HIV infection and immunosenescence: challenges and intervention strategies

Antiretroviral therapy has extended the life expectancy of people with HIV (PWH), leading to a rapidly expanding ageing population of PWH worldwide, including in low- and middle-income countries. The interaction between ageing and chronic HIV infection is closely associated with immunosenescence, and PWH are widely regarded as a model of accelerated immune ageing. Immunosenescence, characterized by a progressive decline in immune function and increased susceptibility to infections, contributes to a higher burden of age-related comorbidities and cancers, posing a major long-term health challenge for this population.

The main focus of this review is on immunosenescence-related phenotypic and functional alterations in innate immune cells in PWH, including natural killer cells, monocytes, macrophages, and dendritic cells. It also outlines immunosenescence-related changes in T and B cells in the context of ageing and chronic HIV infection, such as thymic atrophy, loss of naïve T cell diversity, expansion of terminally differentiated and exhausted T-cell subsets, the impact of cytomegalovirus co-infection, and the emergence of age-associated B cells that impair humoral immunity and vaccine responsiveness. Furthermore, it discusses how persistent low-grade inflammation, mitochondrial damage induced by viral proteins and certain antiretroviral regimens, together with lifestyle factors such as cigarette smoking, accelerate systemic immune ageing, and summarizes emerging therapeutic and lifestyle strategies aimed at mitigating immunosenescence and improving long-term immune health, while noting that robust evidence remains limited.

Despite growing insights into HIV-associated immune ageing, there is still no universally applicable biomarker of immunosenescence. This gap underscores the need to develop robust, population-tailored biomarker panels and targeted interventions for PWH, to support integrated strategies that combine antiretroviral therapy with immune restoration and anti-ageing approaches, ultimately improving immune health and quality of life.