Effi­cient spread of human immun­od­e­fi­cien­cy virus 1 (HIV‑1) is con­trolled by the avail­abil­i­ty and anti-viral state of non-infect­ed bystander cells. The anti-viral state is defined by the activ­i­ty of innate and intrin­sic immune antivi­ral effec­tor path­ways, such as autophagy. Autophagy is an auto-diges­tive process tar­get­ing cel­lu­lar pro­teins or viral com­po­nents for destruc­tion. Like oth­er immune path­ways, autophagy is induced upon infec­tion with HIV‑1. How­ev­er, dis­sec­tion of the response revealed that autophagy lev­els in HIV‑1 infect­ed CD4+ T cells are sur­pris­ing­ly low. In con­trast, in non-infect­ed bystander T cells high lev­els of autophagy are induced. Our data fur­ther showed that bystander autophagy is induced by a sol­u­ble fac­tor released from HIV‑1 infect­ed T cells. We intend to deter­mine how bystander cell autophagy induc­tion in HIV‑1 infec­tion works on a mol­e­c­u­lar lev­el. To this end, we will deter­mine cel­lu­lar sens­ing path­ways and viral deter­mi­nants in infect­ed cells that induce the release of the unknown autophagy-induc­ing fac­tor. Fur­ther­more, we will deter­mine the iden­ti­ty of the sig­nalling fac­tor on which cell types it induces autophagy and which cell types release it after infec­tion. Final­ly, we will use advanced CRISPR approach­es to define deter­mi­nants of autophagy upreg­u­la­tion in bystander cells. To under­stand the impact of bystander autophagy, we will deter­mine its con­se­quences on HIV1 infec­tion of T cells. Our pre­lim­i­nary data show that cells with high autophag­ic flux are less per­mis­sive for HIV‑1, thus viral spread is lim­it­ed. How­ev­er, acti­va­tion of autophagy may even­tu­al­ly come at a cost. Cell death induced by exces­sive autophagy may con­tribute to deple­tion of bystander T cells, a hall­mark of AIDS. Tak­en togeth­er, this project will yield nov­el insights into the patho­gen­e­sis of AIDS, inter­play of HIV‑1 with autophagy and explore reg­u­la­to­ry fea­tures of cell intrin­sic defens­es. We aim to estab­lish the nov­el con­cept of paracrine autophagy acti­va­tion and define key fac­tors involved. Under­stand­ing the impact and reg­u­la­tion of bystander cell autophagy dur­ing HIV‑1 infec­tion will allow us to design strate­gies to fine-tune anti-viral cell-intrin­sic immu­ni­ty. Since autophagy is a broad­ly active anti-micro­bial path­way these strate­gies may be the basis of future ther­a­peu­tic or pre­ven­tive approach­es tar­get­ing not only HIV‑1 but also oth­er pathogens. Fur­ther­more, these fun­da­men­tal insights into autophagy may be rel­e­vant for dis­eases where autophagy is dys­reg­u­lat­ed, among them can­cer and neuropathologies.