Defective HIV proviral particles linked to persistent inflammation and immune activation despite effective ART

US researchers at NIAID report that defective HIV, proviral HIV DNA, RNA and proteins were associated with consistent and continued inflammatory responses, despite viral suppression on ART for many years.

The study, published in the journal AIDS, describes expansion of defective HIV proviral particles in people living with HIV who are on suppressive ART. Whilst these particles are not replication competent they are transcriptionally active and may produce HIV-related proteins that trigger immune and inflammatory responses.

The combined cohort study included 23 participants who were split into cross-sectional (n=20) and longitudinal groups (n=3). In the cross-sectional group, five participants had detectable viral load and all others were on suppressive ART (range: 1 to 11 years). The longitudinal group was followed for up to 20 years with data collected at a minimum of five timepoints per person. Median age at enrolment was 47 years (IQR: 38 to 57) and participants were female (n=5), Black (n=5) and Hispanic (n=5).

Across both groups, levels of HIV DNA, RNA and protein were consistent despite prolonged viral suppression. The study identified a pool of PBMCs that were capable of clonal expansion and producing defective provirus. In one participant, 31 unique proviral clones were identified and proviral proteins generated immune responses.

The levels of inflammatory markers (e.g. TNF-ɑ, IL-6 and CRP) correlated with expression of HIV DNA, RNA and associated proteins. D-Dimer positively correlated with levels of detected HIV RNA (r= 0.53, p<0.01) and protein (r= 0.52, p=0.01). CD8 counts correlated with HIV DNA (r= 0.52, p=0.01) and RNA (r= 0.65, p<0.01).

The authors concluded that long-term replication of defective HIV may provide a source of immunogenic material that promotes continued inflammatory responses in people living with HIV even when viral load is undetectable for many years.