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Background: In late-stage HIV-1 disease, antiretroviral therapy (ART) although controlling viral replication and allowing some immune reconstitution, does not allow restoration of HIV-1-specific T-cell responses. In some cases, lack of response to other pathogens allows for emergence of severe immune reconstitution disease (IRD). Augmentative IL-2+GM-CSF immunotherapy is being considered as an adjunct to ART in such patients.

Methods: Individuals with late-stage HIV-1 infection on effective ART (VL BLD, CD4 <108) presenting with mycobacterial-associated IRD were subdivided into those receiving ART alone (Group 1) or ART+IL-2+GM-CSF immunotherapy (Group 2). Group 2 received IL-2 at 5MU subcutaneously bd for 5 days for 3 4-weekly cycles. During the third cycle concomitant GM-CSF was administered subcutaneously at 150ug daily for 5 days. Chronically infected patients receiving effective ART with higher CD4 counts and no IRD were used as controls (Group 3). We assessed rises in absolute CD4 T-cell numbers, pathogen-specific and HIV-1-specific CD4 T-cell responses, T-cell subsets and activation markers.

Results: Median CD4 T-cell numbers in IRD patients (Group 1 and Group 2) rose from baseline 22 cell/ul of blood, before initiation of ART, to 108 cells/mL after 6 months of therapy, coinciding with IRD diagnosis. This is in comparison with Group 3, who had median CD4 76 cells/mL at baseline, rising to 249 cell/mL at 6 months post-ART, which coincided with strong pathogen-specific responses and no IRD. Both Group 1 and Group 2 had significantly lower levels of naïve CD4 T cells (p <0.005), increased expression of immune-activation markers (HLA-DR and CD38, p<0.005 and p<0.05 respectively), and weak or absent pathogen-specific T-cell responses, compared with Group 3. Immunotherapy with IL-2+GM-CSF induced immediate and strong pathogen-specific T-cell responses in Group 2 IRD patients, which was reflected in clinical benefit. Higher dose (400 mg) of concomitant GM-CSF immunotherapy induced HIV-1-specific responses.

Conclusions: Concomitant administration of IL-2 and GM-CSF immunotherapy with effective ART results in strong pathogen-specific T-cell responses, which are sustained. HIV-1-specific responses are induced with higher doses of GM-CSF. The observed rise in naïve CD4 T cells and decreases in T-cell activation markers paralleled resolution of IRD and clinical recovery. Such immune-based salvage therapy may correct/augment T-cell immunity in late-stage disease.

Keywords: HIV-1; Immunotherapy; T Cell Responses