Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission.
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ABSTRACT:
SUBMITTER: Permar SR
PROVIDER: S-EPMC4613557 | biostudies-literature | 2015 Jul
REPOSITORIES: biostudies-literature
Publications
Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission.
Permar Sallie R SR Fong Youyi Y Vandergrift Nathan N Fouda Genevieve G GG Gilbert Peter P Parks Robert R Jaeger Frederick H FH Pollara Justin J Martelli Amanda A Liebl Brooke E BE Lloyd Krissey K Yates Nicole L NL Overman R Glenn RG Shen Xiaoying X Whitaker Kaylan K Chen Haiyan H Pritchett Jamie J Solomon Erika E Friberg Emma E Marshall Dawn J DJ Whitesides John F JF Gurley Thaddeus C TC Von Holle Tarra T Martinez David R DR Cai Fangping F Kumar Amit A Xia Shi-Mao SM Lu Xiaozhi X Louzao Raul R Wilkes Samantha S Datta Saheli S Sarzotti-Kelsoe Marcella M Liao Hua-Xin HX Ferrari Guido G Alam S Munir SM Montefiori David C DC Denny Thomas N TN Moody M Anthony MA Tomaras Georgia D GD Gao Feng F Haynes Barton F BF
The Journal of clinical investigation 20150608 7
Despite 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 ...[more]
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Project description:UnlabelledInfants 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.ImportanceInfants 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.
| S-EPMC4577885 | biostudies-literature
Project description:Despite the worldwide availability of antiretroviral therapy (ART), approximately 150,000 pediatric HIV infections continue to occur annually. ART can dramatically reduce HIV mother-to-child transmission (MTCT), but inconsistent drug access and adherence, as well as primary maternal HIV infection during pregnancy and lactation are major barriers to eliminating vertical HIV transmission. Thus, immunologic strategies to prevent MTCT, such as an HIV vaccine, will be required to attain an HIV-free generation. A primary goal of HIV vaccine research has been to elicit broadly neutralizing antibodies (bnAbs) given the ability of passive bnAb immunization to protect against sensitive strains, yet we previously observed that HIV-transmitting mothers have more plasma neutralization breadth than nontransmitting mothers. Additionally, we have identified infant transmitted/founder (T/F) viruses that escape maternal bnAb responses. In this study, we examine a cohort of postpartum HIV-transmitting women with neutralization breadth to determine if certain maternal bnAb specificities drive the selection of infant T/F viruses. Using HIV pseudoviruses that are resistant to neutralizing antibodies targeting common bnAb epitopes, we mapped the plasma bnAb specificities of this cohort. Significantly more transmitting women with plasma bnAb activity had a mappable plasma bnAb specificity (six of seven, or 85.7%) compared to that of nontransmitting women with plasma bnAb activity (7 of 21, or 33.3%, P = 0.029 by 2-sided Fisher exact test). Our study suggests that having multispecific broad activity and/or uncommon epitope-specific bnAbs in plasma may be associated with protection against the vertical HIV transmission in the setting of maternal bnAb responses. IMPORTANCE As mother to child transmission (MTCT) of HIV plays a major part in the persistence of the HIV/AIDS epidemic and bnAb-based passive and active vaccines are a primary strategy for HIV prevention, research in this field is of great importance. While previous MTCT research has investigated the neutralizing antibody activity of HIV-infected women, this is, to our knowledge, the largest study identifying differences in bnAb specificity of maternal plasma between transmitting and nontransmitting women. Here, we show that among HIV-infected women with broad and potent neutralization activity, more postpartum-transmitting women had a mappable plasma broadly neutralizing antibody (bnAb) specificity, compared to that of nontransmitting women, suggesting that the nontransmitting women more often have multispecific bnAb responses or bnAb responses that target uncommon epitopes. Such responses may be required for protection against vertical HIV transmission in the setting of maternal bnAb responses.
