# Enhanced HIV-1 Neutralizing Antibody Breadth in HTLV-2 Co-Infected Individuals: Influence of Antiretroviral Regimen and B Cell Subset Distribution

## TL;DR

HTLV-2 co-infection boosts HIV-1 neutralizing antibodies in people on ART, especially when not using boosted protease inhibitors.

## Contribution

Shows HTLV-2 co-infection enhances HIV-1 neutralizing antibody breadth and links it to B cell subset changes and ART regimen.

## Key findings

- HTLV-2 co-infection and lack of r-PIs are independently linked to higher neutralization scores.
- HTLV-2 co-infected individuals show broader neutralization breadth compared to HIV-1 mono-infected individuals.
- HTLV-2 co-infection is associated with more resting memory B cells and fewer activated memory B cells.

## Abstract

Background/Objectives: This study aimed to explore how HTLV-2 infection affects the production of broadly neutralizing antibodies (bNAbs) in persons with HIV-1 (PWH) and to assess the impact of boosted protease inhibitors (PIs). Methods: We evaluated broadly neutralizing antibody (bNAb) activity in 65 PWH, which included 27 who were also co-infected with HTLV-2. All participants were former injection drug users with HCV antibodies and were receiving suppressive antiretroviral therapy (ART). Neutralizing activity was assessed against six recombinant HIV-1 viruses that represent five different subtypes. B cell subsets were also analyzed. Results: HTLV-2 co-infection and the lack of ritonavir-boosted protease inhibitors (r-PIs) were both independently associated with higher neutralization scores (p = 0.017 and p = 0.005, respectively). Among those not on r-PIs, individuals co-infected with HTLV-2 showed significantly higher neutralization scores (p = 0.027) and a broader neutralization breadth (83.4% vs. 48.5%, p = 0.015) compared to those infected only with HIV-1. Additionally, HTLV-2 co-infected individuals had more resting memory B cells (p = 0.001) and fewer activated memory B cells (p = 0.017) than the HIV-1 mono-infected individuals. In our multivariate analysis, only HTLV-2 co-infection remained independently associated with neutralization scores (p = 0.027). Elite neutralizers (with a breadth score of ≥10) had more naive B cells and fewer resting memory B cells compared to those with weaker neutralization in both groups. Conclusions: Co-infection with HTLV-2 enhances bNAb production in PWH on suppressive ART and, in particular, in the absence of r-PI regimens. The prominent neutralizing activity corresponded with B cell subset distributions. The results suggest the complexity regarding the interaction between viral co-infections, antiretroviral regimens, and humoral immune compartments and may inform further H1V-1 pathogenesis inquiries or the appropriate design of a vaccine.