There are 7.5 million HIV-infected persons older than 50 years worldwide, for whom cancer remains a serious concern. Non-small-cell lung cancer (NSCLC) is predicted to be a dominant cancer in the HIV- infected population by 2030. The current standard-of-care for metastatic NSCLC is immune checkpoint PD-1 blockade plus chemotherapy (CHEMO), which, in the general population, prolongs survival by 50% compared to CHEMO alone. However, the clinical trials leading to the approval of this combination did not include HIV patients. As such, HIVinfected patients with NSCLC are treated with antiretroviral therapy (cART) and either CHEMO or PD-1 blockade, but not with the combination of CHEMO plus PD-1 blockade. It is likely that CHEMO plus PD-1 blockade will increase survival in the HIV population. However, potential interactions between cART, CHEMO and PD-1 blockade could increase toxicity, requiring intensive monitoring and adjustment of drug doses. We propose that treatment with PD-1 blockade plus CHEMO in HIV-infected NSCLC patients may be realized by replacement of cART with injectable HIV broadly neutralizing antibodies (bNAbs) during the course of cancer therapy. Unlike cART, bNAbs act directly on the virus, do not involve cell metabolism, do not otherwise interact with cancer drugs, allow infrequent dosing, and overcome intake challenges in cancer patients with difficulties swallowing or retaining ingested pills. Accordingly, our hypothesis is that bNAbs can effectively replace cART during cancer therapy for a period sufficient to deliver a successful course of cancer therapy, and that the latter potentiates more extensive humoral control of HIV replication. We are uniquely positioned to test this hypothesis for two reasons. First, we have identified bNAbs to the CD4 binding site on gp120 that have near pan-neutralizing activity and potency greater than other bNAbs currently in clinical development. Second, we have successfully developed a unique animal model: humanized mice chronically infected with HIV that support growth of human NSCLC tumors and respond to treatments (see Preliminary Studies). Our goal is to use these resources to generate proof-of-concept data showing that HIV replication can be sustainably suppressed by bNAbs for a period sufficient to deliver an efficacious course of cancer therapy, in support of our hypothesis. There are two Specific Aims. Specific Aim 1: To establish that combinations of NSCLC therapy and bNAbs can provide effective and durable HIV suppression while allowing antitumor efficacy; Specific Aim 2: To establish that NSCLC therapy in combination with bNAbs can reduce the size of the resting CD4 T cell HIV reservoir. This project targets 3 overarching NIH HIV/AIDS High research priorities (NOT-OD-15-137): i) HIV-associated comorbidities; ii) development of the next generation of HIV therapies with fewer side effects and complications; and iii) research toward a cure. Lastly, decreased toxicity with the proposed ap...