A Window Remains 72 Hours After Birth: Triple Therapy Blocks the SHIV Reservoir in Infant Macaques

Once HIV hides its genetic material in long-lived cells, it forms a reservoir that is difficult to eliminate, allowing the infection to recur rapidly after treatment is stopped even in people who have taken medication long term. A study led by Oregon Health & Science University now shows in a newborn rhesus macaque model that simultaneously interrupting viral replication, entry, and spread very early after infection may alter the course of infection before the reservoir becomes firmly established.

The study, published in *Nature Microbiology*, included 55 infant macaques and compared single, dual, and triple therapies. After the infant macaques were orally exposed to simian-human immunodeficiency virus (SHIV) carrying the HIV envelope, researchers began treatment at 72 hours. By then, the virus was already detectable in the blood, and treatment began later than the previously established window of within 48 hours during which broadly neutralizing antibodies can effectively clear the virus.

The triple regimen comprised 27 weeks of antiretroviral therapy, a single administration of two broadly neutralizing antibodies, PGT121 and VRC07-523LS, and nine consecutive weeks of injections of the CCR5-blocking antibody leronlimab. All eight infant macaques that received the full combination remained free of viremia after treatment was stopped. By comparison, leronlimab alone reduced viral seeding in lymphatic and gastrointestinal tissues but did not eliminate the infection, while antiretroviral drugs combined with broadly neutralizing antibodies also failed to prevent viral rebound.

At follow-up through week 84 after infection, the research team found no viral nucleic acid in blood, lymphatic tissue, or other tissues collected from the triple-therapy group, and detected neither intact nor defective proviruses. The researchers then depleted CD8-positive immune cells that might have been suppressing the infection, yet none of the eight infant macaques experienced viral rebound. This suggests that the outcome was more than temporary immune control of the virus and supports the interpretation that the three mechanisms worked together to prevent the establishment of a persistent viral reservoir.

The key may lie in their complementary effects: antiretroviral drugs suppress replication, broadly neutralizing antibodies intercept free virus and help clear infected cells, and leronlimab occupies the CCR5 coreceptor that the virus requires to enter certain immune cells. Each intervention has gaps when used individually; only by acting simultaneously might the three constrict the pathways available to the virus enough to prevent the infection from being sustained. No clear safety signals affecting weight gain or development in the infant macaques were observed during the study.

However, “undetectable” does not mean that eradication has been demonstrated in humans. The triple-therapy group included only eight animals, the study used SHIV and a high-dose oral exposure model, and treatment had to begin within 72 hours after infection. Whether newborn infection can be confirmed this quickly in clinical practice, the antibodies obtained, and the complex regimen completed are all practical barriers. Leronlimab itself remains an investigational humanized IgG4 monoclonal antibody, and the dosage, safety, and efficacy of this combination in humans must still be addressed through formal clinical trials.