| S-EPMC9175633 | biostudies-literature
Project description:Cytomegalovirus (CMV) is the most common congenital infection and cause of birth defects worldwide. Primary CMV infection during pregnancy leads to a higher frequency of congenital CMV (cCMV) than maternal re-infection, suggesting that maternal immunity confers partial protection. However, poorly understood immune correlates of protection against placental transmission contributes to the current lack of an approved vaccine to prevent cCMV. In this study, we characterized the kinetics of maternal plasma rhesus CMV (RhCMV) viral load (VL) and RhCMV-specific antibody binding and functional responses in a group of 12 immunocompetent dams with acute, primary RhCMV infection. We defined cCMV transmission as RhCMV detection in amniotic fluid (AF) by qPCR. We then leveraged a large group of past and current primary RhCMV infection studies in late-first/early-second trimester RhCMV-seronegative rhesus macaque dams, including immunocompetent (n = 15), CD4+ T cell-depleted with (n = 6) and without (n = 6) RhCMV-specific polyclonal IgG infusion before infection to evaluate differences between RhCMV AF-positive and AF-negative dams. During the first 3 weeks after infection, the magnitude of RhCMV VL in maternal plasma was higher in AF-positive dams in the combined cohort, while RhCMV glycoprotein B (gB)- and pentamer-specific binding IgG responses were lower magnitude compared to AF-negative dams. However, these observed differences were driven by the CD4+ T cell-depleted dams, as there were no differences in plasma VL or antibody responses between immunocompetent AF-positive vs AF-negative dams. Overall, these results suggest that levels of neither maternal plasma viremia nor humoral responses are associated with cCMV following primary maternal infection in healthy individuals. We speculate that other factors related to innate immunity are more important in this context as antibody responses to acute infection likely develop too late to influence vertical transmission. Yet, pre-existing CMV glycoprotein-specific and neutralizing IgG may provide protection against cCMV following primary maternal CMV infection even in high-risk, immunocompromised settings.
| S-EPMC10621917 | biostudies-literature
Project description:BackgroundHIV-1 envelope gp41 is a transmembrane protein that promotes fusion of the virus with the plasma membrane of the host cells required for virus entry. In addition, gp41 is an important target for the immune response and development of antiviral and vaccine strategies, especially when targeting the highly variable envelope gp120 has not met with resounding success. Mutations in gp41 may affect HIV-1 entry, replication, pathogenesis, and transmission. We, therefore, characterized the molecular properties of gp41, including genetic diversity, functional motifs, and evolutionary dynamics from five mother-infant pairs following perinatal transmission.ResultsThe gp41 open reading frame (ORF) was maintained with a frequency of 84.17% in five mother-infant pairs' sequences following perinatal transmission. There was a low degree of viral heterogeneity and estimates of genetic diversity in gp41 sequences. Both mother and infant gp41 sequences were under positive selection pressure, as determined by ratios of non-synonymous to synonymous substitutions. Phylogenetic analysis of 157 mother-infant gp41 sequences revealed distinct clusters for each mother-infant pair, suggesting that the epidemiologically linked mother-infant pairs were evolutionarily closer to each other as compared with epidemiologically unlinked sequences. The functional domains of gp41, including fusion peptide, heptad repeats, glycosylation sites and lentiviral lytic peptides were mostly conserved in gp41 sequences analyzed in this study. The CTL recognition epitopes and motifs recognized by fusion inhibitors were also conserved in the five mother-infant pairs.ConclusionThe maintenance of an intact envelope gp41 ORF with conserved functional domains and a low degree of genetic variability as well as positive selection pressure for adaptive evolution following perinatal transmission is consistent with an indispensable role of envelope gp41 in HIV-1 replication and pathogenesis.
| S-EPMC1526753 | biostudies-literature
Project description:Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate making it one of the most heavily glycosylated proteins known in nature. HIV-1 Env glycans are derived from the host and present a formidable challenge for host anti-glycan antibody induction. Anti-glycan antibody induction is challenging because anti-HIV-1 glycan antibodies should recognize Env antigen while not acquiring autoreactivity. Thus, the glycan network on HIV-1 Env is referred to as the glycan shield. Despite the challenges presented by immune recognition of host-derived glycans, neutralizing antibodies capable of binding the glycans on HIV-1 Env can be generated by the host immune system in the setting of HIV-1 infection. In particular, a cluster of high mannose glycans, including an N-linked glycan at position 332, form the high mannose patch and are targeted by a variety of broadly neutralizing antibodies. These high mannose patch-directed HIV-1 antibodies can be categorized into distinct categories based on their antibody paratope structure, neutralization activity, and glycan and peptide reactivity. Below we will compare and contrast each of these classes of HIV-1 glycan-dependent antibodies and describe vaccine design efforts to elicit each of these antibody types.
