Feng; Ferrari, Guido; Shaw, George M; Haynes, Barton F
HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.
Open Access
In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies
(Cell, 2021) Li, Dapeng; Edwards, Robert J; Manne, Kartik; Martinez, David R; Schäfer, Alexandra; Alam, S Munir; Wiehe, Kevin; Lu, Xiaozhi; Parks, Robert; Sutherland, Laura L; others
SARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques.
Open Access
Infectious virion capture by HIV-1 gp120-specific IgG from RV144 vaccinees.
(J Virol, 2013-07) Liu, Pinghuang; Yates, Nicole L; Shen, Xiaoying; Bonsignori, Mattia; Moody, M Anthony; Liao, Hua-Xin; Fong, Youyi; Alam, S Munir; Overman, R Glenn; Denny, Thomas; Ferrari, Guido; Ochsenbauer, Christina; Kappes, John C; Polonis, Victoria R; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Rerks-Ngarm, Supachai; Montefiori, David C; Gilbert, Peter; Michael, Nelson L; Kim, Jerome H; Haynes, Barton F; Tomaras, Georgia D
The detailed examination of the antibody repertoire from RV144 provides a unique template for understanding potentially protective antibody functions. Some potential immune correlates of protection were untested in the correlates analyses due to inherent assay limitations, as well as the need to keep the correlates analysis focused on a limited number of endpoints to achieve statistical power. In an RV144 pilot study, we determined that RV144 vaccination elicited antibodies that could bind infectious virions (including the vaccine strains HIV-1 CM244 and HIV-1 MN and an HIV-1 strain expressing transmitted/founder Env, B.WITO.c). Among vaccinees with the highest IgG binding antibody profile, the majority (78%) captured the infectious vaccine strain virus (CM244), while a smaller proportion of vaccinees (26%) captured HIV-1 transmitted/founder Env virus. We demonstrated that vaccine-elicited HIV-1 gp120 antibodies of multiple specificities (V3, V2, conformational C1, and gp120 conformational) mediated capture of infectious virions. Although capture of infectious HIV-1 correlated with other humoral immune responses, the extent of variation between these humoral responses and virion capture indicates that virion capture antibodies occupy unique immunological space.
Open Access
Lack of B cell dysfunction is associated with functional, gp120-dominant antibody responses in breast milk of simian immunodeficiency virus-infected African green monkeys.
(J Virol, 2013-10) Amos, Joshua D; Wilks, Andrew B; Fouda, Genevieve G; Smith, Shannon D; Colvin, Lisa; Mahlokozera, Tatenda; Ho, Carrie; Beck, Krista; Overman, R Glenn; DeMarco, C Todd; Hodge, Terry L; LaBranche, Celia C; Montefiori, David C; Denny, Thomas N; Liao, Hua-Xin; Tomaras, Georgia D; Moody, M Anthony; Permar, Sallie R
The design of an effective vaccine to reduce the incidence of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) via breastfeeding will require identification of protective immune responses that block postnatal virus acquisition. Natural hosts of simian immunodeficiency virus (SIV) sustain nonpathogenic infection and rarely transmit the virus to their infants despite high milk virus RNA loads. This is in contrast to HIV-infected women and SIV-infected rhesus macaques (RhMs), nonnatural hosts which exhibit higher rates of postnatal virus transmission. In this study, we compared the systemic and mucosal B cell responses of lactating, SIV-infected African green monkeys (AGMs), a natural host species, to that of SIV-infected RhMs and HIV-infected women. AGMs did not demonstrate hypergammaglobulinemia or accumulate circulating memory B cells during chronic SIV infection. Moreover, the milk of SIV-infected AGMs contained higher proportions of naive B cells than RhMs. Interestingly, AGMs exhibited robust milk and plasma Env binding antibody responses that were one to two logs higher than those in RhMs and humans and demonstrated autologous neutralizing responses in milk at 1 year postinfection. Furthermore, the plasma and milk Env gp120-binding antibody responses were equivalent to or predominant over Env gp140-binding antibody responses in AGMs, in contrast to that in RhMs and humans. The strong gp120-specific, functional antibody responses in the milk of SIV-infected AGMs may contribute to the rarity of postnatal transmission observed in natural SIV hosts.
Open Access
Leptospirosis and human immunodeficiency virus co-infection among febrile inpatients in northern Tanzania.
(Vector Borne Zoonotic Dis, 2013-08) Biggs, Holly M; Galloway, Renee L; Bui, Duy M; Morrissey, Annie B; Maro, Venance P; Crump, John A
BACKGROUND: Leptospirosis and human immunodeficiency virus (HIV) infection are prevalent in many areas, including northern Tanzania, yet little is known about their interaction. METHODS: We enrolled febrile inpatients at two hospitals in Moshi, Tanzania, over 1 year and performed HIV antibody testing and the microscopic agglutination test (MAT) for leptospirosis. Confirmed leptospirosis was defined as ≥ four-fold rise in MAT titer between acute and convalescent serum samples, and probable leptospirosis was defined as any reciprocal MAT titer ≥ 800. RESULTS: Confirmed or probable leptospirosis was found in 70 (8.4%) of 831 participants with at least one serum sample tested. At total of 823 (99.0%) of 831 participants had HIV testing performed, and 203 (24.7%) were HIV infected. Among HIV-infected participants, 9 (4.4%) of 203 had confirmed or probable leptospirosis, whereas among HIV-uninfected participants 61 (9.8%) of 620 had leptospirosis. Leptospirosis was less prevalent among HIV-infected as compared to HIV-uninfected participants [odds ratio (OR) 0.43, p=0.019]. Among those with leptospirosis, HIV-infected patients more commonly presented with features of severe sepsis syndrome than HIV-uninfected patients, but differences were not statistically significant. Among HIV-infected patients, severe immunosuppression was not significantly different between those with and without leptospirosis (p=0.476). Among HIV-infected adolescents and adults, median CD4 percent and median CD4 count were higher among those with leptospirosis as compared to those with other etiologies of febrile illness, but differences in CD4 count did not reach statistical significance (p=0.015 and p=0.089, respectively). CONCLUSIONS: Among febrile inpatients in northern Tanzania, leptospirosis was not more prevalent among HIV-infected patients. Although some indicators of leptospirosis severity were more common among HIV-infected patients, a statistically significant difference was not demonstrated. Among HIV-infected patients, those with leptospirosis were not more immunosuppressed relative to those with other etiologies of febrile illness.
