Browsing by Subject "Infectious Disease Transmission, Vertical"
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Item Open Access Association of HIV-1 Envelope-Specific Breast Milk IgA Responses with Reduced Risk of Postnatal Mother-to-Child Transmission of HIV-1.(J Virol, 2015-10) Pollara, Justin; McGuire, Erin; Fouda, Genevieve G; Rountree, Wes; Eudailey, Josh; Overman, R Glenn; Seaton, Kelly E; Deal, Aaron; Edwards, R Whitney; Tegha, Gerald; Kamwendo, Deborah; Kumwenda, Jacob; Nelson, Julie AE; Liao, Hua-Xin; Brinkley, Christie; Denny, Thomas N; Ochsenbauer, Christina; Ellington, Sascha; King, Caroline C; Jamieson, Denise J; van der Horst, Charles; Kourtis, Athena P; Tomaras, Georgia D; Ferrari, Guido; Permar, Sallie RUNLABELLED: Infants born to HIV-1-infected mothers in resource-limited areas where replacement feeding is unsafe and impractical are repeatedly exposed to HIV-1 throughout breastfeeding. Despite this, the majority of infants do not contract HIV-1 postnatally, even in the absence of maternal antiretroviral therapy. This suggests that immune factors in breast milk of HIV-1-infected mothers help to limit vertical transmission. We compared the HIV-1 envelope-specific breast milk and plasma antibody responses of clade C HIV-1-infected postnatally transmitting and nontransmitting mothers in the control arm of the Malawi-based Breastfeeding Antiretrovirals and Nutrition Study using multivariable logistic regression modeling. We found no association between milk or plasma neutralization activity, antibody-dependent cell-mediated cytotoxicity, or HIV-1 envelope-specific IgG responses and postnatal transmission risk. While the envelope-specific breast milk and plasma IgA responses also did not reach significance in predicting postnatal transmission risk in the primary model after correction for multiple comparisons, subsequent exploratory analysis using two distinct assay methodologies demonstrated that the magnitudes of breast milk total and secretory IgA responses against a consensus HIV-1 envelope gp140 (B.con env03) were associated with reduced postnatal transmission risk. These results suggest a protective role for mucosal HIV-1 envelope-specific IgA responses in the context of postnatal virus transmission. This finding supports further investigations into the mechanisms by which mucosal IgA reduces risk of HIV-1 transmission via breast milk and into immune interventions aimed at enhancing this response. IMPORTANCE: Infants born to HIV-1-infected mothers are repeatedly exposed to the virus in breast milk. Remarkably, the transmission rate is low, suggesting that immune factors in the breast milk of HIV-1-infected mothers help to limit transmission. We compared the antibody responses in plasma and breast milk of HIV-1-transmitting and -nontransmitting mothers to identify responses that correlated with reduced risk of postnatal HIV-1 transmission. We found that neither plasma nor breast milk IgG antibody responses were associated with risk of HIV-1 transmission. In contrast, the magnitudes of the breast milk IgA and secretory IgA responses against HIV-1 envelope proteins were associated with reduced risk of postnatal HIV-1 transmission. The results of this study support further investigations of the mechanisms by which mucosal IgA may reduce the risk of HIV-1 transmission via breastfeeding and the development of strategies to enhance milk envelope-specific IgA responses to reduce mother-to-child HIV transmission and promote an HIV-free generation.Item Open Access Case 1: Eye Discharge in a 10-day-old Neonate Born by Cesarean Delivery.(Pediatrics in review, 2018-04) Singh, Gagandeep; Galvis, Alvaro; Das, SamratItem 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 SZika 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.Item Open Access Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up.(BMC Infect Dis, 2014-11-07) Dow, Dorothy E; Shayo, Aisa M; Cunningham, Coleen K; Reddy, Elizabeth ABACKGROUND: In Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up. METHODS: This was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained. RESULTS: 161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01). CONCLUSIONS: After viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.Item Open Access Effects of the Pratt pouch model of dispensing nevirapine prophylaxis on HIV exposed infant completion of 6 weeks of prophylaxis in Uganda.(PloS one, 2021-01) Bitarakwate, Edward; Ashburn, Kim; Kazooba, Patrick; Khamasi, Ronald; Natumanya, Eliab; Herrera, Nicole; Owomugisha, Boaz; Malkin, Robert A; Kisaakye, LindaIntroduction
