Pneumocystis (Pc) is a ubiquitious fungal pathogen that causes pneumonia (PCP) and Pc-related pulmonary sequelae in HIV-infected individuals and other immunocompromised populations. Deficiencies in CD4 T cell populations and immunologic dysfunction can limit humoral immunity and vaccine efficacy in Pc-susceptible populations. The ultimate goal of the field is to develop an effective vaccine that can overcome immune deficits in at risk populations and induce long-lasting protective immunity to Pc. Toward this goals, our laboratory has established a model of PCP co-infection in simian immunodeficiency virus (SIV)-infected non-human primates (NHP). We have previously identified a recombinant protein sub-unit vaccine, KEX1, that induces robust anti-Pc immunity in immune-competent macaques that is durable and prevents Pc pneumonia following simian immunodeficiency virus (SIV)-induced immunosuppression and subsequent Pc challenge (Kling and Norris, 2016). In the present study, we used the SIV model of HIV infection to address whether therapeutic vaccination with KEX1 can be effective following virus-induced immunosuppression. Type I, or invariant natural killer T (iNKT) cells have the potential to provide CD4-independent B cell help. When activated, iNKT cells are capable of rapidly expressing a wide array of cytokines and co-stimulatory molecules that can enhance humoral responses. The central hypothesis of this study is that a therapeutic vaccination strategy can induce invariant natural killer (iNKT) cell-B cell help to boost anti-KEX1 titers and enhance immunity to Pc during virus-induced immunosuppression.