Open Access
Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection.
(The Journal of clinical investigation, 2022-08) Semmes, Eleanor C; Miller, Itzayana G; Wimberly, Courtney E; Phan, Caroline T; Jenks, Jennifer A; Harnois, Melissa J; Berendam, Stella J; Webster, Helen; Hurst, Jillian H; Kurtzberg, Joanne; Fouda, Genevieve G; Walsh, Kyle M; Permar, Sallie R
Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses, we measured HCMV-specific IgG binding and antiviral functions in paired maternal and cord blood sera from HCMV-seropositive transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads identified via a large, US-based, public cord blood bank. We found that high-avidity IgG binding to HCMV and antibody-dependent cellular phagocytosis (ADCP) were associated with reduced risk of congenital HCMV infection. We also determined that HCMV-specific IgG activation of FcγRI and FcγRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcγRI and FcγRIIA expressed on human monocytes. These findings suggest that engagement of FcγRI/FcγRIIA and Fc effector functions including ADCP may protect against congenital HCMV infection. Taken together, these data can guide future prospective studies on immune correlates against congenital HCMV transmission and inform HCMV vaccine and immunotherapeutic development.
Open Access
Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection.
(PLoS Med, 2009-07-07) Levesque, Marc C; Moody, M Anthony; Hwang, Kwan-Ki; Marshall, Dawn J; Whitesides, John F; Amos, Joshua D; Gurley, Thaddeus C; Allgood, Sallie; Haynes, Benjamin B; Vandergrift, Nathan A; Plonk, Steven; Parker, Daniel C; Cohen, Myron S; Tomaras, Georgia D; Goepfert, Paul A; Shaw, George M; Schmitz, Jörn E; Eron, Joseph J; Shaheen, Nicholas J; Hicks, Charles B; Liao, Hua-Xin; Markowitz, Martin; Kelsoe, Garnett; Margolis, David M; Haynes, Barton F
BACKGROUND: The antibody response to HIV-1 does not appear in the plasma until approximately 2-5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1-specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4(+) T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells. METHODS AND FINDINGS: In human participants, we analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. We found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT) B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI) included not only HIV-1-specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1-induced polyclonal B cell activation. Follicular damage or germinal center loss in terminal ileum Peyer's patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis. CONCLUSIONS: Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1. Please see later in the article for Editors' Summary.
Open Access
Stabilized HIV-1 envelope immunization induces neutralizing antibodies to the CD4bs and protects macaques against mucosal infection.
(Science translational medicine, 2022-09) Saunders, Kevin O; Edwards, Robert J; Tilahun, Kedamawit; Manne, Kartik; Lu, Xiaozhi; Cain, Derek W; Wiehe, Kevin; Williams, Wilton B; Mansouri, Katayoun; Hernandez, Giovanna E; Sutherland, Laura; Scearce, Richard; Parks, Robert; Barr, Maggie; DeMarco, Todd; Eater, Chloe M; Eaton, Amanda; Morton, Georgeanna; Mildenberg, Benjamin; Wang, Yunfei; Rountree, R Wes; Tomai, Mark A; Fox, Christopher B; Moody, M Anthony; Alam, S Munir; Santra, Sampa; Lewis, Mark G; Denny, Thomas N; Shaw, George M; Montefiori, David C; Acharya, Priyamvada; Haynes, Barton F
A successful HIV-1 vaccine will require induction of a polyclonal neutralizing antibody (nAb) response, yet vaccine-mediated induction of such a response in primates remains a challenge. We found that a stabilized HIV-1 CH505 envelope (Env) trimer formulated with a Toll-like receptor 7/8 agonist induced potent HIV-1 polyclonal nAbs that correlated with protection from homologous simian-human immunodeficiency virus (SHIV) infection. The serum dilution that neutralized 50% of virus replication (ID₅₀ titer) required to protect 90% of macaques was 1:364 against the challenge virus grown in primary rhesus CD4⁺ T cells. Structural analyses of vaccine-induced nAbs demonstrated targeting of the Env CD4 binding site or the N156 glycan and the third variable loop base. Autologous nAb specificities similar to those elicited in macaques by vaccination were isolated from the human living with HIV from which the CH505 Env immunogen was derived. CH505 viral isolates were isolated that mutated the V1 to escape both the infection-induced and vaccine-induced antibodies. These results define the specificities of a vaccine-induced nAb response and the protective titers of HIV-1 vaccine-induced nAbs required to protect nonhuman primates from low-dose mucosal challenge by SHIVs bearing a primary transmitted/founder Env.