The innovative Pratt pouch could optimize dispensing nevirapine prophylaxis to HIV-exposed infants in pre-measured single dose pouches to increase completion of the full 6 week infant nevirapine regimen.Materials and methods
Nineteen health facilities with highest HIV positivity rates among pregnant women across 9 districts in southwest and central Uganda were assigned to control and intervention groups. HIV-positive women enrolled at intervention facilities received pouches filled with premeasured single doses of nevirapine using Uganda national guidelines, which were integrated into the existing drug distribution system. During antenatal care (ANC) women received 14 pouches to cover time until the 6 day postpartum visit, with an additional 8 pouches if women were delayed in returning to the facility, and 28 pouches after delivery. Women enrolled at control facilities received standard nevirapine syrup following delivery for postnatal infant prophylaxis. In a select number of intervention facilities, during ANC, women received all 42 pouches needed to complete the 6 weeks regimen. Medical record data from enrolled women were extracted; interviews with HIV-positive women during postnatal care visits were conducted. Data were collected January to August 2018 (control sites) and October 2019 to February 2020 (intervention sites). Unadjusted and adjusted logistic regression models were used to identify factors associated with facility delivery, postnatal care follow-up visit, and completion of the full 6 weeks infant nevirapine regimen.Results
Significantly more women in the intervention (n = 320) versus control (n = 340) group had facility delivery (292/316, 92.4% versus 169/340, 49.7%, p<0.0001), postnatal visits within 2 weeks postpartum (295/297, 99.3% versus 133/340, 39.1%, p<0.0001) and reported their infants completing the full 6 weeks infant prophylaxis regimen (299/313, 95.5% versus 210/242, 86.8%, p = 0.0002). Dispensing 42 versus 14 pouches during ANC did not have negative effects on these outcomes. Among out-of-facility deliveries, a higher proportion of infants received nevirapine within 72 hours of birth in the intervention versus control group, 95.8% versus 77.9%. In multivariate models, the intervention group was the only significant factor associated with facility delivery or completion of the full 6 weeks infant prophylaxis.Conclusions
Use of the Pratt pouch resulted in an increase in HIV-exposed infants completing the full 6weeks prophylaxis regimen and associated benefits including increasing facility delivery and women's adherence to postnatal care services.Item Open Access Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission.(J Clin Invest, 2015-07-01) Permar, Sallie R; Fong, Youyi; Vandergrift, Nathan; Fouda, Genevieve G; Gilbert, Peter; Parks, Robert; Jaeger, Frederick H; Pollara, Justin; Martelli, Amanda; Liebl, Brooke E; Lloyd, Krissey; Yates, Nicole L; Overman, R Glenn; Shen, Xiaoying; Whitaker, Kaylan; Chen, Haiyan; Pritchett, Jamie; Solomon, Erika; Friberg, Emma; Marshall, Dawn J; Whitesides, John F; Gurley, Thaddeus C; Von Holle, Tarra; Martinez, David R; Cai, Fangping; Kumar, Amit; Xia, Shi-Mao; Lu, Xiaozhi; Louzao, Raul; Wilkes, Samantha; Datta, Saheli; Sarzotti-Kelsoe, Marcella; Liao, Hua-Xin; Ferrari, Guido; Alam, S Munir; Montefiori, David C; Denny, Thomas N; Moody, M Anthony; Tomaras, Georgia D; Gao, Feng; Haynes, Barton