Emergence of neutralizing antibodies associates with clearance of SARS-CoV-2 during HIV-mediated immunosuppression

To design effective vaccines and other immune interventions against a pathogen, it is necessary to know which aspect of immunity associates with protection. We investigated whether neutralizing antibodies associate with infection clearance in long-term SARS-CoV-2 infection during HIV-mediated immunosuppression. We monitored neutralizing antibody activity against SARS-CoV-2 over 1 to 2 years in five participants with advanced HIV disease and delayed control of HIV viremia. These participants had persistent SARS-CoV-2 infection ranging from 110 to 289 days which was associated with low or undetectable neutralizing antibody responses. SARS-CoV-2 clearance was associated with the emergence of neutralizing antibodies and occurred in two participants before suppression of HIV viremia, but after some CD4 T cell reconstitution. Vaccination only further increased neutralizing antibody levels in the advanced HIV disease participants who achieved HIV suppression pre-vaccination. During the prolonged SARS-CoV-2 infection we observed widespread evolution which was particularly pronounced in one Delta variant infection. This resulted in high-level escape from Delta-elicited neutralizing antibodies and a virus antigenically distinct from both ancestral SARS-CoV-2 and Omicron XBB in hamster experimental infections. The results offer new evidence that neutralizing antibodies associate with SARS-CoV-2 clearance and argue that successful management of HIV may be necessary to curtail long-term infection and evolution of co-infecting pathogens. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Bill and Melinda Gates award INV-018944 (AS), Wellcome Trust Award 226137/Z/22/Z (AS and PLM) and the South African Medical Research Council (AS and PLM). PLM is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa. 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: All blood samples used for neutralization studies, nasopharyngeal swabs from the advanced HIV disease participants for outgrowth and sequencing, as well as nasopharyngeal swabs for isolation of the ancestral/D614G, Beta, and Delta virus were obtained after written informed consent from adults with PCR-confirmed SARS-CoV-2 infection enrolled in a prospective cohort of SARS-CoV-2 infected individuals at the Africa Health Research Institute approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal (reference BREC/00001275/2020). The Omicron/BA.1 virus was isolated from residual swab used for diagnostic testing (Witwatersrand Human Research Ethics Committee reference M210752). The nasopharyngeal swab for isolation of the Omicron XBB.1.5 subvariant was collected after written informed consent as part of the COVID-19 transmission and natural history in KwaZulu- Natal, South Africa: Epidemiological Investigation to Guide Prevention and Clinical Care in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) study and approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal (reference BREC/00001195/2020, BREC/00003106/2021). 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 All data produced in the present work are contained in the manuscript