Background
HIV controllers (HICs) spontaneously control an HIV infection and are important to understand HIV immunopathogenesis. We previously showed that HIV-control associated genetic variants in the MHC locus downregulate IL-1β and TNF-α responses to CMV pp65 in PBMCs in people living with HIV (PLHIV) (CROI 2024, abstract 319). Here, we investigated how cytokine responses are organized in HICs versus non-controllers on cART (non-HICs), and how genetic factors regulate these responses.
Methods
1895 virally suppressed PLHIV were included in the 2000HIV study (NTC03994835), of which 114 were HICs. Cytokine production was measured upon PBMC stimulation with a range of stimuli, and co-regulation was assessed using unsupervised hierarchical clustering in HICs and non-HICs separately. Functional effects of HIV control and CMV response associated SNPs were assessed using gene expression QTL summary statistics from the 2000HIV cohort. Memory responses to CMV pp65 and HIVENV peptides were evaluated by measuring IFN-γ and granzyme B production upon 24-hour PBMC stimulation in 57 PLHIV (55 CMV+) and 41 healthy controls (HC) (23 CMV+) from the 2000HIV-TRAINED cohort (NCT04968717). Finally, we tested the association of imputed classical HLA alleles and amino acids with CMV serostatus using logistic regression in 87 CMV-seronegative (CMV-) and 1180 CMV-seropositive (CMV+) PLHIV.
Results
We observed that pro-inflammatory cytokine responses to CMV pp65 and HIVENV clustered more closely in non-HICs compared to HICs (Figure 1). The HIV-control associated SNPs regulating response to CMV were found to regulate the expression of HLA-B, HLA-C and long non-coding RNAs in the MHC locus, suggesting regulation of memory cell responses to CMV pp65. We confirmed the presence of memory IFN-γ responses to CMV pp65, which were stronger in CMV+PLHIV compared to CMV+HC, and more pronounced than responses to HIVENV in PLHIV. Since MHC variants regulate response to CMV, we tested their effect on CMV serostatus. We found suggestive associations (P < 0.05) with 7 classical HLA alleles and 14 HLA amino acids, of which only HLA-A*31:01 has been associated to HIV control.
Conclusions
HICs have a particular co-regulation of CMV-specific responses. HIV control associated SNPs in the MHC locus downregulate IL-1β and TNF-α responses to CMV pp65, presumably through modulating memory responses, which are stronger in PLHIV compared to healthy controls. The role of CMV-driven inflammation should be considered in functional cure efforts.