FDespite the wide availability of antiretroviral drugs, more than 250,000 infants are vertically infected with HIV-1 annually, emphasizing the need for additional interventions to eliminate pediatric HIV-1 infections. Here, we aimed to define humoral immune correlates of risk of mother-to-child transmission (MTCT) of HIV-1, including responses associated with protection in the RV144 vaccine trial. Eighty-three untreated, HIV-1-transmitting mothers and 165 propensity score-matched nontransmitting mothers were selected from the Women and Infants Transmission Study (WITS) of US nonbreastfeeding, HIV-1-infected mothers. In a multivariable logistic regression model, the magnitude of the maternal IgG responses specific for the third variable loop (V3) of the HIV-1 envelope was predictive of a reduced risk of MTCT. Neutralizing Ab responses against easy-to-neutralize (tier 1) HIV-1 strains also predicted a reduced risk of peripartum transmission in secondary analyses. Moreover, recombinant maternal V3-specific IgG mAbs mediated neutralization of autologous HIV-1 isolates. Thus, common V3-specific Ab responses in maternal plasma predicted a reduced risk of MTCT and mediated autologous virus neutralization, suggesting that boosting these maternal Ab responses may further reduce HIV-1 MTCT.Item Open Access Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses.(Science translational medicine, 2021-10) Bordt, Evan A; Shook, Lydia L; Atyeo, Caroline; Pullen, Krista M; De Guzman, Rose M; Meinsohn, Marie-Charlotte; Chauvin, Maeva; Fischinger, Stephanie; Yockey, Laura J; James, Kaitlyn; Lima, Rosiane; Yonker, Lael M; Fasano, Alessio; Brigida, Sara; Bebell, Lisa M; Roberts, Drucilla J; Pépin, David; Huh, Jun R; Bilbo, Staci D; Li, Jonathan Z; Kaimal, Anjali; Schust, Danny J; Gray, Kathryn J; Lauffenburger, Douglas; Alter, Galit; Edlow, Andrea GThere is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.Item Open Access Placental Expression of ACE2 and TMPRSS2 in Maternal Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Are Placental Defenses Mediated by Fetal Sex?(The Journal of infectious diseases, 2021-12) Shook, Lydia L; Bordt, Evan A; Meinsohn, Marie-Charlotte; Pepin, David; De Guzman, Rose M; Brigida, Sara; Yockey, Laura J; James, Kaitlyn E; Sullivan, Mackenzie W; Bebell, Lisa M; Roberts, Drucilla J; Kaimal, Anjali J; Li, Jonathan Z; Schust, Danny; Gray, Kathryn J; Edlow, Andrea GBackground
Expression of angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), host molecules required for viral entry, may underlie sex differences in vulnerability to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated whether placental ACE2 and TMPRSS2 expression vary by fetal sex in the presence of maternal SARS-CoV-2 infection.Methods
Placental ACE2 and TMPRSS2 expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-PCR) and by Western blot in 68 pregnant women (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. The impact of fetal sex and maternal SARS-CoV-2 exposure on ACE2 and TMPRSS2 was analyzed by 2-way analysis of variance (ANOVA).Results
Maternal SARS-CoV-2 infection impacted placental TMPRSS2 expression in a sexually dimorphic fashion (2-way ANOVA interaction, P = .002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on ACE2. TMPRSS2 expression was significantly correlated with ACE2 expression in males (Spearman ρ = 0.54, P = .02) but not females (ρ = 0.23, P = .34) exposed to maternal SARS-CoV-2.Conclusions
