An estimated 39 million people were living with HIV (PLHIV) in 2023, and 630,000 people died from HIV-related illnesses.[1] Advanced HIV disease (AHD), defined immunologically by the World Health Organization (WHO) as a CD4 count less than 200 cells per microlitre (μL),[2] affected approximately 4·3 million PLHIV in 2020,[3] increasing vulnerability to opportunistic infections, malignancies, and death.[4–6] The proportion of PLHIV with CD4 less than 200 cells/μL at antiretroviral therapy (ART) initiation has also been persistently high at around 30% globally since 2015.[7]. The gene discussed is CD4; the disease is mitochondrial DNA depletion syndrome 4a.