Simian-Human Immunodeficiency Virus SHIV.CH505-Infected Infant and Adult Rhesus Macaques Exhibit Similar Env-Specific Antibody Kinetics, despite Distinct T-Follicular Helper and Germinal Center B Cell Landscapes

Abstract

Global elimination of pediatric human immunodeficiency virus (HIV) infections will require the development of novel immune-based approaches, and understanding infant immunity to HIV is critical to guide the rational design of these intervention strategies. Despite their immunological immaturity, chronically HIV-infected children develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults do. However, the ontogeny of humoral responses during acute HIV infection is poorly defined in infants and challenging to study in human cohorts due to the presence of maternal antibodies. To further our understanding of age-related differences in the development of HIV-specific immunity during acute infection, we evaluated the generation of virus-specific humoral immune responses in infant (n = 6) and adult (n = 12) rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human immunodeficiency virus (SHIV) (SHIV.C.CH505 [CH505]). The plasma HIV envelope-specific IgG antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant differences in the magnitude or breadth of these responses. Interestingly, autologous tier 2 virus neutralization responses also developed with similar frequencies and kinetics in infant and adult RMs, despite infants exhibiting significantly higher follicular T helper cell (Tfh) and germinal center B cell frequencies than adults. Finally, we show that plasma viral load was the strongest predictor of the development of autologous virus neutralization in both age groups. Our results indicate that the humoral immune response to SHIV infection develops with similar kinetics among infant and adult RMs, suggesting that the early-life immune system is equipped to respond to HIV-1 and promote the production of neutralizing HIV antibodies.IMPORTANCEThere is a lack of understanding of how the maturation of the infant immune system influences immunity to HIV infection or how these responses differ from those of adults. Improving our knowledge of infant HIV immunity will help guide antiviral intervention strategies that take advantage of the unique infant immune environment to successfully elicit protective immune responses. We utilized a rhesus macaque model of SHIV infection as a tool to distinguish the differences in HIV humoral immunity in infants versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral immune response to HIV are highly comparable to those of adults during the early phase of infection, despite distinct differences in their Tfh responses, indicating that slightly different mechanisms may drive infant and adult humoral immunity.

Analytical treatment interruption after short-term anti-retroviral therapy in a postnatally SHIV infected infant rhesus macaque model

“…We took the opportunity to compare the viral replication kinetics and reservoir in infant RMs to that of adult RMs infected with the same SHIV strain from a separate study, and thus a cohort of convenience (26). Six adult RMs, were intravenously infected with SHIV.CH505.375H.dCT (see methods) and started on triple ART regimen of TDF, FTC and DTG at 12 w.p.i.…”

“…However, we previously demonstrated that vaccination of infants can induce robust HIV Env-specific IgG responses (41). Moreover, we recently reported that infant monkeys are capable of mounting durable anti-HIV humoral immune responses during acute SHIV infection, despite their maturing immune landscape (26). In this study, we observed comparable humoral immune responses between the two age groups during ART and post-ATI (Figure 6).…”

“…Type D retrovirus-, SIV- and STLV-1 free Indian rhesus macaques (RM) ( Macaca mulatta ) were maintained in the colony of California National Primate Research Center (CNPRC, Davis, CA), as previously described (47). Six infant RMs were orally challenged with SHIV.CH505.375H.dCT (22) as described in (26). Briefly, the infant RMs were challenged at 4 weeks of age by bottle feeding 3 times/day for 5 days at a dose of 8.5×10 4 TCID 50 , to mimic breast milk transmission.…”

“…Within three weeks, 4 more became infected and the final one was challenged at increasing doses (1.3×10 6 TCID 50 , followed by 3.4×10 6 TCID 50 ) until infected at 14 weeks of age (Table 1). Six adult RMs (age between 4-10 years), were intravenously infected with SHIV.CH505.375H.dCT at a dose of 3.4×10 5 TCID 50 as described in (26). The plasma viral RNA load of the monkeys were assessed by highly sensitive qRT-PCR (48).…”

“…HIV antigens were covalently conjugated to polystyrene beads (Bio-Rad), and binding of IgG to the bead-conjugated HIV-1 antigens was measured in RM plasma samples (29). The antigens used for the assay have been described in (26). Purified IgG from pooled plasma of HIV-1 vaccinated macaques (RIVIG) was used as positive control.…”