Neuro-HIV: Replication of HIV in Adults in the CNS Early After Infection

March 10, 2014

Replication of HIV within the CNS continues to be a hot topic, because it represents a viral reservoir that can complicate treatment, as well as control and prevention efforts.

Presentation: Replication of HIV-1 in the Central Nervous System of Adults Early After Infection*

Replication of HIV within the CNS continues to be a hot topic, because it represents a viral reservoir that can complicate treatment, as well as control and prevention efforts.

Research presented by Christa Buckheit Sturdevant indicates that in some cases, HIV in the CNS may differ genetically than HIV found in the periphery, and that persistent replication within the CNS may begin early in the course of infection. Her group looked at characteristics and temporal patterns of CSF viral populations in the CNS compared with the blood. Pleocytosis was used as an indication of inflammation and HIV replication in the CNS.

The following patterns of HIV viral populations were considered:
• Compartmentalization: when genetically different viral populations occur in the CNS compared with the blood
• Equilibration: when viral populations are well-mixed and genetically similar between the CNS and the blood

Participants were recruited if they had an HIV diagnosis within the past year and were ART-naive. Blood and CSF samples were collected from 72 patients and were analyzed at time points up to 2 years after infection.

Analysis of CNS inflammation and replication revealed that:
• About two-thirds of participants had low viral loads in the CSF-regardless of the time since infection, indicating minimal replication in the CNS.
• About 19% to 30% had equilibrated viral populations, often with pleocytosis.
• Compartmentalization was not prevalent until about 4 months after infection, indicating that it likely occurs later after HIV exposure.

Analysis of CSF samples that had low viral burdens showed that the concentration of the viral populations in the CSF was about 1% to 2% of the population found in the blood. This could result from viral distribution between the compartments, Sturdevant said, or just normal trafficking of human T cells from the periphery into the CNS.

Pleocytosis was found in about 36% of participants. Viral load was statistically increased in those with equilibrated viral populations and pleocytosis, as well as those with compartmentalization. Two possibilities might account for this:
• Influx of infected T cells from the periphery into the CNS which then release genetically similar virus into the CNS
• Local production of virus within the CNS

Fifty-five percent of participants had high CSF viral loads above the cutoff of >1000 viral RNA copies/mL, and about 20% of participants showed evidence for persistent or intermittent replication in the CNS during the first 2 years of infection. Compartmentalization in the CNS seemed to occur in 2 ways:
• Initial clonal amplification, followed by a second, independent clonal amplification
• Initial clonal amplification, followed by overlapping of clonal amplification, recombination between the two populations, and persistence within the CNS over time

Viral phenotyping indicated that all isolated viruses were T-cell tropic. A small amount of variability in the compartmentalized subjects could indicate HIV replication in different cell types like macrophages, although the jury is still out on this.

“Clonal amplification can be transient, can occur as early as 2 to 3 months postinfection, and is associated with a higher CSF viral load, although persistent replication can occur in the CSF early,” Sturdevant emphasized.

The next step will be to correlate this research with neuropsychiatric clinical data, which has already been performed on the study participants. Integrating the two data sets could provide helpful information about the natural course and pathophysiology of HIV infection in the CNS.

Although translating this type of research into effective treatments you can use with your patients may still be several years down the road, the research presented here could be an important step in that direction.

References:

Session O-2 Oral Abstracts, Tues, March 4, 2014: NeuroHIV: Developments in Treatment and Pathogenesis

Moderators: Edwina J. Wright, The Alfred Hospital, Monash University, Melbourne, Australia, Victor G. Valcour, University of California San Francisco, San Francisco, CA, United States

Presentation: “Replication of HIV-1 in the Central Nervous System of Adults Early After Infection

*Christa Buckheit Sturdevant, UNC Chapel Hill, Chapel Hill, NC, Gretja Schnell, UNC Chapel Hill, Chapel Hill, NC, Richard W. Price, University of California San Francisco, Serena Spudich, Yale University, New Haven CT, Ronald Swanstrom, UNC Chapel Hill, Chapel Hill, NC