Plasmatic HIV-1 soluble gp120 is associated with immune dysfunction and inflammation in ART-treated individuals with undetectable viremia

Background Chronic inflammation persists in some people living with HIV (PLWH), even during antiretroviral therapy (ART) and is associated with premature aging. The gp120 subunit of the HIV-1 envelope glycoprotein can shed from viral and cellular membranes and can be detected in plasma and tissues, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasmatic soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, which were previously linked to CD4 depletion in vitro , could contribute to chronic inflammation, immune dysfunction, and sub-clinical cardiovascular disease in participants of the Canadian HIV and Aging cohort (CHACS) with undetectable viremia. Methods Cross-sectional assessment of plasmatic sgp120 and anti-cluster A antibodies was performed in 386 individuals from CHACS. Their association with pro-inflammatory cytokines, as well as subclinical coronary artery disease measured by computed tomography coronary angiography was assessed using linear regression models. Results In individuals with high levels of sgp120, anti-cluster A antibodies inversely correlated with CD4 count (p=0.042) and CD4:CD8 ratio (p=0.004). The presence of sgp120 was associated with increased plasma levels of IL-6. In participants with detectable atherosclerotic plaque and detectable sgp120, sgp120 levels, anti-cluster A antibodies and their combination correlated positively with the total volume of atherosclerotic plaques (p=0.01, 0.018 and 0.006, respectively). Conclusion Soluble gp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of PLWH, contributing to the development of premature comorbidities. Whether drugs targeting sgp120 could mitigate HIV-associated comorbidities in PLWH with suppressed viremia warrants further studies. Key points Soluble gp120 is detected in the plasma of people living with HIV-1 with undetectable viremia. The presence of soluble gp120 and anti-cluster A antibodies is associated with immune dysfunction, chronic inflammation, and sub-clinical cardiovascular disease. ### Competing Interest Statement W.M., M.P., C.T. and A.F. received funding from ViiV Healthcare. A.C. is a full-time employee of ViiV Healthcare. ### Funding Statement The authors thank the CRCHUM BSL3 platform. This study was supported by grants from the National Institutes of Health: R01 AI148379), R01 AI150322 to A.F; R01 AI129769 to A.F and M.P; and R01 AI116274 to MP. It was also supported by a FRQS AIDS and Infectious Diseases Network grant to J.R., M.D. and A.F. This work was also partially supported by a CIHR foundation grant #352417 and a CIHR Team grant #422148 to A.F. The study was also supported by Canada Foundation for Innovation grant #41027 to D.E.K., N.C., and A.F. The Canadian HIV and Aging cohort Study is supported by CIHR team grant on HIV and healthy living (HAL398643 CIHR-IRSC:0635001811) and receives in kind support from the CIHR HIV Clinical Trial Network (CTN-272). This study was also supported by a pilot study grant from the CIHR HIV Clinical Trial Network (CTNPT 052). A.F. is the recipient of a Canada Research Chair on Retroviral Entry #RCHS0235 950-232424. CT is the Pfizer/Universite de Montreal chair on HIV translational research. M.B. was supported by a CIHR fellowship. M.D. is supported by a clinician-researcher salary award from the Fonds de recherche du Quebec-Sante. [Supplemental Figure 1][1] was prepared using illustrations from BioRender. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research project was reviewed and approved by the Centre Hospitalier de l Universite de Montreal (CHUM) Research Ethics Board (Ethics Committee approval number 22.173, 11.063, and 11.062.). Written informed consent was obtained from all study participants, and the research adhered to the standards indicated by the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes [1]: #F5