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

Abstract: 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.