Intra-host SARS-CoV-2 diversity in immunocompromised people living with HIV provides insight into the evolutionary trajectory of SARS-CoV-2.

Ongoing viral evolution in immunocompromised individuals with persistent infection may facilitate the evolution of SARS-CoV-2 and emergence of variants of concern (VOC). This study was conducted in the Western Cape Province of South Africa where the HIV prevalence is around 8%, with limited information on the frequency of persistent SARS-CoV-2 infection, the pattern of evolution in these individuals, and if these variants contribute to the diversity of circulating viruses. This study investigated 75 individuals with two or more SARS-CoV-2 diagnoses at least one month apart. Of the 75, 13 were people living with Human Immunodeficiency Virus (PLWH) of which three were immunocompromised, 23 were HIV-negative, and the status of the remaining 39 was unknown. SARS-CoV-2 full-length genome sequence analysis identified 72 as reinfections with a distinct variant and 3 as persistent infections with B.1.1 (20B), B.1.1.459 (20B), and B.1.351 (20H) for 7, 4, and 3 months, respectively. All persistent infections were in severely immunocompromised PLWH with CD4+ T cell count below 30 cells/µL. We identified the emergence of uncommon mutations (global prevalence <0.01%) in SARS-CoV-2, together with permanent and/or transient non-lineage defining mutations with immune escape potential particularly in Spike (141-144del; 241-244del; D215G; E484K; Q498R; P681R; A701V). Some of these mutations were found in later VOCs including Omicron lineages (L18F; 141-144del; D215G; E484K; Q498R; P681R; A701V). Longitudinal viral sequences from these persistent infections provided insights into the evolutionary trajectory of SARS-CoV-2 and are suggestive of convergent evolution and host adaptation. IMPORTANCE: Unlike other respiratory viruses, SARS-CoV-2 has not yet established a seasonal pattern. Thus, resurgence and the emergence of novel variants including VOCs remain a concern. Ongoing SARS-CoV-2 replication in immunocompromised individuals may serve as reservoirs that could facilitate the emergence of mutations conferring transient and/or long-lasting immune escape potential and seed future outbreaks. Two of the five variants, Beta variant and Omicron variant, were first described in Southern Africa-a region with one of the highest rates of HIV infection globally. Targeted genomic surveillance in immunocompromised individuals including PLWH will provide insight into the evolutionary trajectory of SARS-CoV-2 and inform vaccine design that may help to circumvent resurgence.