Using specialized sequencing technology to analyze a clinically diverse cohort of PWH and PWOH, we find that permissiveness for SARS-CoV-2 replication in PWH who have low CD4 counts – which was often coupled with uncontrolled plasma HIV viremia – is associated with high levels of SARS-CoV-2 spike genetic diversity just days after COVID-19 symptom onset. The gene discussed is CD4; the disease is COVID-19.