Determining which immunological mechanisms contribute to the development of broadly neutralizing antibodies (bNAbs) during HIV-1 infection is a goal to inform vaccine design. It is not understood if factors during the acute stages of infection impact the generation of neutralization breadth years later.
Utilizing 178 longitudinal samples from 72 HIV-1 infected, ART-naïve individuals within the RV217 cohort, we identified 16 individuals who neutralized >70% of a panel of 34 viruses (broad neutralizers) and 12 individuals not able to neutralize >35% after 3 years of infection (non-broad neutralizers). Founder env genes were sequenced, and gp140 founder Env proteins were produced to characterize respective early autologous B cell responses. Founder Env+ and total B cell populations were phenotyped at pre-infection, peak viral load (day 11-18), month 1 (day 30-43), and chronic infection timepoints (day 391-2115).
Reduced peripheral B cells starting at month 1 post-viremia were predictive of the development of bNAbs (HR=0.37, 95% CI: 0.18-0.76, p=0.007). Individuals with less than 160 B cells/mm3 at month 1 were 42 times more likely to develop neutralization breadth. Reduced peripheral B cells were driven by a reduction in peripheral naïve B cells occurring at 14 days post-viremia. Naïve B cell frequencies at day 14 inversely correlated with frequencies of founder Env-specific (p<0.02), plasmablast (p<0.0001), and integrin beta7+ (p<0.001) B cell populations, suggesting early B cell engagement, differentiation, and migration to lymph nodes. Additionally, increased B cell engagement of respective founder gp140 Envelopes at 1 month predicted the development of bNAbs (OR=1.13, 95% CI: 1.02-1.28, p=0.035). Individuals with high engagement of their respective autologous founder Env at 1 month had a higher probability of developing neutralization breadth compared to individuals with low engagement of their autologous founder Env (p=0.02).
These data demonstrate development of neutralization breadth is influenced by early immunological mechanisms within the first month of acute infection. The reduction of peripheral naïve B cells in broad neutralizers and early, heightened engagement of the founder Env favored the development of broadly neutralizing antibodies, providing evidence that acute infection events lead to downstream functional outcomes.