Neurocognitive disorder, persistent inverted CD4:CD8 ratios and immune activation in the CNS
Gareth Hardy, HIV i-Base
Given the concerns that HIV positive people commonly have about neurocognitive changes, a recent paper published in the Annals of Clinical and Translational Neurology is important to review in HTB as the suggested link to residual immune activation did not appear to be supported by the research. 
Oliver Grauer and colleagues at the Department of Neurology at the University Hospital Muenster, Germany, investigated whether HIV-associated neurocognitive disorders (HAND) are associated with residual immune activation during antiretroviral treatment (ART), and whether immune activation markers may have utility in identifying those at risk of developing HAND.
HAND generally presents as a subcortical dementia with cognitive, behavioural, and motor decline that occurs over weeks or months, and interferes with activities of daily living and cannot be explained by any other cause of dementia. There are three levels of HAND: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HAD (HIV-associated dementia). Severe cognitive disorders are rare in HIV positive people on ART who have controlled viral loads, however subtle cognitive impairments can be found in as many as 50% of HIV positive people on ART and are particularly associated with CD4 count nadir.
Factors that might be involved in development of neurocognitive dysfunctions during ART include failure of ART to fully suppress HIV replication in the central nervous system and potential toxic effects of anti-retrovirals on the central nervous system. These factors may contribute to a slow, progressive process of brain infection, inflammation and injury that can be characterised by increased levels of inflammatory cytokines in the cerebrospinal fluid (CSF). In an attempt to identify biomarkers that may be predictive of risk for HAND, the researchers assessed whether immune activation makers on CD4 and CD8 T cells in peripheral blood and CSF showed any relation with viral load, the grade of neurocognitive dysfunction or the severity of MRI signal abnormalities.
Grauer and colleagues conducted clinical evaluations that consisted of medical history, standardised neurologic examinations and a neuropsychological assessment for the presence of HAND that were classified according to the following Frascati criteria:
- Grade 0: HIV patients with normal test performances.
- Grade 1: patients with HIV-associated ANI that does not interfere with everyday functioning.
- Grade 2: patients with HIV-associated MND with mild interference in daily functioning.
- Grade 3: patients with HAD with marked interference with day-to-day functioning. MRI scans were also graded according to the severity of cerebral signal abnormalities and abnormalities in the periventricular white matter and the basal ganglia.
Over two years, 86 participants were recruited (male = 71, female = 15) with a median age of 49 years (range 19 to 72 years). 89% of participants were on ART and most had suppressed viral load (<37 copies/mL) in blood (69.8%) and CSF (75.6%) with a median CD4 count of 552 cells/mm3 (range 3 to 1327). The control group consisted of participants who had been suspected of having a neurologic disorder but who were retrospectively found to be suffering from a somatisation disorder. In these participants there was no evidence of elevated inflammatory markers in the CSF. The 17 control participants had a median age of 45 years (range 23–59 years).
The researchers found that the ratio of CD4:CD8 T cells, both in peripheral blood and CSF, was associated with the grade of neurocognitive impairment. The more inverted the CD4:CD8 ratio, the greater the grade of impairment. The researchers next found significant upregulation of the activation marker HLA-DR on CD4 and CD8 T cells in peripheral blood and CSF of HIV positive people in comparison to the control group. The percentage of CD4 T cells that express HLA-DR in peripheral blood and CSF of HIV positive participants was significantly greater than in controls (p <0.0001 for both blood and CSF). The difference in HLA-DR positive CD8 T cells between HIV positive participants and controls was not as strong, though still statistically significant (p <0.01 in peripheral blood and p < 0.05 in CSF).
