Infant transmitted/founder HIV-1 viruses from peripartum transmission are neutralization resistant to paired maternal plasma

Kumar, Amit; Smith, Claire; Giorgi, Elena E.; Eudailey, Joshua; Martinez, David R.; Yusim, Karina; Douglas, Ayooluwa O.; Stamper, Lisa; McGuire, Erin; LaBranche, Celia C.; Montefiori, David C.; Fouda, Genevieve G.; Gao, Feng; Permar, Sallie R.

doi:10.1371/journal.ppat.1006944

Cited by 30 publications

(38 citation statements)

References 67 publications

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“…V H 1-69 was the most frequently occurring allelic variant of Env-specific IgG in both nontransmitting and transmitting mothers. To examine the V H mutation differences among the Envspecific IgG MAbs obtained from nontransmitting and transmitting mothers, we utilized a previously described permutation test which accounts for multiple measurements (i.e., multiple MAbs obtained per patient) from each patient (25). We detected no significant difference in the V H somatic mutation levels of Env-specific IgG MAbs obtained from nontransmitting and transmitting HIV-infected mothers (P ϭ 0.22) (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…HIV can escape from host autologous-virus-neutralizing antibodies via several mechanisms, which include shifting Env glycans, epitope sequence alteration, and conformational masking of proximal and distal epitopes (23,24). We recently reported that infant-transmitted founder (infant-T/F) viruses are more neutralization resistant to paired maternal-plasma viruses than to nontransmitted maternal-plasma viruses, indicating that a potential mechanism by which infant-T/F viruses are selected is via the escape from maternal-plasma autologous-virus-neutralizing antibodies (25). A better understanding of the evolution dynamics of maternal neutralizing antibodies and maternal autologous viruses, which is the precursor pool of the infant-T/F viruses, will be important to design immunologic strategies to block the vertical transmission of HIV.…”

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confidence: 99%

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Maternal Broadly Neutralizing Antibodies Can Select for Neutralization-Resistant, Infant-Transmitted/Founder HIV Variants

Martinez

Tu²,

Kumar³

et al. 2020

mBio

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Each year, >180,000 infants become infected via mother-to-child transmission (MTCT) of HIV despite the availability of effective maternal antiretroviral treatments, underlining the need for a maternal HIV vaccine. We characterized 224 maternal HIV envelope (Env)-specific IgG monoclonal antibodies (MAbs) from seven nontransmitting and transmitting HIV-infected U.S. and Malawian mothers and examined their neutralization activities against nontransmitted autologous circulating viruses and infant-transmitted founder (infant-T/F) viruses. Only a small subset of maternal viruses, 3 of 72 (4%), were weakly neutralized by maternal linear V3 epitope-specific IgG MAbs, whereas 6 out of 6 (100%) infant-T/F viruses were neutralization resistant to these V3-specific IgG MAbs. We also show that maternal-plasma broadly neutralizing antibody (bNAb) responses targeting the V3 glycan supersite in a transmitting woman may have selected for an N332 V3 glycan neutralization-resistant infant-T/F virus. These data have important implications for bNAb-eliciting vaccines and passively administered bNAbs in the setting of MTCT. IMPORTANCE Efforts to eliminate MTCT of HIV with antiretroviral therapy (ART) have met little success, with >180,000 infant infections each year worldwide. It is therefore likely that additional immunologic strategies that can synergize with ART will be required to eliminate MTCT of HIV. To this end, understanding the role of maternal HIV Env-specific IgG antibodies in the setting of MTCT is crucial. In this study, we found that maternal-plasma broadly neutralizing antibody (bNAb) responses can select for T/F viruses that initiate infection in infants. We propose that clinical trials testing the efficacy of single bNAb specificities should not include HIV-infected pregnant women, as a single bNAb might select for neutralization-resistant infant-T/F viruses.

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Section: Resultsmentioning

confidence: 93%

mentioning

confidence: 99%

Maternal Broadly Neutralizing Antibodies Can Select for Neutralization-Resistant, Infant-Transmitted/Founder HIV Variants

Martinez

Tu²,

Kumar³

et al. 2020

mBio

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“…SGA. Single-genome amplification (SGA) of plasma virus was done as described previously (63). The primer used for cDNA preparation was SHIVEnv.R3out.…”

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confidence: 99%

Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model

Goswami

Nelson

et al. 2019

mBio

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To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure. IMPORTANCE Novel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children, who currently rely on lifelong ART. Considering the risks and expense associated with ART interruption trials, the identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant nonhuman primate models of HIV rebound. In this study, we developed an infant RM model of oral infection with simian-human immunodeficiency virus expressing clade C HIV Env and short-term ART followed by ATI, longitudinally characterizing the immune responses to viral infection during ART and after ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of the time to viral rebound after ATI.