| S-EPMC7480283 | biostudies-literature
Project description:The CD4 binding site (CD4BS) of the HIV-1 envelope glycoprotein (Env) contains epitopes for broadly neutralizing antibody (nAb) and is the target for the vaccine development. However, the CD4BS core including residues 425-430 overlaps the B cell superantigen site and may be related to B cell exhaustion in HIV-1 infection. Furthermore, production of nAb and high-affinity plasma cells needs germinal center reaction and the help of T follicular helper (Tfh) cells. We believe that strengthening the ability of Env CD4BS in inducing Tfh response and decreasing the effects of the superantigen are the strategies for eliciting nAb and development of HIV-1 vaccine. We constructed a gp120 mutant W427S of an HIV-1 primary R5 strain and examined its ability in the elicitation of Ab and the production of Tfh by immunization of BALB/c mice. We found that the trimeric wild-type gp120 can induce more non-specific antibody-secreting plasma cells, higher serum IgG secretion, and more Tfh cells by splenocyte. The modified W427S gp120 elicits higher levels of specific binding antibodies as well as nAbs though it produces less Tfh cells. Furthermore, higher Tfh cell frequency does not correlate to the specific binding Abs or nAbs indicating that the wild-type gp120 induced some non-specific Tfh that did not contribute to the production of specific Abs. This gp120 mutant led to more memory Tfh production, especially, the effector memory Tfh cells. Taken together, W427S gp120 could induce higher level of specific binding and neutralizing Ab production that may be associated with the reduction of non-specific Tfh but strengthening of the memory Tfh.
| S-EPMC4278894 | biostudies-literature
Project description:Antibodies against the HIV-1 V1V2 loops were the only correlate of reduced infection risk in the RV144 vaccine trial, highlighting the V1V2 loops as promising targets for vaccine design. The V1V2 loops are structurally plastic, exhibiting either an α-helix-coil or β-strand conformation. V1V2-specific antibodies may thus recognize distinct conformations, and an antibody's conformational specificity can be an important determinant of breadth and function. Restricting V1V2 conformational plasticity in an immunogen may thus provide control over the conformational specificity and quality of a vaccine-elicited antibody response. Previously, we identified a V1V2 sequence variant (K155M) that results in enhanced recognition by cross-reactive antibodies recognizing the β-strand conformation. Here, we relate V1V2 antigenicity to immunogenicity by comparing the immunogenicity profiles of wildtype and K155M immunogens in two mouse models. In one model, immunization with gp70 V1V2 K155M but not wildtype elicited antibody responses that were cross-reactive to a panel of heterologous gp120 and gp140 antigens. In a second model, we compared the effect of K155M on immunogenicity in the context of gp70 V1V2, gD V1V2 and gp120, examining the effects of scaffold, epitope-focusing and immunization regimen. K155M variants, especially in the context of a gp120 immunogen, resulted in more robust, durable and cross-reactive antibody responses than wildtype immunogens. Restriction of the β-stranded V1V2 conformation in K155M immunogens may thus be associated with the induction of cross-reactive antibody responses thought to be required of a protective HIV-1 vaccine.
| S-EPMC7132531 | biostudies-literature
Project description:BackgroundAccumulating data suggest that immune effector functions mediated through the Fc portion of HIV-1-specific immunoglobulin G (IgG) are a key component of HIV-1 protective immunity, affecting both disease progression and HIV-1 acquisition. Through studying Fc gamma receptor (FcγR) variants known to alter IgG Fc-mediated immune responses, we indirectly assessed the role of FcγR-mediated effector functions in modulating perinatal HIV-1 transmission risk. In this study, genotypic data from 79 HIV-1 infected mothers and 78 HIV-1 infected infants (transmitting cases) were compared to 234 HIV-1 infected mothers and 235 HIV-1 exposed-uninfected infants (non-transmitting controls). Associations, unadjusted and adjusted for multiple comparisons, were assessed for overall transmission and according to mode of transmission-intrapartum (n = 31), in utero (n = 20), in utero-enriched (n = 48).ResultsThe maternal FcγRIIIa-158V allele that confers enhanced antibody binding affinity and antibody-dependent cellular cytotoxicity capacity significantly associated with reduced HIV-1 transmission [odds ratio (OR) 0.47, 95 % confidence interval (CI) 0.28-0.79, P = 0.004; PBonf > 0.05]. In particular, the FcγRIIIa-158V allele was underrepresented in the in utero transmitting group (P = 0.048; PBonf > 0.05) and in utero-enriched transmitting groups (P = 0.0001; PBonf < 0.01). In both mother and infant, possession of an FcγRIIIb-HNA1b allotype that reduces neutrophil-mediated effector functions associated with increased transmission (OR 1.87, 95 % CI 1.08-3.21, P = 0.025; PBonf > 0.05) and acquisition (OR 1.91, 95 % CI 1.11-3.30, P = 0.020; PBonf > 0.05), respectively. Conversely, the infant FcγRIIIb-HNA1a|1a genotype was significantly protective of perinatal HIV-1 acquisition (OR 0.42, 95 % CI 0.18-0.96, P = 0.040; PBonf > 0.05).ConclusionsThe findings of this study suggest a potential role for FcγR-mediated effector functions in perinatal HIV-1 transmission. However, future studies are required to validate the findings of this study, in particular associations that did not retain significance after adjustment for multiple comparisons.
