1. Young macaques infected with simian-human immunodeficiency virus (SHIV) were treated with a combination of two human neutralizing monoclonal antibodies (NmAbs), which prevented plasma viremia for up to 24 weeks post-infection.
2. Animals treated with NmAbs did not develop adaptive immunity towards SHIV and showed no establishment of viral reservoirs.
Evidence Rating Level: 2 (Good)
Study Rundown: Despite the success of antiretroviral therapy (ART), mother-to-child transmission continues to increase the number of childhood HIV cases. Moreover, ART poses risks to newborns and infants, including the development of drug-resistant viral strains. Here, researchers evaluated the efficacy of a cocktail of NmAbs in young macaques over a 6-month period.
Macaques were treated with two NmAbs on days 1, 4, 7, and 10 following SHIV inoculation. Compared to the non-treated group, animals with NmAb treatment showed no detectable virus levels in the plasma or blood cells. Two weeks after infection, virus was absent from the range of organs and tissues evaluated. Over longer periods of time, macaques treated with NmAbs continued to have undetectable levels of SHIV in plasma and blood cell samples. In animals with NmAb treatment, no SHIV-specific T cell responses were observed the blood, spleen or lymph nodes. After the CD8+ T cell population in treated animals was depleted, viremia continued to remain at untraceable levels for several weeks, indicating the absence of viral reservoirs that would be controlled by T cell-mediated suppression.
This work presents important evidence supporting the ability of NmAbs to protect against SHIV infection. In contrast, ART only controls viral replication rate. This study also aids in defining a time window in which NmAb treatment may be effective after exposure to HIV during childbirth. A phase I clinical trial for antibodies similar to the ones presented in this work has demonstrated general safety and tolerance in healthy adults. Follow-up studies to demonstrate safety in HIV-exposed newborns are underway in the U.S. and South Africa.
In-Depth [animal study]: One-month-old macaques were orally infected with a 50% animal infection dose (AID50) of SHIVSF162P3, corresponding to ~7×108 viral RNA copies. Two cocktails of NmAbs (PGT121 and VRC07-523) were prepared at 10mg/kg (5mg/kg for each mAb) or 40mg/kg (20mg/kg for each mAb) and delivered subcutaneously to animals at days 1, 4, 7, and 10 post-SHIV infection. Plasma viral loads (PVL) and cell-associated viral loads (CAVL) of peripheral blood mononuclear cells in 8 animals were monitored using quantitative RT-PCR and quantitative PCR measurements for simian immunodeficiency virus (SIV) RNA copies. Tissue distribution of SHIV in these animals was also monitored using ultrasensitive nested quantitative PCR and RT-PCR targeting for the SIV gag region. By day 14 after infection, animals treated with 40mg/kg NmAbs showed no detectable levels of viral gag copies.
Longitudinal studies that spanned up to 24 weeks post-infection illustrated that PVL and CAVL remained unchanged and undetectable in macaques treated with either the low (n=4) or high (n=6) doses of NmAbs. In the animals with low-dose NmAb treatment, T cell immunity to SHIV components (SIVmac239 proteins Gag and Vif) was probed through intracellular cytokine staining of blood, spleen, and lymph node cells. Fragments of DNA encoding for Gag or Vif did not elicit any inflammatory response from the isolated T cells as measured by flow cytometry, whereas incubation with the positive control staphylococcal enterotoxin B generated a strong increase in immune response. In the animals treated with low doses of NmAbs, CD8+ T cells were depleted using the CD8-α–depleting antibody M-T807R1 24 weeks after initial infection. PVL and CAVL levels in these macaques remained undetectable for up to 4 weeks during the depletion phase.
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