neutralizing antibodies can suppress viraemia when given to macaques

Recent studies have isolated antibodies from people infected with HIV that have the remarkable ability to neutralize most circulating strains of HIV-1. Two studies in Nature now show that these neutralizing antibodies can suppress viraemia when given to macaques that are chronically infected with simian–human immunodeficiency virus (SHIV). A third study in Cell also highlights the benefits of antibodies in providing protection to monkeys from repeated challenges with SHIV following vaccination with a synthetic HIV-1 vaccine.

The studies published in Nature confirm previous work in humanized mice and are the first to assess the therapeutic potential of these potent neutralizing antibodies in primates with an intact immune system. Both studies used rhesus macaques infected with pathogenic strains of SHIV (a hybrid virus that uses the HIV envelope for cell entry) that establish sustained set-point viraemia and cause unrelenting depletion of CD4+ T cells. Both groups of investigators observed a rapid and marked decline in viraemia (often to undetectable levels) in chronically infected monkeys following one infusion of individual monoclonal antibodies. This suppression persisted for weeks in some animals but the virus rebounded when monoclonal antibodies were lost below the level of detection. Shingai et al. observed that in some animals the rebound virus was resistant to the effects of the infused antibody but this could be limited by giving a combination of antibodies.

Indeed, further experiments showed that the infusion of combinations of monoclonal antibodies improved viral suppression, although Barouch et al. found that the glycan-dependent antibody PGT121 (alone or in combination) was the most effective in providing prolonged viral suppression. Of note, Barouch et al. also showed that the antibody infusion depleted proviral DNA not only in the blood but also in the gut and lymph nodes, which suggests that the antibodies may be effective against both free virus particles and virally infected cells.

Credit: PIXTAL

Interestingly, Barouch et al. showed that host T cell responses improved after administration of antibodies; in particular, HIV Gag-specific CD8+ T cells showed greater functional capacity and reduced signs of activation-induced exhaustion. The authors suggest that the improved immune responses contributed to the lower set-point of rebound viral loads and the long-term viral control observed in a few monkeys.

Antibodies also take centre stage in the vaccine study published in Cell. Here, the authors tested the ability of a synthetic vaccine comprising bivalent HIV-1 mosaic antigens to protect monkeys from repeated intrarectal challenge with a highly pathogenic (and difficult to neutralize) strain of SHIV. The vaccine was given using prime–boost regimens with various vaccine vector constructs. In all cases, the vaccine induced a variety of antibody responses: binding antibodies, neutralizing antibodies and non-neutralizing antibodies (that function in antibody-dependent complement deposition and antibody-dependent cellular phagocytosis). Strong and broad CD4+ and CD8+ T cell responses were also induced by the vaccine. The vaccine afforded a significant reduction in the acquisition of infection following the first few challenges with SHIV, but this protection reduced following additional challenges, such that after six challenges only three of 23 vaccinated animals remained uninfected. The protective effect correlated with the presence of all types of vaccine-elicited antibody, suggesting that multiple antibody functions contribute to protection against viruses that are difficult to neutralize.

Together, these three studies provide hope and set a precedent for the next phase of studies in humans.