| S-EPMC4902924 | biostudies-literature
Project description:BackgroundBreastfeeding mothers with HIV infection not qualifying for antiretroviral therapy (ART) based on country-specific guidelines at the time of the Promoting Maternal-Infant Survival Everywhere trial and their uninfected neonates were randomized to maternal ART (mART) or infant nevirapine prophylaxis (iNVP) postpartum. HIV transmission proportions were similar (<1%) in the 2 arms. We assessed whether maternal viral load (MVL) and CD4 cell counts were associated with breastfeeding HIV transmission.MethodsMVL was collected at entry (7-14 days postpartum) and at weeks 6, 14, 26, and 50 postpartum. CD4 cell counts were collected at entry and weeks 14, 26, 38, and 50 postpartum. Infant HIV-1 nucleic acid test was performed at weeks 1 and 6, every 4 weeks until week 26, and then every 12 weeks. The associations of baseline and time-varying MVL and CD4 cell counts with transmission risk were assessed using time-to-event analyses by randomized treatment arm.ResultsTwo thousand four hundred thirty-one mother-infant pairs were enrolled in the study. Baseline MVL (P = 0.11) and CD4 cell counts (P = 0.51) were not significantly associated with infant HIV-1 infection. Time-varying MVL was significantly associated with infant HIV-1 infection {hazard ratio [95% confidence interval (CI)]: 13.96 (3.12 to 62.45)} in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 1.04 (0.20 to 5.39)]. Time-varying CD4 cell counts were also significantly associated with infant HIV-1 infection [hazard ratio (95% CI): 0.18 (0.03 to 0.93)] in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 0.38 (0.08 to 1.77)].ConclusionsIn women receiving mART, increased MVL and decreased CD4 cell counts during breastfeeding were associated with increased risk of infant HIV-1 infection.
| S-EPMC8434954 | biostudies-literature
Project description:BACKGROUND:Congenital cytomegalovirus (CMV) infection (cCMV) is an important cause of hearing loss and cognitive impairment. Prior studies suggest that HIV-exposed children are at higher risk of acquiring cCMV. We assessed the presence, magnitude and risk factors associated with cCMV among infants born to HIV-infected women, who were not receiving antiretrovirals during pregnancy. METHODS:cCMV and urinary CMV load were determined in a cohort of infants born to HIV-infected women not receiving antiretrovirals during pregnancy. Neonatal urines obtained at birth were tested for CMV DNA by qualitative and reflex quantitative real-time polymerase chain reaction. RESULTS:Urine specimens were available for 992 (58.9%) of 1684 infants; 64 (6.5%) were CMV-positive. Mean CMV load (VL) was 470,276 copies/ml (range: < 200-2,000,000 copies/ml). Among 89 HIV-infected infants, 16 (18%) had cCMV versus 42 (4.9%) of 858 HIV-exposed, uninfected infants (P < 0.0001). cCMV was present in 23.2% of infants with in utero and 9.1% infants with intrapartum HIV infection (P < 0.0001). Rates of cCMV among HIV-infected infants were 4-fold greater (adjusted OR, 4.4; 95% CI: 2.3-8.2) and 6-fold greater among HIV in utero-infected infants (adjusted OR, 6; 95% CI: 3-12.1) compared with HIV-exposed, uninfected infants. cCMV was not associated with mode of delivery, gestational age, Apgar scores, 6-month infant mortality, maternal age, race/ethnicity, HIV viral load or CD4 count. Primary cCMV risk factors included infant HIV-infection, particularly in utero infection. CONCLUSION:High rates of cCMV with high urinary CMV VL were observed in HIV-exposed infants. In utero HIV infection appears to be a major risk factor for cCMV in infants whose mothers have not received combination antiretroviral therapy in pregnancy.
| S-EPMC6129438 | biostudies-literature