A new paper published in The Lancet Microbe details the case of a person living with advanced HIV who remained persistently infected with SARS-CoV-2 for 776 days. The study, led by researchers at Boston University and the Harvard T.H. Chan School of Public Health, documents extensive within-host viral evolution and mutations overlapping with those later seen in the Omicron variant.
While this is a single case, it offers valuable insights into the potential for persistent infections in immunocompromised individuals to serve as environments for the emergence of significant viral mutations.
Case Overview and Genomic Findings
The patient, a 41-year-old man with untreated HIV and profound immunosuppression (CD4+ count <35), first developed COVID-19 symptoms in May 2020 but was not diagnosed until September that year. Despite repeated hospitalizations and positive PCR tests, he never received antiretroviral therapy (ART) for HIV or therapeutics for COVID-19. He remained viremic until his death in July 2022 from causes not directly linked to SARS-CoV-2.
Eight clinical samples were sequenced over the course of infection. Genomic analysis revealed 68 consensus and 67 subconsensus single nucleotide variants (SNVs), including 10 non-synonymous mutations in the spike protein that appeared at the same positions as defining mutations in Omicron (BA.1 and BA.2). Notably, nine of these mutations were present in samples collected before November 2021, prior to Omicron’s emergence.
Mutations and Evolution Within the Host
The virus remained within the early-pandemic B.1 lineage for the entire infection, with no evidence of reinfection or superinfection from other variants such as Alpha, Delta, or Omicron. Despite this, the virus accumulated mutations commonly associated with immune evasion and increased ACE2 binding.
The researchers observed fluctuations in the frequency and composition of subconsensus variants over time, indicating that multiple viral subpopulations were circulating simultaneously within the host. The presence of distinct mutational profiles at different time points supports the idea that within-host viral evolution can proceed along divergent paths—even in a single infection.
Interestingly, the ratio of non-synonymous to synonymous mutations was consistently higher than expected under neutral evolution, suggesting that selective pressures—possibly including adaptation to host-specific conditions—were acting on the virus even in the absence of a strong immune response.
No Detected Onward Transmission, but Implications Remain
Despite high viral loads and the duration of infection, phylogenetic analysis of global SARS-CoV-2 databases showed no evidence of onward transmission from this case. The patient’s viral genomes formed a distinct monophyletic clade, with some fixed mutations extremely rare or unique in global datasets.
This raises the possibility that some adaptations that enhance viral persistence within a host may simultaneously reduce transmissibility—an observation that has been made in other studies of chronic infection.
However, the lack of detected transmission does not eliminate concern. As the authors note, this infection took place in a rural region of South Carolina, with limited public health infrastructure and no wastewater surveillance, making undetected short transmission chains possible.
Broader Significance for Health Security and Surveillance
While only a single case, this infection illustrates a mechanism by which SARS-CoV-2 could acquire combinations of mutations associated with known variants. Similar observations have been made in other long-term infections in immunocompromised hosts, particularly in people with uncontrolled HIV.
The case reinforces the argument that persistent infections should be considered in pandemic preparedness planning. Surveillance systems and clinical protocols that can identify and manage such cases are likely to be increasingly important—not just for patient care, but for understanding and mitigating potential sources of viral evolution.
The National and Global Health Context
Persistent infections in immunocompromised individuals are not rare. According to the CDC, over a third of people with HIV in the U.S. are not virally suppressed. Globally, nearly 10 million people living with HIV are not receiving ART.
This case underscores how gaps in access to HIV treatment—driven by socioeconomic barriers, stigma, and geographic disparities—can have consequences beyond the individual level. As an accompanying commentary by Frances Ue, M.D. and Paul Sax, M.D. notes, “The emergence of SARS-CoV-2 variants in the population further exemplifies how individual health is inextricably linked to the health of the broader community.”
Policy and Practice Implications
- Expand ART access and retention: Ensuring people living with HIV receive and stay on treatment is a critical public health priority, particularly in settings with constrained resources.
- Monitor persistent SARS-CoV-2 infections: Routine genomic surveillance in high-risk populations could help detect unusual patterns of viral evolution early.
- Bridge care gaps: Integrating HIV and COVID-19 care services and addressing social determinants of health are key to preventing long-term, untreated infections.
The findings emphasize that managing long-term infections is not only a matter of improving outcomes for individuals, but also a strategy for preventing future viral variants that may have broader population-level consequences.
Sources and Further Reading
Velasquez-Reyes JM, Schaeffer B, Curry S, et al. Characterisation of a persistent SARS-CoV-2 infection lasting more than 750 days in a person living with HIV: a genomic analysis. The Lancet Microbe, 21 July 2025.
Ue FV, Sax PE. Clinical and public health implications of persistent SARS-CoV-2 infection in a person with HIV disease. The Lancet Microbe, 21 July 2025.