Assessing Human Alloimmunization as a Strategy for Inducing HIV Type 1 Neutralizing Anti-HLA Responses

Abstract

Xenovaccination of rhesus macaques with human HLA Class I and II proteins has been demonstrated to elicit protective immunity against challenge with SIV grown in human cells. To determine if alloimmunization in humans could lead to protective immunity against HIV-1, we prospectively followed a small group of women receiving whole-cell alloimmunization in the form of leukocyte immunotherapy for recurrent spontaneous abortion. Whole-cell vaccine recipients and their respective partners (referred to as donors) provided pre- and postimmune blood samples for analysis. Study participants were HLA typed by sequence-specific PCR and antibodies specific for HLA Class I and II antigens were measured in recipient plasma. To determine if anti-HLA antibody responses detected in recipient plasma samples were capable of neutralizing HIV-1 in vitro, we grew laboratory strain HIV-1(IIIB) and primary isolate HIV-1(301660) in donor-derived CD4(+) T lymphocytes. The ability of purified whole IgG from responding patients to neutralizing infectivity of the respective donor-derived virus was then assayed in vitro. All donor-recipient pairs were determined to be HLA discordant for at least one Class I and one Class II locus. Two of seven female recipients in total made strong anti-HLA antibody responses specific to the HLA haplotype of the male donor in response to the alloimmunization regimen. For one recipient, IgG antibodies specific for donor HLA Class I and II antigens were able to neutralize both HIV-1(IIIB) and a primary isolate HIV-1(301660). In addition polyclonal anti-HLA class II antibodies against a single determinant (DR4) of this donor were also neutralizing. In contrast, the other recipient exhibiting antibodies only against donor HLA Class I antigens did not neutralize HIV-1(IIIB). Using samples from a small number of women undergoing leukocyte immunotherapy, we have demonstrated for the first time that allele-specific anti-HLA antibodies elicited through human alloimmunization are capable of neutralizing HIV-1 in vitro.

Immunization with Recombinant HLA Classes I and II, HIV-1 gp140, and SIV p27 Elicits Protection against Heterologous SHIV Infection in Rhesus Macaques

“…Together with observations in humans, indicating that alloimmune responses may confer protection against HIV (18,20,29,35), this provides support for the hypothesis that this vaccination strategy could be transferred to humans and HIV. However, this would require alloimmunization with MHC class I and II antigens.…”

“…So far this possibility has not been extensively studied, but several observations support the concept. Whole-cell alloimmunization of women with their partner's leukocytes elicited resistance to HIV replication in vitro (46), and their sera neutralized HIV grown in their partner's peripheral blood mononuclear cells (PBMC) (18). There were no adverse effects, and since similar alloimmunization procedures have been carried out with over 1,000 women, this practice appears to be safe.…”

Quantitation of HLA Proteins Incorporated by Human Immunodeficiency Virus Type 1 and Assessment of Neutralizing Activity of Anti-HLA Antibodies

“…Since the HIV-1 envelope molecule is relatively large and it forms a spike that bulges out of the membrane, the binding of anti-HLA antibodies may not interfere with the interaction between viral gp160 and the CD4 receptor. Although this could be anticipated without experimental investigation, the complexity of the mechanism of viral entry into the target cell, experimental evidence (8,9,14,30,31,40), and the potential advantage of this approach (13) prompted further investigation. This study shows the lack of HIV-1-neutralizing activity by anti-HLA antibodies.…”

“…As with xenogeneic anti-HLA antibodies, few studies suggest a protective role of allogeneic anti-major histocompatibility complex antibodies of human origin against HIV-1. Neutralization of HIV-1 virions was observed in the presence of immunoglobulin G (IgG) from women undergoing leukocyte immunotherapy (14) and in the sera of polytransfused patients (30,31,40) in vitro.…”

Working Group Consultation: Alloimmunity as a Vaccine Approach Against HIV/AIDS: National Institutes of Health Meeting Report, May 24, 2012

“…18 In humans, in vitro and ex vivo infectivity of CD4 + T cells by primary or laboratoryadapted HIV was notably decreased after in vivo alloimmunization. 19,20 Advantages and Disadvantages of Alloimmunization Table 2 summarizes the risks and potential benefits of alloimmunization, as highlighted by the Consultation. Extreme variability and mutability of HIV are major obstacles to AIDS vaccine development.…”