In the JournalsPerspective

HIV persists in CSF of patients on ART; linked to cognitive impairment

John W. Mellors, MD,
John W. Mellors

Almost half of patients with HIV who are on long-term ART have HIV-infected cells present in their cerebrospinal fluid, or CSF, and these cells are associated with poorer neurocognitive performance, according to findings published in The Journal of Clinical Investigation.

“The research shows persistence of HIV in the fluid surrounding the brain despite long-term clinically effective ART,” John W. Mellors, MD, professor of medicine and chief of the division of infectious diseases at the University of Pittsburgh, told Infectious Disease News. “The brain is likely to be a difficult reservoir to cure of HIV.”

According to Mellors and colleagues, HIV persistence in sanctuary sites like the central nervous system despite ART “presents a barrier to remission and may affect neurocognitive function.” Prior studies have attempted to assess HIV RNA in CSF, but efforts have been limited, they said.

In their analysis, Mellors and colleagues included 69 participants who started ART during chronic infection and were enrolled in the HIV Reservoirs Cohort Study, which was conducted by the AIDS Clinical Trials Group — the world's largest HIV research network. The researchers used sensitive quantitative PCR (qPCR) to measure cell-associated HIV DNA and RNA in peripheral blood mononuclear cells and in cell pellets from CSF. They used qPCR with single-copy sensitivity to measure cell-free HIV RNA in CSF supernatant and blood plasma. They measured inflammatory biomarkers using enzyme immunoassay.

Of the 69 participants, 97% were male. Participants had a median age of 50 years, CD4 cell count of 696 cells/mm3 and plasma HIV RNA of less than 100 copies/mL. They were assessed after a median 8.6 years of ART.

The researchers found that cell-free HIV RNA was present in CSF in just 4% of patients and cell-associated RNA in 9%, but that cell-associated DNA was present in 48% of patients, indicating the presence of latent virus, according to an NIH news release.

Detection of cell-free CSF HIV RNA was associated with higher plasma HIV RNA (P = .007), whereas CSF inflammatory biomarkers did not correlate with HIV persistence measures, the researchers reported.

The presence of CSF cell-associated HIV DNA was associated with worse neurocognitive outcomes (P = .005), even after adjusting for nadir CD4 cell count and patient age, according to Mellors and colleagues. Specifically, 30% of patients with persistent HIV DNA in the CSF were clinically neurologically impaired, compared with 11% among participants with no detectable CSF HIV DNA, they reported.

“While the clinical implications of these findings remain uncertain at present, we do know that HIV persists in the brain despite currently available treatment,” Mellors said. “It’s surprising that almost 50% of people living with HIV/AIDS had infected cells surrounding their brains, despite many years of therapy.” – by Joe Gramigna

Disclosures: Mellors reports working as a consultant for Gilead Sciences and Merck, as well as owning share options in Cocrystal Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures.

John W. Mellors, MD,
John W. Mellors

Almost half of patients with HIV who are on long-term ART have HIV-infected cells present in their cerebrospinal fluid, or CSF, and these cells are associated with poorer neurocognitive performance, according to findings published in The Journal of Clinical Investigation.

“The research shows persistence of HIV in the fluid surrounding the brain despite long-term clinically effective ART,” John W. Mellors, MD, professor of medicine and chief of the division of infectious diseases at the University of Pittsburgh, told Infectious Disease News. “The brain is likely to be a difficult reservoir to cure of HIV.”

According to Mellors and colleagues, HIV persistence in sanctuary sites like the central nervous system despite ART “presents a barrier to remission and may affect neurocognitive function.” Prior studies have attempted to assess HIV RNA in CSF, but efforts have been limited, they said.

In their analysis, Mellors and colleagues included 69 participants who started ART during chronic infection and were enrolled in the HIV Reservoirs Cohort Study, which was conducted by the AIDS Clinical Trials Group — the world's largest HIV research network. The researchers used sensitive quantitative PCR (qPCR) to measure cell-associated HIV DNA and RNA in peripheral blood mononuclear cells and in cell pellets from CSF. They used qPCR with single-copy sensitivity to measure cell-free HIV RNA in CSF supernatant and blood plasma. They measured inflammatory biomarkers using enzyme immunoassay.

Of the 69 participants, 97% were male. Participants had a median age of 50 years, CD4 cell count of 696 cells/mm3 and plasma HIV RNA of less than 100 copies/mL. They were assessed after a median 8.6 years of ART.

The researchers found that cell-free HIV RNA was present in CSF in just 4% of patients and cell-associated RNA in 9%, but that cell-associated DNA was present in 48% of patients, indicating the presence of latent virus, according to an NIH news release.

Detection of cell-free CSF HIV RNA was associated with higher plasma HIV RNA (P = .007), whereas CSF inflammatory biomarkers did not correlate with HIV persistence measures, the researchers reported.

The presence of CSF cell-associated HIV DNA was associated with worse neurocognitive outcomes (P = .005), even after adjusting for nadir CD4 cell count and patient age, according to Mellors and colleagues. Specifically, 30% of patients with persistent HIV DNA in the CSF were clinically neurologically impaired, compared with 11% among participants with no detectable CSF HIV DNA, they reported.

“While the clinical implications of these findings remain uncertain at present, we do know that HIV persists in the brain despite currently available treatment,” Mellors said. “It’s surprising that almost 50% of people living with HIV/AIDS had infected cells surrounding their brains, despite many years of therapy.” – by Joe Gramigna

Disclosures: Mellors reports working as a consultant for Gilead Sciences and Merck, as well as owning share options in Cocrystal Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Anthony S. Fauci

    Anthony S. Fauci

    These findings underscore the difficulty that we will face in getting an absolute HIV cure, where essentially the virus is eradicated from all the cells, as opposed to keeping it suppressed. In patients who are virally suppressed, we would not expect that just the presence of DNA in cells without virus replication would have any kind of functional impact at all. When subtle standard neurocognitive evaluation is performed, we find that the relationship between the presence of viral DNA and cognitive difficulties is very clear. People with more viral DNA in their CSF cells had more cognitive impairment compared with people who did not. The findings from Spudich and colleagues provide further confirmation that it is going to be a difficult task to eradicate a replication-competent virus from every single region of the body, particularly the central nervous system (CNS), which can serve as a protected sanctuary of the virus.

    It is important for clinicians to know that even when their patients seem to be well suppressed with regard to viral load in the peripheral blood, they should still pay attention to the possibility that the patient might have some neurocognitive impairment. The mechanism for finding this out has now been shown in this paper. Most patients had very good control of peripheral viral replication, yet the correlation between the presence of latent HIV DNA in the CNS and cognitive impairment was very clear. 

    • Anthony S. Fauci, MD
    • Director
      National Institute of Allergy and Infectious Diseases

    Disclosures: Fauci reports no relevant financial disclosures.