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.