SAIDS Vaccines

Abstract: In the current global AIDS pandemic, more than half of new human immunodeficiency virus type 1 (HIV-1) infections are acquired by women through intravaginal HIV exposure. For this study, we explored pathogenesis issues relevant to the development of effective vaccines to prevent infection by this route, using an animal model in which female rhesus macaques were exposed intravaginally to a high dose of simian immunodeficiency virus (SIV). We examined in detail the events that transpire from hours to a few days after intravaginal SIV exposure through week 4 to provide a framework for understanding the propagation, dissemination, and establishment of infection in lymphatic tissues (LTs) during the acute stage of infection. We show that the mucosal barrier greatly limits the infection of cervicovaginal tissues, and thus the initial founder populations of infected cells are small. While there was evidence of rapid dissemination to distal sites, we also show that continuous seeding from an expanding source of production at the portal of entry is likely critical for the later establishment of a productive infection throughout the systemic LTs. The initially small founder populations and dependence on continuous seeding to establish a productive infection in systemic LTs define a small window of maximum vulnerability for the virus in which there is an opportunity for the host, vaccines, or other interventions to prevent or control infection.

Abstract: A substantial risk in using live attenuated, multiply deleted viruses as vaccines against AIDS is their potential to induce AIDS. A mutant of the simian immunodeficiency virus (SIV) with large deletions in nef and vpr and in the negative regulatory element induced AIDS in six of eight infant macaques vaccinated orally or intravenously. Early signs of immune dysfunction were seen in the remaining two offspring. Prolonged follow-up of sixteen vaccinated adult macaques also showed resurgence of chronic viremia in four animals: two of these developed early signs of disease and one died of AIDS. We conclude that this multiply deleted SIV is pathogenic and that human AIDS vaccines built on similar prototypes may cause AIDS.

Abstract: A major challenge for the development of a highly effective AIDS vaccine is the identification of mechanisms of protective immunity To address this question, we used a nonhuman primate challenge model with simian immunodeficiency virus (SIV) We show that antibodies to the SIV envelope are necessary and sufficient to prevent infection Moreover, sequencing of viruses from breakthrough infections revealed selective pressure against neutralization-sensitive viruses; we identified a two-amino-acid signature that alters antigenicity and confers neutralization resistance A similar signature confers resistance of human immunodeficiency virus (HIV)-1 to neutralization by monoclonal antibodies against variable regions 1 and 2 (V1V2), suggesting that SIV and HIV share a fundamental mechanism of immune escape from vaccine-elicited or naturally elicited antibodies These analyses provide insight into the limited efficacy seen in HIV vaccine trials The analysis of multiple SIV vaccine regimens in macaques leads to the identification of a key two-amino-acid signature that confers resistance to neutralizing antibodies; a similar mechanism of immune escape is shown to operate in HIV and may explain the limited efficacy seen in HIV vaccine trials Clinical trials of human immunodeficiency virus-1 (HIV-1) vaccines have so far proved disappointing, achieving either low-level efficacy or zero protection Here Mario Roederer et al analyse the effects of multiple vaccine regimens in the macaque simian immunodeficiency virus (SIV) model and identify a key two-amino-acid signature that confers resistance to neutralizing antibodies A similar mechanism of immune escape is shown to operate in HIV, suggesting that this type of vaccine-elicited antibody response may explain the limited efficacy seen in HIV vaccine trials