SHIV.CH505-infected infant and adult rhesus macaques exhibit similar HIV Env-specific antibody kinetics, despite distinct T-follicular helper (Tfh) and germinal center B cell landscapes

Abstract

Word count: 224 22 Text Word count: 6,229 23 2 Abstract 24Pediatric HIV infection remains a large global health concern despite the 25 widespread use of antiretroviral therapy (ART). Thus, global elimination of pediatric HIV 26 infections will require the development of novel immune-based approaches, and 27 understanding infant immunity to HIV is critical to guide the rational design of these 28 intervention strategies. Despite their immunological immaturity, HIV-infected children 29 develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults 30 do. Furthermore, T-follicular helper (Tfh) cells have been associated with bnAb 31 development in HIV-infected children and adults. To further our understanding of age-32 related differences in the development of HIV-specific immunity, we evaluated the 33 generation of virus-specific humoral immune responses in infant (n=6) and adult (n=12) 34 rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human 35 immunodeficiency virus (SHIV.C.CH505). The plasma HIV envelope-specific IgG 36 antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant 37 differences in the magnitude or breadth of these responses. Interestingly, autologous 38 tier 2 virus neutralization responses also developed with similar frequency and kinetics 39 in infant and adult RMs, despite infants exhibiting significantly higher Tfh and germinal 40 center B cell frequencies compared to adults. Our results indicate that the humoral 41 immune response to SHIV infection develops with similar kinetics among infant and 42 adult RMs, suggesting that the early life immune system is equipped to respond to HIV-43 1 and promote the production of neutralizing HIV antibodies.44 45 46 Importance 47There is a lack of understanding on how the maturation of the infant immune system 48 influences immunity to HIV infection, or how these responses differ from those of adults. 49Improving our knowledge of infant HIV immunity will help guide antiviral intervention 50 strategies that take advantage of the unique infant immune environment to successfully 51 elicit protective immune responses. We utilized a rhesus macaque model of SHIV 52 infection as a tool to distinguish the differences in HIV humoral immunity in infants 53 versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral 54 immune response to HIV are highly comparable to that of adults during the early phase 55 of infection, despite distinct differences in their Tfh responses, indicating that slightly 56 different mechanisms may drive infant and adult humoral immunity. 57 Word count: 129/150 58 59

Immunological mechanisms of inducing HIV immunity in infants

“…Studies in NHP models can therefore be very useful to further our understanding of neutralization breadth development in early life. Nelson and collaborators recently compared the development nAb responses in infant and adult rhesus macaques infected with T/F SHIV CH505 [44], and observed comparable kinetics in the two groups of animals. However, their study was restricted to the first few months following infection, before the development of neutralization breadth.…”