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. 2024 May 31;6(4):fcae188.
doi: 10.1093/braincomms/fcae188. eCollection 2024.

Self-reported neurocognitive complaints in the Swiss HIV Cohort Study: a viral genome-wide association study

Marius Zeeb  1   2 , Chloé Pasin  1   2 , Matthias Cavassini  3 , Mélanie Bieler-Aeschlimann  3 , Paul Frischknecht  1 , Katharina Kusejko  1   2 , Jacques Fellay  3   4 , François Blanquart  5 , Karin J Metzner  1   2 , Kathrin Neumann  1 , Lisa Jörimann  1   2 , Jasmin Tschumi  1   2 , Enos Bernasconi  6   7 , Michael Huber  2 , Helen Kovari  8 , Karoline Leuzinger  9   10 , Julia Notter  11 , Matthieu Perreau  12 , Andri Rauch  13 , Alban Ramette  14 , Marcel Stöckle  10 , Sabine Yerly  15 , Huldrych F Günthard  1   2 , Roger D Kouyos  1   2 ; Swiss HIV Cohort Study
Collaborators, Affiliations

Self-reported neurocognitive complaints in the Swiss HIV Cohort Study: a viral genome-wide association study

Marius Zeeb et al. Brain Commun. .

Abstract

People with HIV may report neurocognitive complaints, with or without associated neurocognitive impairment, varying between individuals and populations. While the HIV genome could play a major role, large systematic viral genome-wide screens to date are lacking. The Swiss HIV Cohort Study biannually enquires neurocognitive complaints. We quantified broad-sense heritability estimates using partial 'pol' sequences from the Swiss HIV Cohort Study resistance database and performed a viral near full-length genome-wide association study for the longitudinal area under the curve of neurocognitive complaints. We performed all analysis (i) restricted to HIV Subtype B and (ii) including all HIV subtypes. From 8547 people with HIV with neurocognitive complaints, we obtained 6966 partial 'pol' sequences and 2334 near full-length HIV sequences. Broad-sense heritability estimates for presence of memory loss complaints ranged between 1% and 17% (Subtype B restricted 1-22%) and increased with the stringency of the phylogenetic distance thresholds. The genome-wide association study revealed one amino acid (Env L641E), after adjusting for multiple testing, positively associated with memory loss complaints (P = 4.3 * 10-6). Other identified mutations, while insignificant after adjusting for multiple testing, were reported in other smaller studies (Tat T64N, Env *291S). We present the first HIV genome-wide association study analysis of neurocognitive complaints and report a first estimate for the heritability of neurocognitive complaints through HIV. Moreover, we could identify one mutation significantly associated with the presence of memory loss complaints. Our findings indicate that neurocognitive complaints are polygenetic and highlight advantages of a whole genome approach for pathogenicity determination.

Keywords: HIV; cohort study; genome-wide association study; neurocognitive complaints; viral genome.

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Conflict of interest statement

An.R. received research grants from Gilead, paid to his institution; travel expenses from Gilead and Pfizer, paid to his institution; and honoraria for data safety monitoring board or advisory board consultations from MSD and Moderna, paid to his institution. C.P. received personal research grants from the Swiss HIV Cohort Study, Collegium Helveticum and the University of Zurich. E.B. received research grants from MSD, paid to his institution; consulting fees from Moderna, paid to his institution; honoraria for presentations from Pfizer, paid to his institution; travel expenses from ViiV, MSD, Gilead and Pfizer, paid to his institution; and honoraria for data safety monitoring board or advisory board consultations from ViiV, MSD, Pfizer, Gilead, Moderna, AstraZeneca, AbbVie and Ely Lilly, paid to his institution. H.F.G. has received research grants from the Swiss National Science Foundation, Swiss HIV Cohort Study, Yvonne Jacob Foundation, NIH, Gilead, ViiV and Bill and Melinda Gates foundation, paid to his institution; personal honoraria for data safety monitoring board or advisory board consultations from Merck, ViiV healthcare, Gilead Sciences, Janssen, Johnson and Johnson, Novartis and GSK; and personal travel expenses from Gilead. J.N. received research grants from the Swiss HIV Cohort Study and the cantonal hospital St. Gallen, paid to her institution, and travel expenses from Gilead. K.J.M. received unrestricted research grants from Gilead and Novartis, paid to her institution, and personal honoraria for advisory board consultations from ViiV. M.C. received research grants from Gilead, ViiV and MSD, paid to his institution; payment for expert testimony from Gilead, ViiV and MSD, paid to his institution; and travel expenses from Gilead, paid to his institution. M.S. received honoraria for data safety monitoring board advisory board consultations from Gilead, ViiV, Moderna, Pfizer and MSD, paid to his institution, and travel expenses for conferences from Gilead, paid to his institution. P.F. received personal travel expenses from the University Zurich, payment for equipment from the University Zurich and personal honoraria for presentations from the University of Zurich. R.D.K. received research grants from Gilead and NIH, paid to his institution. All other authors report no potential conflicts.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Flowchart showing available SHCS participants with and without SRNCs and HIV-1 genome data (status from 1 May 2023; Subtype distribution: see Supplementary Table 4).
Figure 2
Figure 2
SRNCs among people with HIV (PWH) in Switzerland as the AUC across study visits in the SHCS. SRNCs are defined with the following levels: 0, ‘no’; 1, ‘hardly ever’; and 2, ‘yes, definitely’, for cognitive slowing, concentration difficulties, frequent memory loss and their combination. The bold bar indicates those with an AUC of 0, i.e. PWH who never report the respective SRNCs.
Figure 3
Figure 3
Broad-sense heritability of the SRNCs phenotypes cognitive slowing, concentration difficulties, frequent memory loss and their combination approximated by intraclass correlation (ICC). ICC is estimated by comparison of a mixed tobit model using phylogenetic cluster under specified thresholds as random effects and a tobit model without mixed effects. The number above the bars indicate the test statistic [*test statistic: χ2 (chi2)] and P value of the respective ICC. Phenotypes are calculated as the AUC of longitudinally measured cognitive slowing, concentration difficulties, frequent memory loss or the combination of all three. Analysis was done on 6966 partial ‘pol’ (all subtypes) sequences. Absence of confidence intervals is non-converged models.
Figure 4
Figure 4
Genome-wide association study of the HIV-1 genome (including all subtypes) and associations with SRNCs in people with HIV (PWH). SRNCs are defined as the AUC of longitudinally measured cognitive slowing, concentration difficulties, frequent memory loss or the combination of all three. The P values were calculated with a multivariable tobit model (test statistic: z).
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