Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Sep:48:100780.
doi: 10.1016/j.epidem.2024.100780. Epub 2024 Jun 27.

Assessing the impact of autologous virus neutralizing antibodies on viral rebound time in postnatally SHIV-infected ART-treated infant rhesus macaques

Ellie Mainou  1 , Stella J Berendam  2 , Veronica Obregon-Perko  3 , Emilie A Uffman  4 , Caroline T Phan  4 , George M Shaw  5 , Katharine J Bar  5 , Mithra R Kumar  6 , Emily J Fray  7 , Janet M Siliciano  8 , Robert F Siliciano  8 , Guido Silvestri  9 , Sallie R Permar  10 , Genevieve G Fouda  10 , Janice McCarthy  11 , Ann Chahroudi  3 , Jessica M Conway  12 , Cliburn Chan  11
Affiliations

Assessing the impact of autologous virus neutralizing antibodies on viral rebound time in postnatally SHIV-infected ART-treated infant rhesus macaques

Ellie Mainou et al. Epidemics. 2024 Sep.

Abstract

While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early initiation is not always possible in postnatal pediatric HIV infections. The timing of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear and has never been modeled in infants. To investigate this question we used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. To gain insight into early after analytic treatment interruption (ATI), we constructed mathematical models to investigate the effect of time of ART initiation in delaying viral rebound when treatment is interrupted, focusing on the relative contributions of latent reservoir size and autologous virus neutralizing antibody responses. We developed a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound for RMs rebounding up to 60 days post-ATI. We find that the latent reservoir size is an important determinant in explaining time to viral rebound in infant macaques by affecting the growth rate of the virus. The presence of neutralizing antibodies can also delay rebound, but we find this effect for high potency antibody responses only. Finally, we discuss the therapeutic implications of our findings.

Keywords: Latent reservoir; Mathematical modeling; Neutralizing antibodies; Pediatric HIV; Viral rebound.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Conway has served as a consultant for Excision BioTherapeutics and Merck. Dr. Permar serves a consultant for Moderna, Merck, Pfizer, GSK, Dynavax, and Hoopika on their CMV vaccine program and has led a sponsored program with Moderna and Merck on CMV vaccines.

Figures

Fig. 1.
Fig. 1.
Description of the experiments. Study schematic showing ART timing (gray shaded area) and tissue collection for the three treatment groups.
Fig. 2.
Fig. 2.
Fitted distributions to CD4+ T cell measurements and estimated antibody neutralization. (A) Fitted distributions to total CD4+ T cell counts measured in the late treatment group. The distribution that best explains CD4+ T cell data is logN(19.22, 0.53) (red line). (B) Example of the 4-parameter logistic model fitted curve to the antibody neutralization measurements for the RM RQc19.
Fig. 3.
Fig. 3.
Model schematic. We assume that following ATI, latent cell activations are followed by chains of infection that may die out, i.e., go extinct, with probability q, or successfully re-establish high viral loads associated with chronic infection, with probability 1-q. In the latter case, we further assume a delay τ between activation and the time when plasma viral load crosses the detection threshold.
Fig. 4.
Fig. 4.
Model predictions on time to viral rebound for RMs (gray shaded area) and the average time to viral rebound for the best model (thick, solid line) along with the predicted average time to viral rebound predicted by the null model (dotted line), for (a) all treatment groups combined, (b) the late treatment group, (c) the intermediate treatment group, and (d) the early treatment group.
Fig. 5.
Fig. 5.
Increase in median time to viral rebound through an intervention that elevates the antibody neutralization strength by 10% and 50% (A), or decreases the latent reservoir size by 1 or 2 logs (B). Each point represents a RM from the late treatment group. Green dotted lines represent the mean increase in rebound time across all RMs. For RMs where a 10% and 50% increase in neutralization both give ϕ≥1,PVR is computed for ϕ=1 and these points are represented in black. Cases where the increase leads to different ϕ values are shown in blue.
See this image and copyright information in PMC

Update of

Similar articles

See all similar articles

Cited by

References

    1. Adkins Becky, Leclerc Claude, Marshall-Clarke Stuart, 2004. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4 (7), 553–564. 10.1038/nri1394. - DOI - PubMed
    1. Akaike H, 1974. A new look at the statistical model identification. IEEE Trans. Autom. Control 19, 716–723. 10.1109/TAC.1974.1100705. - DOI
    1. Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, Dewar R, Marovich M, van Griensven F, Sekaly R, Pinyakorn S, Phanuphak N, Trichavaroj R, Rutvisuttinunt W, Chomchey N, Paris R, Peel S, Valcour V, Maldarelli F, Chomont N, Michael N, Phanuphak P, Kim JH, RV254/SEARCH 010 Study Group, 2012. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS One 7, e33948. 10.1371/journal.pone.0033948. - DOI - PMC - PubMed
    1. Bailon Lucia, Mothe Beatriz, Berman Lance, Brander Christian, 2020. Novel approaches towards a functional cure of HIV/AIDS. Drugs 80 (9), 859–868. 10.1007/s40265-020-01322-y. - DOI - PMC - PubMed
    1. Bar KJ, Coronado E, Hensley-McBain T, O’Connor MA, Osborn JM, Miller C, Gott TM, Wangari S, Iwayama N, Ahrens CY, Smedley J, Moats C, Lynch RM, Haddad EK, Haigwood NL, Fuller DH, Shaw GM, Klatt NR, Manuzak JA, 2019. Simian-human immunodeficiency virus SHIV.CH505 infection of rhesus macaques results in persistent viral replication and induces intestinal immunopathology. J. Virol. 93, e00372–19. 10.1128/JVI.00372-19. - DOI - PMC - PubMed

MeSH terms

Substances