Maternal HIV-1 envelope–specific antibody responses and reduced risk of perinatal transmission

Permar, Sallie R.; Fong, Youyi; Vandergrift, Nathan; Fouda, Genevieve G.; Gilbert, Peter B.; Parks, Robert; Jaeger, Frederick H.; Pollara, Justin; Martelli, A; Liebl, Brooke E.; Lloyd, Krissey E.; 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.; Holle, Tarra Von; 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 F.

doi:10.1172/jci81593

Cited by 70 publications

(117 citation statements)

References 29 publications

(23 reference statements)

Supporting

Mentioning

112

Contrasting

Order By: Relevance

“…In the WITS cohort, maternal V3-specific IgG binding responses predicted reduced MTCT risk (odds ratio [OR] ϭ 0.86; confidence interval [CI] ϭ 0.75 to 1.00; P ϭ 0.04) (22). The V3 loop, located near the apex of HIV Env gp120, has been previously described as the principal neutralizing domain (PND), as it is readily accessible to V3-specific binding and neutralizing antibodies (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Studies have also evaluated the association of maternal plasma neutralization breadth and MTCT risk with inconclusive results (20,21). To gain a deeper understanding of the role of maternal protective antibody (Ab) responses during MTCT, our group recently conducted a comprehensive maternal humoral correlate of risk against MTCT of HIV using samples from the historic Women and Infant Transmission Study (WITS), a North American clade B infection cohort that was enrolled prior to the availability of ART (22). We identified an association between high levels of maternal plasma V3-specific IgG binding and tier 1 ("easy-to-neutralize") virus-neutralizing responses with lower MTCT risk (22).…”

Section: Importancementioning

confidence: 99%

“…To gain a deeper understanding of the role of maternal protective antibody (Ab) responses during MTCT, our group recently conducted a comprehensive maternal humoral correlate of risk against MTCT of HIV using samples from the historic Women and Infant Transmission Study (WITS), a North American clade B infection cohort that was enrolled prior to the availability of ART (22). We identified an association between high levels of maternal plasma V3-specific IgG binding and tier 1 ("easy-to-neutralize") virus-neutralizing responses with lower MTCT risk (22). Importantly, it was recently shown that Env-specific IgG antibodies that mediate tier 1 virus-neutralizing activity exert immune pressure on autologous circulating viruses and therefore select for neutralization-resistant autologous viruses that repopulate the plasma virus pool (23).…”

Section: Importancementioning

confidence: 99%

“…Therefore, the ability of maternal antibodies to neutralize concurrently circulating autologous viruses may be an important feature for blocking infection against MTCT of HIV. We hypothesized that maternal plasma tier 1 virus-neutralizing activity that predicted reduced risk of MTCT of HIV could be a surrogate marker for maternal autologous virus-neutralizing antibodies (22). Therefore, defining the epitope specificities of maternal tier 1 virus-neutralizing antibodies is important for designing maternal vaccine strategies aimed at reducing MTCT risk.…”

Section: Importancementioning

confidence: 99%

“…In the setting of MTCT of HIV, we also found maternal V3-specific IgG binding responses targeting amino acid residues in the C-terminal region V3 to be associated with reduced MTCT risk. In this study, we employed a multivariable logistic regression model to define the fine specificity and neutralizing function of potentially protective maternal V3-specific IgG responses using transmitting (case) and nontransmitting (control) maternal plasma samples from the WITS cohort (22). Further defining the fine specificity and function of maternal V3-specific IgG responses that are predictive of reduced MTCT risk could inform maternal immunization strategies aimed at temporarily raising the level of potentially protective V3-specific antibodies targeting autologous maternal viruses.…”

Section: Importancementioning

confidence: 99%

See 4 more Smart Citations

Maternal Binding and Neutralizing IgG Responses Targeting the C-Terminal Region of the V3 Loop Are Predictive of Reduced Peripartum HIV-1 Transmission Risk

