No Conflicts of Interest to declare. HIV Reservoirs in the Brain and its Association with Sex and Neurocognition during Virologically Suppressive ART Michelli F. Oliveira1, Masato Nakazawa1, Andrej Vitomirov1, Mitchell Zhao1, Ben Gouaux1, David Moore1, Ron Ellis1, Davey Smith1,2, Sara Gianella1 Abstract #: MOPDA0103 Thank you to all the study participants! No Conflicts of Interest to declare.

Approach OUR GOALS Compare HIV DNA levels in post-mortem brain tissues from ART suppressed HIV-infected women and men. Evaluate its association with pre-mortem neurocognitive functioning. 63 virologically suppressed HIV-infected cases from the National NeuroAids Tissue Consortium: 12 women and 51 men. Neurocognitive (NC) functioning: t-scores (7 neuropsychological abilities) at last visit (3 months before death). Paired Post-mortem: [i] frontal (FC) [ii] occipital cortex (OCC) [iii] basal ganglia (BG) [iv] peripheral lymph tissues (lymph node or spleen). Levels of HIV DNA (gag and 2-LTR) by ddPCR, normalized for cells input (rpp30).

Results HIV gag: majority of brains (65%) and all lymph tissues; 2-LTR: 21% of brains and 54% of lymph tissues. Lymph tissue had higher levels of HIV DNA than brain tissues (p<0.01), but did not predict the levels in brain tissues (p=0.7). BG and FC had similar levels of HIV DNA (p>0.2); OCC had lower levels than the other brain regions (p=0.01). Women had higher levels of HIV DNA in tissues (gag: p=0.03; 2-LTR, p=0.05). None of the tested covariates (age, EDI, time on ART, most recent CD4, race, study site) were associated with HIV DNA levels (all p>0.1). Overall, lymph tissue had significantly higher levels of both gag and 2-LTR than brain tissues (p-values <0.01), but no correlation between lymph HIV DNA and brain tissues (p=0.7). BG and FC had similar levels of HIV DNA (p>0.2), while OCC had lower levels compared to the other brain regions (p=0.01);. the 3 regions had similar 2-LTR levels (p>0.2). Figure 1 shows the log levels of HIV DNA (gag and 2-LTR)/million of cells across lymph and brain tissues. Pink represents women and blue represents men: Female sex was associated with higher levels of HIV gag and 2-LTR in brain and lymph tissues (gag: p=0.03; 2-LTR, p=0.05). None of the tested covariates (age, EDI, time on ART, CD4, race, study site) were associated with HIV DNA levels (all p>0.1). NOTE that in the abstract we reported a negative correlation with age but it was NOT confirmed when we analyzed the full dataset.

Results Levels of HIV gag in OCC were associated with worse NC functioning (p=0.04) in both sexes; 2-LTR levels were not associated with NC functioning (p>0.2). Sex-differences in NC functioning were observed in Motor and Speed of Information processing sub-domains, with women having better functioning (p<0.05), regardless of HIV gag levels. Overall, NC functioning ranged from mild to moderate impaired. The figure shows the associations between levels of HIV gag in OCC and NC functioning (measured t-scores) by sex. Levels of HIV gag in OCC were negatively associated with global t-score (p=0.04) in both sexes; 2-LTR in any of the brain regions was not associated with t-score (p>0.2) (figure on the left). When evaluating NC sub-domains, levels of HIV gag in OCC was negatively associated with motor t-score (p<0.01), regardless of sex (Figure on the right). Sex-differences in NC functioning were observed in Motor and Speed of Information processing sub-domains, with women having better functioning (p<0.05), regardless of HIV gag levels.

Conclusions Our study shows a differential distribution of HIV reservoirs in the brain. Lymph tissues HIV DNA levels do not predict the levels in brain, suggesting that HIV persistence in brain tissue might be driven by different mechanisms. Higher levels of HIV reservoir in women may be due to higher HIV replication in tissues (measured by levels of 2-LTR). Levels of HIV DNA in OCC poorer global NC functioning and the motor sub-domain. Future studies including larger cohorts, especially with an increased number of women are needed to confirm our findings