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Inflammation in the Brain Continues Even With Undetectable Plasma Viral Load

June 16, 2017

A person living with HIV had an undetectable viral load in the blood but detectable virus in the cerebrospinal fluid (CSF). That virus was resistant to every drug in the person's then-current antiretroviral therapy (ART) regimen. Once the regimen was changed to reflect that resistance, the person's neurological symptoms disappeared. Serena S. Spudich, M.D., of the Yale University School of Medicine gave this example in a recent IAS webinar, but conceded that such cases were "exceedingly rare." They show, however, that the virus not only can penetrate the blood-brain barrier but also, once in the central nervous system (CNS), can replicate independently there. Studies have shown that viral strains in the systemic (body) and CNS compartments can differ substantially, indicating separate viral mutation within the CNS.

More commonly, HIV causes macrophages and microglial cells in the brain to be activated at much higher levels than in people who do not live with HIV. Brain autopsies of people who died suddenly (e.g., in car accidents) have shown this to be the case, even if the person's viral load had otherwise been well controlled. Clinical trials among people with acute HIV found that the virus had migrated to the brain as early as five days after the estimated date of seroconversion. Within four months, the virus started to evolve locally within the CNS, and it had compartmentalized by the end of primary infection. Acute infection occurs during the first three months after the virus is contracted, followed by primary infection between three months and one year after acquiring HIV and chronic infection thereafter.

If ART is started during the acute phase, less viral RNA reaches the brain, fewer macrophages are activated and neuronal injury is prevented. However, even then, some virus persists in the CSF and activates macrophages there. "Shock and kill" strategies for a functional cure of HIV may cause that latent virus to become active, which could lead to neurological damage. This line of cure research relies on activating dormant HIV to then "kill" the virus with antiretrovirals. While the initial inflammation and replication of such "shocked" virus in the blood can be controlled with medication, "We don't know if that is true in the CNS compartment," Spudich cautioned. She advocated for neurological exams to be incorporated into clinical trials that test such strategies.

Treatment interruptions, which are needed to see whether a strategy suppresses HIV without ART, may also cause problems in the brain. One study found very high white blood cell counts, indicating inflammation, in the CSF of participants who had stopped therapy. Treatment interruptions may also cause HIV in the CNS to "leak" back into the blood. Spudich cited the case of someone who had unique viral strains in the CSF before starting ART, took antiretrovirals for some time and then stopped treatment. When that person resumed medical care, the viral strains in their blood were mostly related to the strains in the CSF, not the ones in their blood before ART. However, today's cure studies monitor participants very closely and resume treatment immediately when a person's viral load reaches detectable levels, Spudich noted. This seems to prevent the greater brain inflammation seen in earlier studies.

HIV thus seems to breach the blood-brain barrier rather quickly, then evolve independently in the CNS and continue to activate the immune system there. HIV replication in the brain appears to continue even if a person's viral load in the blood is undetectable. However, immediate ART may reduce that ongoing inflammation, as well as the amount of virus that reaches the brain in the first place. Researchers are investigating the addition of anti-inflammatory drugs to medication regimens during acute HIV to counter that persistent inflammation.

Barbara Jungwirth is a freelance writer and translator based in New York.

Follow Barbara on Twitter: @reliabletran.


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