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“…On the other hand, non-transmitted (NT) variants constitute a genetically diverse population of HIV-1 isolates that are sensitive to maternal antibodies 27 . Studies have shown that the viral variants in the transmitting partner were different from the transmitted founder virus in the newly infected partner 25 .…”

Section: Definition Of Tf and Nt Variantsmentioning

confidence: 99%

In vitro replicative fitness of early Transmitted founder HIV-1 variants and sensitivity to Interferon alpha

Ashokkumar

Sonawane

Sperk

et al. 2020

Sci Rep

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Type I interferons, particularly interferon-alpha (IFN-α), play a vital role in the host's anti-viral defensesby interfering with viral replication. However, the virus rapidly evolves to exploit the IFN-α response for its replication, spread, and pathogenic function. In this study, we attempted to determine IFN-α susceptibility and productivity of infectious transmitted/founder (TF) (n = 8) and non-transmitted (NT) viruses (n = 8) derived from HIV-1 infected infants. Independent experiments were carried out to determine IFN-α resistance, replication fitness, and viral productivity in CD4 + T cells over a short period. In vitro studies showed that TF viruses were resistant to IFN-α during the very near moment of transmission, but in the subsequent time points, they became susceptible to IFN-α. We did not observe much difference in replicative fitness of the TF viruses in cultures treated with and without IFN-α, but the difference was significant in the case of NT viruses obtained from the same individual. Despite increased susceptibility to IFN-α, NT viruses produced more viral particles than TF viruses. Similar results were also obtained in cultures treated with maraviroc (MVC). The study identified unique characteristics of TF viruses thus prompting further investigation into virus-host interaction occurring during the early stages of HIV infection. Determination of saturation point for maraviroc. TZM-bl and GHOST (3) CCR5+ (Hi-5) celllines were employed to assess the sensitivity of chimeric viruses to the CCR5 antagonist, maraviroc. Briefly, 10 4 TZM-bl and Hi-5 cells were plated in each well of a 96-well plate 24 hours before infection. Cells were incubated with different dilutions of MVC (10-fold dilutions starting from 10 μM up to 10 −3 nM) overnight at 37 °C before inoculation with chimeric viruses. Virus infected cells cultured in the absence of MVC served as negative control. At 48 hours post-infection, cells were lysed with 1X passive lysis buffer (Bright-Glo luciferase assay system) and luciferase expression was measured using an Infinite M200Pro plate reader (Tecan, Switzerland) as the number of relative light units (RLU). All conditions were tested in triplicate in each of at least two independent experiments.Single round virus replication kinetics assay. For single cycle infectivity assay, virus stocks normalized by TCID 50 and further diluted to 0.01 MOI were used to infect TZM-bl cells (1 × 10 4 cells/well) in triplicates in the presence of DEAE dextran (10 μg/mL). Cells were pre-incubated for 2 hours with different concentrations (0, 250, 500 and 750 IU/mL) of IFN-α at 37 °C before infection with chimeric viruses. 48 hours after infection, luciferase activity was measured using the Bright-Glo luciferase assay system (Promega). Multiple round virus replication kinetics assay. CD4 + T cells were isolated from buffy coats by deplet-ing CD8 + T cells and stimulated with PHA (20 μg/mL) in the presence of 20 U/mL IL-2 in RPMI medium containing 10% FBS at a concentration of 1 × 10 6 cells per milliliter....

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Infant transmitted/founder HIV-1 viruses from peripartum transmission are neutralization resistant to paired maternal plasma

Cited by 30 publications

References 67 publications

Maternal Broadly Neutralizing Antibodies Can Select for Neutralization-Resistant, Infant-Transmitted/Founder HIV Variants

Maternal Broadly Neutralizing Antibodies Can Select for Neutralization-Resistant, Infant-Transmitted/Founder HIV Variants

Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model

In vitro replicative fitness of early Transmitted founder HIV-1 variants and sensitivity to Interferon alpha

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