The majority of HIV infections in children are from their mothers, called vertical transmission. In order to prevent the development of a similar infection caused by simian-human immunodeficiency virus (SHIV) in infant macaque monkeys, the current research tested two options.
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The first was the use of 2 broadly neutralizing antibodies (bNAbs) in a single dose 30 hours after exposure, or alternatively 21 days of the triple-drug antiretroviral therapy (ART) regimen from 48 hours of exposure. They found that either regimen could achieve complete clearance of the virus in blood and almost no virus in tissues.
This could lead to developing a highly effective treatment regimen for post-exposure prophylaxis (PEP), preventing HIV infection in children born to infected mothers even when there is a delay in instituting treatment.
What is known
Currently, more than 180 000 children get HIV-1 from their mothers each year, either late in pregnancy or during childbirth. Without treatment, 50% of these babies die by the age of 2 years.
Research has already established that HIV-1 infection causes a reservoir of persistent virus to establish itself in the body. Daily ART is the standard of care and eliminates detectable virus in the blood. However, once the treatment stops, the viral load rises again.
Using ART to achieve PEP can be effective within 72 hours of exposure, though the earlier the treatment, the more likely it is to prevent infection. Ideally, PEP would be given by treating the women in late pregnancy and the newborns as soon as they are born. After six weeks of ART, a repeat testing decides whether the babies must have the treatment for life or if infection has been successfully prevented.
Even if the women are not treated, ART within 48 hours of birth reduces the chances of infection with the virus, but not when begun at 72 hours or later. ART must then be given lifelong in the vast majority of cases to keep the blood free of detectable virus.
Simian immunodeficiency virus (SIV) and chimeric simian-human immunodeficiency virus (SHIV) have been used in nonhuman primates to find out how the virus spreads and how well it is suppressed by pre-exposure and PEP. Scientists found that both viruses spread fast in the infant macaques and can be detected in one day in peripheral tissues.
Other studies showed that adult macaques achieved very good control of viremia after a 600-day course of ART starting within 4-5 days of infection with SIV, which lasted after stopping treatment, but not if the ART start was delayed to 6 days after infection.
ART has many difficulties when it comes to treating infants. It is a complex regimen, tastes bad, must be given often, and, if not administered properly, leads to drug resistance. Side effects are also a worry, as is the potential for long-term consequences on the future development of the child.
Treatment with bNAbs is superior in allowing longer dosing intervals, simpler regimens, and the ability to eliminate infected cells via the host immune system. Powerful bNAbs have been shown to prevent SHIV infection in other primates, and chronic human infection was transiently controlled as well.
In infant macaques, short-term courses of bNAbs cleared the virus completely and durably when given a day after SHIV exposure. The exact duration to which this can be achieved needed to be defined in the face of the oft-occurring delay in treatment of a baby exposed to HIV in real-life. This was the focus of the present study.
The scientists looked at the effects of treating exposed one-month-old infant macaques from 30 hours to 2 days after exposure, either with one dose of 2 bNAbs at 40mg/kg at 30 hours or with 4 doses of bNAbs at 10 mg/kg from 48 hours following exposure.
The first regimen completely and permanently cleared the virus. The second showed similar results in only 50% of cases. The half-life of the bNAbs was significantly longer with the single-dose treatment than with the 4-dose regimen.
Alternatively, they administered a short course of ART for 21 days from 2 days post-exposure and found no virus in blood after stopping therapy, with little or no virus detectable in tissues.
The researchers say their findings show some of the variables that decide the duration of the period in which PEP can be achieved in newborns, and also that virus can be cleared completely using either single-dose bNAbs or ART in this model.
The mechanism of tight control in either case (ART or bNAbs ) is not via adaptive immunity, apparently. The use of bNAbs is associated with antibody-mediated killing of infected cells, but both bNAbs and ART act at this stage primarily by preventing the replication and spread of the virus.
More work will be needed to find out how this tight control is achieved, whether because it prevents seeding of a virus reservoir which can later give rise to replicating viruses or because of localized innate immunity, an unfit virus, the cell’s own resistance to the infection, trapping of the virus in one or more sites, or a combination of these factors. The scientists want to know: do the bNAbs kill or only limit replication of the virus?
They will also need to test this method in newborn macaques to find out how the immune system contributes to this tight control because, at one month of age, the immunological responses show rapid development. Finally, the use of a combination of bNAbs and ART should be tested for its efficacy in preventing infection in newborns who are exposed during birth or while breastfeeding.
Shapiro, M.B. et al. (2020). Single-dose bNAb cocktail or abbreviated ART post-exposure regimens achieve tight SHIV control without adaptive immunity. Nature Communications. DOI: https://doi.org/10.1038/s41467-019-13972-y