HIV 'reservoirs' may form earlier than expected

"Early HIV drugs 'may not stop virus'," BBC News reports. The report is based on a study of HIV treatments in monkeys, and has been linked by the BBC to the emergence of HIV in a four-year-old girl thought to have been cured of the virus as the result of treatment from birth – the so-called "Mississippi girl".

HIV infection levels in the blood can be managed through antiretroviral therapy (ART), allowing most people to live a normal life. But if the therapy is stopped, the virus re-emerges from "viral reservoirs" in the body that are immune to ART.

It was thought these reservoirs are formed during the initial infection, when the virus spreads to the bloodstream. But this study has shown the monkey version of HIV can form reservoirs within three days of infection. This occurs before the virus is detectable in the bloodstream.

It is likely such rapid development of reservoirs also occurs in humans and gives very limited chances of success for current ART to prevent their formation.

This is likely to have happened to the "Mississippi girl", who is reported to have been given ART within hours of birth and for 18 months afterwards, until she stopped attending appointments. The virus was not detectable and she was believed to have been cured, but it has now resurfaced.

Read the latest BBC report on the "Mississippi girl" for more information.

Drug development for treating the HIV virus will therefore continue to focus on new techniques to target the cells in these reservoirs.

Where did the story come from?

The study was carried out by researchers from Harvard and universities and institutes in Massachusetts, Bioqual in Maryland, Gilead Sciences in California, and the US Military HIV Research Program in Maryland.

It was funded by the National Institutes of Health, the US Army Medical Research and Material Command, the US Military HIV Research Program, and the Ragon Institute of MGH, MIT and Harvard.

The study was published in the peer-reviewed journal, Nature.

The BBC reported the story accurately and informatively.

What kind of research was this?

This was an animal study using rhesus monkeys to investigate simian immunodeficiency virus (SIV), a monkey virus similar to HIV. The researchers wanted to investigate the speed of infection – in particular, how quickly "viral reservoirs" are formed.

HIV infection is known to create what are known as viral reservoirs. These are pockets of infected memory CD4+ cells that are the source of reactivation of the virus when antiretroviral therapy (ART) is stopped.

It was believed these reservoirs are formed during the initial stages of infection, when the virus is present in the bloodstream (viraemia), but it was not known how quickly they form.

As ART is largely ineffective against the cells located in the reservoirs, the researchers wanted to know if there is a window of opportunity after infection to prevent the reservoirs forming in the first place.

What did the research involve?

Twenty rhesus monkeys were given an injection of SIV into the lining of the rectum. At this point, the virus was not detectable in the bloodstream.

Some of the monkeys then received antiretroviral therapy (ART), starting on either day 3, 7, 10 or 14 after infection and continued for 24 weeks. Control monkeys did not receive ART.

The monkeys were monitored during the six months to see if and when the virus was detectable in the bloodstream, lymph nodes and rectal lining. They were also monitored for 24 weeks after the ART was stopped to see if or how quickly the SIV came back.

What were the basic results?

After stopping treatment, SIV infection became detectable in the bloodstream of all of the monkeys. This took a little longer to occur in the monkeys that started treatment on day 3 (mean 21 days) compared with days 7, 10 or 14, (mean 7 days), but it still occurred.

This indicated the viral reservoirs, where cells are able to effectively hide from ART, are formed within the first three days of infection with SIV.

The virus was not detectable in the blood of monkeys given ART on day 3, either before the injections started or during the next 24 weeks. The researchers did find the virus in lymph nodes and the rectal lining, but both reduced during ART treatment.

All other monkeys had detectable, rapidly increasing levels of the virus in the blood, lymph nodes and rectal lining. The ART reduced the levels compared with the control monkeys.

The levels of the treated monkeys became undetectable within three to four weeks, and this continued for the treatment period. The control monkeys had sustained, high levels of virus in the bloodstream throughout the length of the study.

Monkeys given ART on days 10 and 14 had viral infection in the lymph nodes, which initially reduced a little but then remained constant from week 12.

How did the researchers interpret the results?

The researchers conclude that: "These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies."

Conclusion

This study has shown SIV infection spreads to locations in the bodies of monkeys, forming "viral reservoirs" during the first three days of infection, before the virus is detectable in the bloodstream.

Cells in the reservoirs are resistant to treatment with ART and are the source of rebound infection when treatment is stopped. Because of the similarities between SIV and HIV, it is likely an equivalent chain of events occurs when humans are infected with the HIV virus.

This appears to have been the case for the "Mississippi girl", a four-year-old girl who was treated with ART for the first 18 months of her life and was presumed to be cured, but has now shown evidence of the infection.

This research indicates drug-resistant HIV reservoirs are likely to occur rapidly during infection in humans, and remain a challenging target for drug development.

Although it is not yet possible to eradicate HIV infection, long-term treatment with ART can help most people live full and normal lives.