Sex differences in placental TMPRSS2 but not ACE2 were observed in the setting of maternal SARS-CoV-2 infection, which may have implications for offspring vulnerability to placental infection.Item Open Access Postnatal cytomegalovirus exposure in infants of antiretroviral-treated and untreated HIV-infected mothers.(Infect Dis Obstet Gynecol, 2014) Meyer, Sarah A; Westreich, Daniel J; Patel, Emily; Ehlinger, Elizabeth P; Kalilani, Linda; Lovingood, Rachel V; Denny, Thomas N; Swamy, Geeta K; Permar, Sallie RHIV-1 and CMV are important pathogens transmitted via breastfeeding. Furthermore, perinatal CMV transmission may impact growth and disease progression in HIV-exposed infants. Although maternal antiretroviral therapy reduces milk HIV-1 RNA load and postnatal transmission, its impact on milk CMV load is unclear. We examined the relationship between milk CMV and HIV-1 load (4-6 weeks postpartum) and the impact of antiretroviral treatment in 69 HIV-infected, lactating Malawian women and assessed the relationship between milk CMV load and postnatal growth in HIV-exposed, breastfed infants through six months of age. Despite an association between milk HIV-1 RNA and CMV DNA load (0.39 log(10) rise CMV load per log(10) rise HIV-1 RNA load, 95% CI 0.13-0.66), milk CMV load was similar in antiretroviral-treated and untreated women. Higher milk CMV load was associated with lower length-for-age (-0.53, 95% CI: -0.96, -0.10) and weight-for-age (-0.40, 95% CI: -0.67, -0.13) Z-score at six months in exposed, uninfected infants. As the impact of maternal antiretroviral therapy on the magnitude of postnatal CMV exposure may be limited, our findings of an inverse relationship between infant growth and milk CMV load highlight the importance of defining the role of perinatal CMV exposure on growth faltering of HIV-exposed infants.Item Open Access Postnatally-transmitted HIV-1 Envelope variants have similar neutralization-sensitivity and function to that of nontransmitted breast milk variants.(Retrovirology, 2013-01-10) Fouda, Genevieve G; Mahlokozera, Tatenda; Salazar-Gonzalez, Jesus F; Salazar, Maria G; Learn, Gerald; Kumar, Surender B; Dennison, S Moses; Russell, Elizabeth; Rizzolo, Katherine; Jaeger, Frederick; Cai, Fangping; Vandergrift, Nathan A; Gao, Feng; Hahn, Beatrice; Shaw, George M; Ochsenbauer, Christina; Swanstrom, Ronald; Meshnick, Steve; Mwapasa, Victor; Kalilani, Linda; Fiscus, Susan; Montefiori, David; Haynes, Barton; Kwiek, Jesse; Alam, S Munir; Permar, Sallie RBACKGROUND: Breastfeeding is a leading cause of infant HIV-1 infection in the developing world, yet only a minority of infants exposed to HIV-1 via breastfeeding become infected. As a genetic bottleneck severely restricts the number of postnatally-transmitted variants, genetic or phenotypic properties of the virus Envelope (Env) could be important for the establishment of infant infection. We examined the efficiency of virologic functions required for initiation of infection in the gastrointestinal tract and the neutralization sensitivity of HIV-1 Env variants isolated from milk of three postnatally-transmitting mothers (n = 13 viruses), five clinically-matched nontransmitting mothers (n = 16 viruses), and seven postnatally-infected infants (n = 7 postnatally-transmitted/founder (T/F) viruses). RESULTS: There was no difference in the efficiency of epithelial cell interactions between Env virus variants from the breast milk of transmitting and nontransmitting mothers. Moreover, there was similar efficiency of DC-mediated trans-infection, CCR5-usage, target cell fusion, and infectivity between HIV-1 Env-pseudoviruses from nontransmitting mothers and postnatal T/F viruses. Milk Env-pseudoviruses were generally sensitive to neutralization by autologous maternal plasma and resistant to breast milk neutralization. Infant T/F Env-pseudoviruses were equally sensitive to neutralization by broadly-neutralizing monoclonal and polyclonal antibodies as compared to nontransmitted breast milk Env variants. CONCLUSION: Postnatally-T/F Env variants do not appear to possess a superior ability to interact with and cross a mucosal barrier or an exceptional resistance to neutralization that define their capability to initiate infection across the infant gastrointestinal tract in the setting of preexisting maternal antibodies.Item Open Access Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk.