Dysfunctional activation of the immune system is a defining feature of progressive HIV disease. It is characterised by inflammation, activated T cells and myeloid cells and the translocation of microbial products across the gut mucosa. Immune activation is present to some extent even in patients for whom the virus has been successfully suppressed through combined antiretroviral therapy (cART) and immune reconstitution is often incomplete. This residual immune activation may contribute to HIV-1 comorbidities including atherothrombosis, neurocognitive disorders and osteoporosis. Thus a greater understanding of the causes of immune activation are required in order to develop new therapies to improve immune system function andcompliment both cART and therapies developed from “cure” research. We have previously identified that antibodies specific for a heterodimeric peptide construct comprising the C5501-512 region and a compatible region on gp41732-744 within the HIV envelope protein (Vacc-C5) are correlated with slow disease progression in HIV-1 infected subjects and in certain patients with a natural viral suppressor phenotype. In this study we sought to determine whether levels of anti-Vacc-C5 correlated with markers of immune function or immune activation. 45 HIV-1 infected subjects undertaking ART were recruited for the study. HIV-1 infected subjects demonstrated a range of anti-Vacc-C5 antibody titres between 0.04-19.87 μg/mL. Anti-Vacc-C5 antibody titres greater than 1 μg/mL were positively associated with greater CD4+ counts and increased IFN-γ responses to class I or class II restricted peptides and peptides derived from HIV-1 p24. High anti- Vacc-C5 antibody titres were inversely correlated with T cell activation measured by HLA-DR and CD38, and sera levels of IL-6. Associations with LPS, sCD14 and myeloid cell and NK cell phenotype have also been made. These data support a role of anti-Vacc-C5 antibodies in the maintenance of functional immune phenotypes in HIV-1 infected individuals.