Absence of Clinical, Virological, and Immunological Signs of Progression in HIV-1-Infected Patients Receiving Active Anti-Interferon-α Immunization: A 30-Month Follow-Up Report

Abstract

Twenty-seven HIV-1-infected patients, 16 at early stage of disease and without concomitant antiretroviral therapy and 11 at more advanced stage of disease receiving antiretroviral therapy, have been followed since their enrollment, November 1992 and July 1993, respectively, in phase I/II studies to evaluate safety and immunogenicity of an anti-interferon-alpha (IFN-alpha) vaccine, aimed at modulating the impaired cytokine network in AIDS patients by counteracting IFN-alpha overproduction. We compared clinical, virological, and immunological markers of disease progression, including circulating IFN-alpha levels in a 24- to 30-month follow-up period with those of 62 patients fulfilling the same enrollment criteria and comparable for sex, risk factor, and age, regularly followed at our center. Anti-IFN-alpha immunization consisted of four-six intramuscular injections 1 month apart of a water-in-oil emulsion of 500 micrograms formalin-inactivated recombinant IFN-alpha-2b (iIFN-alpha) followed by intramuscular injections of 250 micrograms iIFN-alpha adsorbed onto calcium phosphate every 3 months. Neither clinical deterioration nor a CD4+ cell count decrease from pretreatment values was observed in IFN-alpha-immunized patients in the follow-up period, whereas clinical and immunological disease progressions were observed among open-comparison patients. Furthermore, statistical analysis showed a strong association between occurrence of clinical manifestations and high circulating IFN-alpha titers, while nonprogression of IFN-alpha-immunized patients was associated with decreased levels of circulating IFN-alpha.

Altered expression of the receptor-ligand pair CXCR5/CXCL13 in B cells during chronic HIV-1 infection

“…51 Type 1 interferons (IFNs) have also been shown to increase CXCL12-and CCL21-mediated migration, 24 which may be relevant for HIV-1 pathogenesis as the levels of IFNs are elevated with disease progression. 54 Our finding of an increase in migration toward CXCL12, CXCL13, and CCL21 in HIV-1 patients with CD4 ϩ T-cell counts less than 350 cells/L may thus reflect polyclonal stimulation of B cells, either by CD40-CD40L interactions, by IFNs or via TLR signaling during HIV-1. Our findings suggest that there may be an altered migration profile of B cells during HIV-1.…”

Tat as one key to HIV-induced immune pathogenesis and Pat toxoid as an important component of a vaccine

“…In my view, these in vitro and in vivo results taken together, as well as animal experiments showing the safety and immunogenicity of inactivated Tat (35), are powerful arguments for clinical intervention. Indeed, they have already prompted a clinical therapeutic (33) and a preventive (34) vaccine study in humans utilizing a chemically detoxified but immunogenic Tat called Tat toxoid (33).…”

“…Preliminary results of these studies in immune deficient patients show safety and immunogenicity (33). These clinical trials were complemented by earlier and ongoing studies that utilized a preparation of inactivated IFN-␣ as a therapeutic vaccine, i.e., used only in infected individuals (35,36). As in the recent Tat studies, safety and immunogenicity were demonstrated, and CD4 ϩ T cell numbers were stabilized (35,36).…”

Interferon α and Tat involvement in the immunosuppression of uninfected T cells and C-C chemokine decline in AIDS

“…(ii) IL-2 secretion is another effector component of the cellular immune response by PBMC, and we have shown previously (11) that the decline in IL-2 secretion from activated T cells derived from AIDS patients is repaired partially in the presence of anti-IFN␣ Abs (11). (iii) High levels of circulating IFN␣ in AIDS patients are associated with a poor prognosis (41).…”