Immune Responses but No Protection against SHIV by Gene-Gun Delivery of HIV-1 DNA Followed by Recombinant Subunit Protein Boosts

AbstractThe efficacy of combining immunization with human immunodeficiency vitus type 1 (HIV-1) DNA and HIV-1 recombinant proteins to obtain protection from chimeric simian/human immunodeficiency virus (SHIV) was determined. Four cynomolgus monkeys received four gene-gun immunizations intraepidermally of plasmid DNA encoding HIV-1laienv(gp160),gag, tat, nef,andrevproteins. Ten micrograms of DNA was used per immunization. The animals were boosted twice intramuscularly with 50 μg of HIV-1laiEnv (MicroGeneSys), Gag, Tat, Nef, and Rev recombinant proteins mixed in Ribi adjuvant. The antibody responses were amplified following the administration of the recombinant subunit boosts. One month after the final subunit immunization, the vaccinated animals together with four control animals were challenged intravenously with 10 monkey infectious doses of SHIV that expresses theenv, tatandrevgenes of HIV-1 and gag and nef from SIV. However, only low titers of neutralizing antibodies were present at the day of challenge. The consecutive HIV-1 DNA and recombinant protein immunizations induced B- and T-cell responses but not protection against SHIV replication nor reduction of the viral load

The central role of the CD4 T-helper cell in HIV infection : Analysis of cell mediated responses and CCR-5 genotypes in HIV-1 infected individuals

Human immunodeficiency virus (HIV) infection is characterized by progressive immunologic dysregulation. The main target of HIV is the CD4 cell resulting in malfunction of the immune system, with a decline in CD4 cells and subsequent development of the acquired immunodeficiency syndrome (AIDS). HIV-infected individuals show impaired responses to antigenic stimulation, particularly to HIV proteins, even before a significant decline in the number of CD4 cells is observed. Together with the CD4 molecule, certain chemokine receptors have been identified as coreceptors for the cellular entry of HIV. The main coreceptor CCR-5 is used by most primary viral isolates (NSI). A switch in coreceptor usage to the CXCR-4 receptor phenotype (SI) is associated with poor prognosis. A deletion in the CCR-5 gene (delta32) has been identified and is linked with resistance to HIV infection. We found that the delta32/wt CCR-5 genotype has a protective effect against HIV-1 disease progression. This was limited to individuals carrying HIV- 1 variants with the NSI phenotype. Immunization with the HIV envelope gp160 reduced the frequency of SI phenotypes. Therapeutic vaccination with recombinant gpl60 and with HIV DNA constructs was evaluated for efficacy of induction of immune responses in humans. Immunization with rgpl60 induced strong and persistent antigen-specific T helper responses in asymptomatic HIV infected individuals. DNA vaccination mimics the natural infection and allows presentation of the encoded gene products to both CD8 and CD4 cells. In HIV-infected patients, the DNA immunization induced both HIV-specific cytotoxic and proliferative cellular responses. Increased levels of cytotoxic memory cells were induced in all DNAimmunized patients. None of the immunizations by themselves reduced the viral load. HIV-specific cellular immune responses were evaluated in patients who started highly active antiretroviral treatment (HAART). Significant reductions in viral load and increases in CD4 counts were observed in those patients. The initiation of HAART alone did not cause obvious re- induction of HIV specific T-helper cell responses nor of cytotoxicity. The long-term viral suppression by HAART in patients with advanced HIV-1 infection was related to no prior exposure to nucleoside analogues and low baseline viral load. The prior CD4 lymphocyte count, CCR-5 genotype and viral tropism had less influence on the outcome. Immunization with rgpl60 led to new and reactivated immune responses in HAART receiving patients. This included increased CD4 cell numbers, induction of new HIV-specific responses and recall responses to other antigens. Prior HAART strengthened the magnitude and persistence of such responses. The possibility to induce strong and persistent immune responses in HAART treated individuals raises the hope that immunized individuals may better control the viral replication when therapy interruptions will be performed in the future. In these studies we have identified some of the factors that are important in, induction of immune responses and regulation of disease outcome in HIV infected individuals. The safety and efficacy of both protein and DNA vaccines in inducing immune responses in humans were demonstrated. The full knowledge of the underlying mechanisms for the failure of the immune system and decline in CD4 cell numbers that leads to development of AIDS are still lacking. The attempt in vaccine development is however to induce as broad and long-lasting immune responses as possible. Clearly, new combination strategies will be needed in order to reach these goals

Induction of specific T-cell responses in HIV infection

Objectives: To induce recovery of HIV-1-specific immune responses by combining immunization with antiviral chemotherapy. Design: Forty HIV-infected patients entered a double-blind study with recombinant gp160 in combination with zidovudine or placebo. The pretreatment observation period was around 2 years and the treatment period 5 years. Eighty matched HIV-infected patients served as controls. Methods: Immune status was monitored by proliferation assays with HIV-specific antigens, mitogens and recall antigens. Viral load, CD4 cell counts, apoptosis, T-cell clonal analysis and CC-chemokine receptor (CCR)-5 status were determined. Results: All immunized patients showed a strong and HIV-specific T-cell proliferative response. This response was related to the immunizations, and was not enhanced by the zidovudine monochemotherapy given during the first 6 months of the immunizations. The treatments did not significantly alter viral load. Potent antiviral combination therapy given to non-immunized individuals reduced their viral load but did not influence HIV-specific immune responses. There was a trend for an increased frequency of non-progression in the immunized group compared with controls. These individuals had both wild-type and mutant CCR-5 genes. Conclusion: The results clearly show that restoration of HIV-specific T-cell immunity occurs after immunization with the HIV gp160 antigen and is not influenced by the addition of antiviral monochemotherapy. Even intensive chemotherapy alone did not restore HIV-specific immunity and immunization alone did not influence viral load. This suggests that combinations of intensive chemotherapy with specific HIV immunization would result both in viral load reduction and improved immune responses to HIV.SCOPUS: ar.jinfo:eu-repo/semantics/publishe