Genetic diversity of the HIV envelope (env) complicates use of broadly neutralizing antibodies (bNAbs) for HIV treatment and cure. Antiretroviral therapy (ART) during acute or early HIV infection (AEHI) restricts reservoir size and diversity, increasing the likelihood of bNAb susceptibility. Successful treatment of ART-suppressed patients with bNAbs requires understanding the evolution of env diversity. We characterized env diversity and bNAb sensitivity at initiation of ART during AEHI and after ART suppression in a multinational prospective study.
Plasma and peripheral blood mononuclear cells (PBMC) were collected pre-ART and after 60 weeks from 89 participants in ACTG A5354 who initiated ART during protocol-defined AEHI: Fiebig I/II (Group 1), Fiebig III/IV (Group 2), or Fiebig V (Group 3). Viral env diversity was assessed by average pairwise distance analysis using a sliding window approach across env. AEHI participant env diversity was compared to virus from individuals in Gilead studies who initiated ART during chronic infection. Susceptibility to bNAbs elipovimab (EVM; PGT121 derivative) and 3BNC117 was determined using previously described env signatures.
Env diversity in pre-ART plasma and PBMC virus was lower in participants initiating ART during AEHI than in chronic infection; there were no significant differences between Fiebig stages (Figure). Env diversity was not correlated with plasma HIV RNA levels at ART initiation. Compared to pre-ART, no significant difference in env diversity after 60 weeks of ART was observed in any group. The proportion of EVM-sensitive sequences did not differ in pre-ART plasma (42/87 [48%]), pre-ART PBMC (44/88 [50%]), and post-ART PBMC (40/79 [51%]) (p=.95). Susceptibility to bNAbs was comparable across groups, with 22/48 (46%) of Group 1, 7/14 (50%) of Group 2, and 13/25 (52%) of Group 3 sensitive to EVM in pre-ART plasma; sensitivities were maintained in pre- and post-ART PBMCs. Similar findings were observed for 3BNC117.
Env diversity was low in AEHI relative to chronic infection and did not differ significantly by Fiebig stage or after 60 weeks of ART. Similarly, susceptibility to bNAbs did not differ by stage of AEHI before or after ART. Collectively, these data argue against major differences in HIV diversity or bNAb sensitivity across AEHI stage or following more than one year of suppressive ART and suggest individuals who initiate ART during AEHI as a desirable population for bNAb treatment or cure trials.