(Proceedings of the National Academy of Sciences of the United States of America, 2013-11) Fouda, Genevieve G; Jaeger, Frederick H; Amos, Joshua D; Ho, Carrie; Kunz, Erika L; Anasti, Kara; Stamper, Lisa W; Liebl, Brooke E; Barbas, Kimberly H; Ohashi, Tomoo; Moseley, Martin Arthur; Liao, Hua-Xin; Erickson, Harold P; Alam, S Munir; Permar, Sallie RAchieving an AIDS-free generation will require elimination of postnatal transmission of HIV-1 while maintaining the nutritional and immunologic benefits of breastfeeding for infants in developing regions. Maternal/infant antiretroviral prophylaxis can reduce postnatal HIV-1 transmission, yet toxicities and the development of drug-resistant viral strains may limit the effectiveness of this strategy. Interestingly, in the absence of antiretroviral prophylaxis, greater than 90% of infants exposed to HIV-1 via breastfeeding remain uninfected, despite daily mucosal exposure to the virus for up to 2 y. Moreover, milk of uninfected women inherently neutralizes HIV-1 and prevents virus transmission in animal models, yet the factor(s) responsible for this anti-HIV activity is not well-defined. In this report, we identify a primary HIV-1-neutralizing protein in breast milk, Tenascin-C (TNC). TNC is an extracellular matrix protein important in fetal development and wound healing, yet its antimicrobial properties have not previously been established. Purified TNC captured and neutralized multiclade chronic and transmitted/founder HIV-1 variants, and depletion of TNC abolished the HIV-1-neutralizing activity of milk. TNC bound the HIV-1 Envelope protein at a site that is induced upon engagement of its primary receptor, CD4, and is blocked by V3 loop- (19B and F39F) and chemokine coreceptor binding site-directed (17B) monoclonal antibodies. Our results demonstrate the ability of an innate mucosal host protein found in milk to neutralize HIV-1 via binding to the chemokine coreceptor site, potentially explaining why the majority of HIV-1-exposed breastfed infants are protected against mucosal HIV-1 transmission.Item Open Access When separation is not the answer: Breastfeeding mothers and infants affected by COVID-19.(Maternal & child nutrition, 2020-10) Tomori, Cecília; Gribble, Karleen; Palmquist, Aunchalee EL; Ververs, Mija-Tesse; Gross, Marielle SThe World Health Organization (WHO) has provided detailed guidance on the care of infants of women who are persons under investigation (PUI) or confirmed to have COVID-19. The guidance supports immediate post-partum mother-infant contact and breastfeeding with appropriate respiratory precautions. Although many countries have followed WHO guidance, others have implemented infection prevention and control (IPC) policies that impose varying levels of post-partum separation and discourage or prohibit breastfeeding or provision of expressed breast milk. These policies aim to protect infants from the potential harm of infection from their mothers, yet they may fail to fully account for the impact of separation. Global COVID-19 data are suggestive of potentially lower susceptibility and a typically milder course of disease among children, although the potential for severe disease in infancy remains. Separation causes cumulative harms, including disrupting breastfeeding and limiting its protection against infectious disease, which has disproportionate impacts on vulnerable infants. Separation also presumes the replaceability of breastfeeding-a risk that is magnified in emergencies. Moreover, separation does not ensure lower viral exposure during hospitalizations and post-discharge, and contributes to the burden on overwhelmed health systems. Finally, separation magnifies maternal health consequences of insufficient breastfeeding and compounds trauma in communities who have experienced long-standing inequities and violence, including family separation. Taken together, separating PUI/confirmed SARS-CoV-2-positive mothers and their infants may lead to excess preventable illnesses and deaths among infants and women around the world. Health services must consider the short-andlong-term impacts of separating mothers and infants in their policies.