HIV vaccine design and the neutralizing antibody problem

Although CD8 ؉ T cells play an important role in controlling viral infections, boosting specific CD8 ؉ T cells by prophylactic vaccination with simian immunodeficiency virus (SIV) epitopes fails to provide sterilizing immunity. Viral replication rates and viral contraction rates after the peak viremia hardly depend on the presence of memory CD8 ؉ T cells. To study these paradoxical findings, we parameterize novel mathematical models for acute SIV and human immunodeficiency virus infection. These models explain that failure of vaccination is due to the fact that effector/target ratios are too low during the viral expansion phase. Because CD8 ؉ T cells require cell-to-cell contacts, immune protection requires high effector/target ratios at the primary site of infection. Effector/target ratios become favorable for immune control at the time of the peak in the viral load when the virus becomes limited by other factors, such as the availability of uninfected target cells. At the viral set point, effector/target ratios are much higher, and perturbations of the number of CD8 ؉ effector cells have a large impact on the viral load. Such protective effector/target ratios are difficult to achieve with nucleic acid-or protein-based vaccines.

mentioning

confidence: 99%

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Boer

2007

“…Despite more than two decades of research since the discovery of HIV as the etiologic agent of AIDS, the development of an effective HIV type 1 (HIV-1) vaccine remains an unfulfilled priority. While it is generally accepted that ultimately a prophylactic HIV-1 vaccine should induce both humoral and cellmediated immune responses to a number of different HIV antigens (40,63), envelope-based immunogens capable of inducing broadly neutralizing responses currently are not available (13,79,98). Recent approaches have focused on vaccines capable of inducing potent CD8 ϩ T-cell responses to control the virus load, to reduce transmission, and to slow disease development (26,53).…”

mentioning

confidence: 99%

Differential CD4⁺versus CD8⁺T-Cell Responses Elicited by Different Poxvirus-Based Human Immunodeficiency Virus Type 1 Vaccine Candidates Provide Comparable Efficacies in Primates

Mooij

Balla-Jhagjhoorsingh

Koopman

et al. 2008

Poxvirus vectors have proven to be highly effective for boosting immune responses in diverse vaccine settings. Recent reports reveal marked differences in the gene expression of human dendritic cells infected with two leading poxvirus-based human immunodeficiency virus (HIV) vaccine candidates, New York vaccinia virus (NYVAC) and modified vaccinia virus Ankara (MVA). To understand how complex genomic changes in these two vaccine vectors translate into antigen-specific systemic immune responses, we undertook a head-to-head vaccine immunogenicity and efficacy study in the pathogenic HIV type 1 (HIV-1) model of AIDS in Indian rhesus macaques. Differences in the immune responses in outbred animals were not distinguished by enzymelinked immunospot assays, but differences were distinguished by multiparameter fluorescence-activated cell sorter analysis, revealing a difference between the number of animals with both CD4 ؉ and CD8 ؉ T-cell responses to vaccine inserts (MVA) and those that elicit a dominant CD4 ؉ T-cell response (NYVAC). Remarkably, vector-induced differences in CD4 ؉ /CD8 ؉ T-cell immune responses persisted for more than a year after challenge and even accompanied antigenic modulation throughout the control of chronic infection. Importantly, strong preexposure HIV-1/simian immunodeficiency virus-specific CD4 ؉ T-cell responses did not prove deleterious with respect to accelerated disease progression. In contrast, in this setting, animals with strong vaccine-induced polyfunctional CD4 ؉ T-cell responses showed efficacies similar to those with stronger CD8 ؉ T-cell responses.

“…Among the most challenging and important unsolved problems in human immunodeficiency virus type 1 (HIV-1) vaccine development is the inability to produce broadly neutralizing antibodies to HIV-1 (11). Antibodies to HIV-1 envelope proteins, including the CD4 and chemokine receptor binding sites, have been produced by HIV infection or vaccination, but because of mutation at critical sites, or because of steric effects, neutralization by antibodies is generally not broadly effective for preventing HIV-1 viral infection.…”

mentioning

confidence: 99%

Monoclonal Antibodies to Phosphatidylinositol Phosphate Neutralize Human Immunodeficiency Virus Type 1: Role of Phosphate-Binding Subsites

Brown

Karasavvas

Beck

et al. 2007

Both a murine monoclonal antibody to phosphatidylinositol phosphate (PIP) and a human monoclonal antibody (4E10) that is known to have broadly neutralizing capabilities against primary isolates of human immunodeficiency virus type 1 (HIV-1) bound to PIP, as determined by enzyme-linked immunosorbent assay. Each of the antibodies had antigen subsite binding specificities in aqueous medium for small phosphatecontaining molecules and for inositol. The anti-PIP monoclonal antibody inhibited infection by two HIV-1 primary isolates in neutralization assays employing primary human peripheral blood mononuclear cells. The data suggest that PIP or related lipids having free phosphates could serve as targets for the neutralization of HIV-1.