Though there did not appear to be a difference in the percentage of HLA-DR positive CD4 and CD8 in peripheral blood or CSF according to whether viral load was detectable or not, in virologically suppressed participants the percentage of HLA-DR positive T cells in blood and CSF significantly increased with the severity of neurocognitive impairment. In addition, the percentage of HLA-DR positive CD4 T cells was higher in virologically suppressed participants with more severe cerebral MRI scan signal abnormalities. While the researchers found some relationships between T cell expression of HLA-DR and neurocognitive impairments, they do not at any point justify their choice of HLA-DR as a single activation marker. Most studies that assess pathological T cell activation in HIV infection use HLA-DR in conjunction with CD38, or CD38 in conjunction with memory cell markers. The role of HLA-DR as a single marker of pathological immune activation is contentious and the role of this molecule on the surface of T cells is still not known.
In order to assess whether the associations between neurocognitive dysfunction and immune activation translated into any changes in the distribution of memory and naive T cell populations, the researchers assessed their frequencies in peripheral blood and CSF. While results in peripheral blood confirm population perturbations that have long been known in HIV infection, in CSF only the frequency of naive CD4 T cells was significantly reduced in HIV positive people in comparison to controls (p <0.0001) and terminally differentiated CD4 T cells (p <0.01). Lastly the researchers assessed levels of the immune check-point molecule, programmed death receptor-1 (PD-1), which is associated with antigen- driven T cell exhaustion and chronic activation. In comparison to controls, participants with grade 2-3 (mild or severe) neurocognitive impairment had significantly elevated expression of PD-1 on peripheral blood effector memory CD4 T cells (p <0.01) and central memory CD4 T cells (p <0.05).
This study aimed to identify potential new biomarkers for HAND. CD4:CD8 ratio and the cell surface immune activation marker HLA-DR, in peripheral blood and CSF, may be informative in understanding the pathology of HAND. However their utility as new markers for HAND will have to be determined in larger, more comprehensive studies.
The unsubstantiated claims in this paper includes reporting a correlation between grade of neurocognitive dysfunction and naive and effector cells numbers in the CSF. Although the authors emphasise this point, they show no such correlation, merely that if you take one or two of the most severe grades of impairment as a single group there was a relationship within that group between the numbers of naive and effector cells.
HIV is clearly linked to all sorts of neurological complications, even in the context of ART, but although many studies report associations, the interpretation of the clinical importance of tentative results is more complex.
Neurological problems will – and are – certainly affecting some HIV positive people – just like they affect some HIV negative people – with ageing and other factors being primary risks. HIV positive people might even be at a higher risk for some of these complications – and this study is trying to see whether we can find markers for increased risk.
However, current evidence doesn’t suggest neurological complications will broadly affect all HIV positive people, especially in the context of having undetectable HIV RNA in CSF on ART. Having a lower CD4:CD8 ratio has long been linked to poorer outcomes, so there is plausibility but no interventions that can directly improve the ratio other than earlier diagnosis and earlier use of ART which is already now in guidelines. it is also difficult to know whether this association is just a bystander marker or causally linked – as with the other immunological responses.
Even when studies report small or marginal increased risks in HIV positive people, this is remarkably good news given how extensively HIV is distributed within weeks of infection and that many people have years of unsuppressed infection before starting ART. It is also reassuring that increased rates of Parkinson’s or Alzheimer’s disease, which might plausibly have been expected, have not been reported. 
It will be interesting to see the results from the START neurological substudy. This is an ideal group to see whether either HIV or ART affects cognitive function as it includes a large randomised group with several years uncontrolled HIV, including presumably in the CSF, and a comparison group where ART is likely to have suppressed this to undetectable very early in infection.
- Grauer OM et al. Neurocognitive decline in HIV patients is associated with ongoing T-cell activation in the cerebrospinal fluid. Annals of Clinical and Translational Neurology. 2015 (18 August). Vol 2. 906–919. DOI: 10.1002/acn3.227.
- Moulignier A et al. Does HIV Infection Alter Parkinson Disease? JAIDS (2015): 70(2);129–136. doi: 10.1097/QAI.0000000000000677. (1 October 2015)