"Therapeutic immunization with Remune stimulates cell mediated host immune responses against HIV"
<ATP DocFax Report: AIDS Treatment Projects "Doctor Fax"
ISSUE 75 - 17.09.99, Paul Blanchard, ATP.
Gives details of the article published recently in the Journal of Infectious Disease:
"Phenotypic Analysis of Human Immunodeficiency Virus (HIV) Type 1 Cell-Mediated Immune Responses after Treatment with an HIV-1 Immunogen "
>Cell mediated immune responses against HIV are believed to be the major controlling factor in those infected persons able to contain viral replication without antiretroviral therapy, so called long term non-progressors. These responses are characterized by strong T-helper
lymphocyte proliferation responses against core (p24) HIV antigens.
Successful antiretroviral therapy reduces viral replication to very low levels and allows partial reconstitution of immune responses even in those with advanced immunodeficiency. There has, however, been little evidence so far that recovery of host immune responses to HIV itself takes place, even with prolonged antiretroviral treatment. In fact, in those patients who display evidence of these responses prior to antiretroviral treatment, the responses have been seen to weaken and may disappear all together if viral suppression is successful.
This disappearance of host responses to HIV is perhaps unsurprising given that maintenance of cell mediated responses normally requires ongoing stimulation through the continuing presence of viral antigen. As viral turnover is reduced to very low levels by antiretroviral therapy infected cells no longer produce viral antigens and stimulation of host responses wane. Indeed, the reduced activation state of lymphocytes is taken as a marker of successful therapy with anti-HIV drugs.
The paradox in this situation is that prolonged and unremitting antigenic stimulation accompanying uncontrolled HIV replication does not sustain anti-HIV host responses but is thought to be responsible for their demise. This may be happening through hyperactivation and exhaustion of the immune system, or by the destruction of the T-helper cells promoting these responses. The activated T-helper lymphocytes are one of the primary targets for HIV-infection itself.
It has been suggested that sufficient stimulation of anti-HIV cell mediated responses by immunization with modified forms of HIV while the native infection is being suppressed by antiretrovirals may reverse the anergy of host responses accompanying chronic infection. One of the leading candidates to test this approach is the immunizing antigen known as Remune(TM), developed by Jonas Salk and the Immune Response Corporation and being carried forward into clinical trials by Agouron Pharmaceuticals.
This product is a whole killed vaccine prepared from HIV-1 with a clade A envelope and clade G gag. The outer envelope protein (gp-120) is depleted and the subsequent antigen preparation inactivated both chemically and by irradiation.
In a paper to The Journal of Infectious diseases, Ronald B Moss and Mark Wallace report the results of a study that assessed immune recognition of HIV after stimulation with the Remune vaccine combined with potent antiviral drug therapy. HIV-1 specific lymphocyte proliferation in 15 HIV-infected subjects was measured before and after immunization while combination antiretroviral therapy was maintained. The subjects had mean baseline CD4 count of 586 cells/mm3 (range 223 - 1147) and plasma HIV RNA of 953 copies/mL (range <400 - 4625). A variety of antiretroviral combinations were used but all consisted of 2 nucleoside analogues together with one or two protease inhibitors. The HIV-1 immunogen (Remune) was administered at day 1 and every 12 weeks thereafter and consisted of the gp-120 depleted inactivated HIV-1 at a dose of 10 U of p24 antigen in incomplete Freund's adjuvant.
The subsequent in vitro immune function assays used a range of antigens: the complete gp-120 depleted immunogen, p24 antigen purified from the Remune vaccine (np24), a recombinant p24 (rp24) and Candida antigen as a control. Recognition of these antigens was assessed before and after treatment (immunization) by standard lymphocyte proliferation assays (LPA) and by a flow cytometry method. Additional proliferation assays were also performed on PBMC's depleted of CD4, CD8 and NK cells (CD56). Chemokine production responses to antigen were measured by ELISA of MIP-1 beta.
After the first injection of immunogen a significant augmentation of
responses to the immunizing antigen, purified np24 and rp24 was observed. In contrast, responses to Candida antigen did not significantly change after treatment. These responses were not further stimulated with additional injections but remained significantly elevated from pre-treatment levels throughout the study period. Antigen specific flow cytometric assays revealed that CD4, CD8 and NK cell phenotypes were the
predominant cells proliferating in response to HIV antigen. Increased
production of HIV antigen stimulated beta-chemokine (MIP-1beta) after
treatment with HIV immunogen was also observed. Cell depletion studies
revealed that depletion of Th (CD4) cells resulted in the strongest
abrogation of the HIV specific lymphocyte proliferation response.
The study authors conclude that ".the results of the study suggest that HIV-1 functional immune unresponsiveness can be reversed by an HIV-1 specific immune-based therapy in chronic HIV-infection."
Ref: Moss RB, Wallace MR, Giermakowska WK, et al. Journal of Infectious Diseases, 1999; 180:641-8.
Full paper is available on the Web at:
journals.uchicago.edu
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