Deciphering the association between HIV-specific immunity and immune reconstitution

Abstract

Numerous observational studies have reported elevated risk of cardiovascular disease, chronic lung disease, infections and cancers among people living with HIV (PLWH) compared to non-HIV infected individuals [1,2]. The association between HIV infection and increased risk of these non-AIDS related comorbidities is strongest for viraemic individuals as highlighted by two pivotal randomized trials, the Strategies for Management of Antiretroviral Therapy (SMART) study and Strategic Timing of Antiretroviral Treatment START study [3,4]. However, even PLWH on long-term ART with suppressed viral replication and high CD4 cell counts appear to have a moderately higher risk of these common comorbidities than people without HIV infection [2]. The cause of this excess comorbidity remains unknown and may be multifactorial. Several causative mechanisms not directly related to the virus have been proposed including life-style factors which can be difficult to account for in epidemiological studies, socioeconomic status, and drug-related toxicities. Indeed, some antiretroviral drugs have been associated with increased risk of specific medical conditions such as myocardial infarction, renal insufficiency, and osteoporosis [5]. However, studies have also shown that HIV itself, despite suppressed plasma HIV RNA, can lead to low-level immune activation which may be a potential driving force for increased risk of non-AIDS related comorbidity [6]. All PLWH harbour a latent HIV reservoir which is not eliminated by antiretroviral therapy (ART) [7]. Low level immune activation can be induced by continuous release of viral proteins from the latent proviral reservoir which triggers a detrimental inflammatory response [6]. The frequency of intact proviruses in individuals on long-term ART is often as low as 1-100 intact proviruses per 1 million CD4 T cells whereas the frequency of defect proviruses may be up to 50 times higher than that of intact proviruses [8]. However, a recent study suggests that even defective proviruses can give rise to HIV