# To Kill a Macrophage: Targeted Strategies to Eliminate Macrophage Reservoirs of HIV

## TL;DR

This paper reviews challenges in eliminating HIV-infected macrophages and explores strategies to overcome their resistance to death.

## Contribution

The paper highlights novel strategies and methodological improvements needed to target macrophage HIV reservoirs.

## Key findings

- HIV-infected macrophages are more resistant to death than CD4+ T cells.
- HIV modulates apoptotic pathways and uses survival mechanisms like autophagy.
- Improved pre-clinical models are essential for eliminating macrophage reservoirs.

## Abstract

Persistent HIV reservoirs in long-lived macrophages pose a unique and formidable challenge to achieving HIV cure. HIV-infected macrophages are more resistant than CD4+ T cells to both virus- and immune-mediated death pathways including apoptosis, facilitating their persistence in tissue sanctuary sites and potential to contribute to viral rebound upon therapy cessation. This resistance is driven by HIV-induced modulation of both intrinsic and extrinsic apoptotic pathways, alongside survival mechanisms including autophagy. In this review, we examine the biological mechanisms promoting macrophage survival and explore novel translational strategies aimed at subverting this resistance. Crucially, we highlight the methodological limitations hindering progress, including the scarcity of robust in vitro macrophage models, the influence of culture conditions, and physiological relevance to macrophages in vivo. We emphasise that a macrophage-inclusive approach, incorporating improved pre-clinical models and developing clinical measurements to quantify the reservoir in human tissue, is essential to successfully eliminate this distinct reservoir and advance toward sustained ART-free remission.