Strategies for AIDS vaccines

Abstract

In the global AIDS epidemic, over half of all infections have occurred in people less than 25 years old resulting in profound social, economic and demographic consequences. Current estimates indicate that the present 15 million HIV infections will increase to over 30 million by the end of the millennium. For most countries a safe and effective vaccine offers the only hope of controlling the spread of this disease. The development of an effective vaccine against HIV is beset with formidable obstacles. Despite these difficulties, substantial progress has been made towards developing effective strategies for vaccination. Human clinical trials and animal models for AIDS, particularly simian immunodeficiency virus (SIV) infection of macaques, have proved invaluable in this quest. Inactivated virus vaccines induced potent protection in this model, but subsequent studies revealed that protection was mediated by antibody to cellular proteins present in the vaccine preparations and on the surface of infecting virions. This surprising observation has provided an alternative and complementary approach to the development of vaccines against HIV in man which is still being pursued. Live attenuated vaccines were initially dismissed as far too hazardous. However, the concept has recently been reexamined in the light of powerful evidence that attenuated SIV induces potent protection against a wide variety of viruses administered by intravenous or mucosal routes and even against challenge with viable virus-infected spleen cells. Efforts are now underway to understand the mechanism of this protection and to attempt to reproduce it by less hazardous means. Considerable effort has been devoted to the development of subunit HIV vaccines, predominantly based on the envelope glycoproteins of the virus. Extensive clinical trials in human volunteers have established that these vaccines are safe and antigenic. However, the immune responses appear to be transient and the antibodies induced do not neutralize the primary isolates of HIV which are circulating in the population. There are now three possible approaches to an AIDS vaccine which are being actively pursued.

AIDS Vaccination Studies Using an Ex Vivo Feline Immunodeficiency Virus Model: Failure To Protect and Possible Enhancement of Challenge Infection by Four Cell-Based Vaccines Prepared with Autologous Lymphoblasts

“…Only one of nine animals in the mock-1 and mock-2 groups became FIV infected, a result most likely reflecting the suboptimal virus dose used. However, due to the lack of an untreated control group, we could not exclude that mock immunization contributed to prevent the full success of challenge by stimulating innate resistance or otherwise (16,58,63). In the vaccine groups the FC PLB -, ID-1-, ID-2-, and ID-3-infected animals were three, two, two, and one of five, respectively (Table 6 and Fig.…”

A vaccine for HIV type 1: The antibody perspective

“…A claim that ''neutralizing'' antibody is affecting or failing to affect the course of infection requires that neutralization is carried out with the challenge virus grown and assayed under as similar physiological conditions as possible (64). Most interestingly, protection against SIV in macaques has been consistently observed by passive transfer of antibodies to host cell components (56,65,66). Briefly, if SIV is grown in human cells then human cell surface molecules are incorporated into the virion envelope, and macaques make a vigorous antibody response to these molecules when infected with virus.…”

Potent, Broad-Spectrum Inhibition of Human Immunodeficiency Virus Type 1 by the CCR5 Monoclonal Antibody PRO 140

“…Moreover, CCR5 belongs to a family of seven transmembrane-spanning receptors that have historically provided excellent targets for pharmaceutical interventions (62).…”