Data on soluble gp120 (sgp120) and anti-HIV antibodies are lacking in people with HIV (PWH) and multidrug resistance, characterized by high inflammation and disease burden. We aimed to investigate the relationship between immuno-virological features and sgp120, anti-cluster A, anti-p24, and anti-CD4 binding site (anti-CD4bs) antibodies in 4-class drug-resistant (4DR) individuals.

Cross-sectional study on PWH with resistance to nucleoside and non-nucleoside reverse transcriptase, protease, and integrase inhibitors. Sgp120, anti-cluster A, anti-p24, and anti-CD4bs antibodies were measured using enzyme-linked immunosorbent assays. K-means clustering based on normalized anti-cluster A and anti-p24 levels identified antibody profiles. Associations with clinical variables were assessed using descriptive statistics and multinomial logistic regression.

Overall, 80 4DR-PWH evaluated. Sgp120 and anti-CD4bs antibodies were detected in 12.5 % and 8.8 %, respectively, and not significantly associated with immuno-virological characteristics.

Based on anti-cluster A and anti-p24 levels, four PWH clusters were identified. Participants with low anti-p24 and high anti-cluster A antibodies showed more frequent detectable viremia (p = 0.018), lower CD4+/CD8+ (p = 0.044), and shorter ART duration (p = 0.025). CD4+ nadir (p = 0.036) followed a similar trend, except with high anti-p24 levels. Recent 4DR onset (p = 0.029) was linked to increasing anti-cluster A antibodies. At multivariable analysis, detectable viremia (p = 0.035) and ART duration (p = 0.022) remained significantly associated with cluster assignment.

Among 4DR-PWH, a specific antibody signature characterized by high anti-cluster A and low anti-p24 levels was associated with unsuppressed viremia and, potentially, immunological impairment. These findings provide preliminary insights into the interplay between anti-HIV humoral responses and immuno-virological features in this fragile population.