Martinez

Vandergrift²,

Douglas³

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

The development of an effective maternal HIV-1 vaccine that could synergize with antiretroviral therapy (ART) to eliminate pediatric HIV-1 infection will require the characterization of maternal immune responses capable of blocking transmission of autologous HIV to the infant. We previously determined that maternal plasma antibody binding to linear epitopes within the variable loop 3 (V3) region of HIV envelope (Env) and neutralizing responses against easy-to-neutralize tier 1 viruses were associated with reduced risk of peripartum HIV infection in the historic U.S. Woman and Infant Transmission Study (WITS) cohort. Here, we defined the fine specificity and function of the potentially protective maternal V3-specific IgG antibodies associated with reduced peripartum HIV transmission risk in this cohort. The V3-specific IgG binding that predicted low risk of mother-to-child-transmission (MTCT) was dependent on the C-terminal flank of the V3 crown and particularly on amino acid position 317, a residue that has also been associated with breakthrough transmission in the RV144 vaccine trial. Remarkably, the fine specificity of potentially protective maternal plasma V3-specific tier 1 virus-neutralizing responses was dependent on the same region in the V3 loop. Our findings suggest that MTCT risk is associated with neutralizing maternal IgG that targets amino acid residues in the C-terminal region of the V3 loop crown, suggesting the importance of the region in immunogen design for maternal vaccines to prevent MTCT. IMPORTANCE Efforts to curb HIV-1 transmission in pediatric populations by antiretroviral therapy (ART) have been highly successful in both developed and developing countries. However, more than 150,000 infants continue to be infected each year, likely due to a combination of late maternal HIV diagnosis, lack of ART access or adherence, and drug-resistant viral strains. Defining the fine specificity of maternal humoral responses that partially protect against MTCT of HIV is required to inform the development of a maternal HIV vaccine that will enhance these responses during pregnancy. In this study, we identified amino acid residues targeted by potentially protective maternal V3-specific IgG binding and neutralizing responses, localizing the potentially protective response in the C-terminal region of the V3 loop crown. Our findings have important implications for the design of maternal vaccination strategies that could synergize with ART during pregnancy to achieve the elimination of pediatric HIV infections.KEYWORDS HIV, mother-to-child transmission, V3, antibodies

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Importancementioning

confidence: 99%

Section: Importancementioning

confidence: 99%

Section: Importancementioning

confidence: 99%

Section: Importancementioning

confidence: 99%

See 3 more Smart Citations

Maternal Binding and Neutralizing IgG Responses Targeting the C-Terminal Region of the V3 Loop Are Predictive of Reduced Peripartum HIV-1 Transmission Risk

Martinez

Vandergrift²,

Douglas³

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

Change point testing in logistic regression models with interaction term

Fong

Permar³

2015

Statist. Med.

Self Cite

View full text Add to dashboard Cite

A threshold effect takes place in situations where the relationship between an outcome variable and a predictor variable changes as the predictor value crosses a certain threshold/change point. Threshold effects are often plausible in a complex biological system, especially in defining immune responses that are protective against infections such as HIV-1, which motivates the current work. We study two hypothesis testing problems in change point models. We first compare three different approaches to obtaining a p-value for the maximum of scores test in a logistic regression model with change point variable as a main effect. Next, we study the testing problem in a logistic regression model with the change point variable both as a main effect and as part of an interaction term. We propose a test based on the maximum of likelihood ratios test statistic and obtain its reference distribution through a Monte Carlo method. We also propose a maximum of weighted scores test that can be more powerful than the maximum of likelihood ratios test when we know the direction of the interaction effect. In simulation studies, we show that the proposed tests have correct type I error and higher power than several existing methods. We illustrate the application of change point model-based testing methods in a recent study of immune responses that are associated with the risk of mother to child transmission (MTCT) of HIV-1.

show abstract

Maternal Vaccination for Protection Against Maternal and Infant Bacterial and Viral Pathogens

Martinez

Mangold²,

Permar

2020

Mucosal Vaccines

View full text Add to dashboard Cite

Maternal HIV-1 envelope–specific antibody responses and reduced risk of perinatal transmission

Abstract: B r i e f r e p o r t 2 7 0 2

Cited by 70 publications

References 29 publications

Maternal Binding and Neutralizing IgG Responses Targeting the C-Terminal Region of the V3 Loop Are Predictive of Reduced Peripartum HIV-1 Transmission Risk

Maternal Binding and Neutralizing IgG Responses Targeting the C-Terminal Region of the V3 Loop Are Predictive of Reduced Peripartum HIV-1 Transmission Risk

Change point testing in logistic regression models with interaction term

Maternal Vaccination for Protection Against Maternal and Infant Bacterial and Viral Pathogens

Contact Info

Product

Resources

About