Induction of vigorous cytotoxic T-lymphocyte responses by live attenuated simian immunodeficiency virus

Abstract

Although live attenuated vaccine strains of simian immunodeficiency virus (SIV) have proven highly effective in protecting macaques against challenge with pathogenic SIV strains, little is known about the mechanisms of protective immunity induced by these vaccines. We examined cytotoxic T-lymphocyte (CTL) responses against SIV in animals infected with SIVmac239⌬nef (deficient in nef) or SIVmac239⌬3 (deficient in nef, vpr, and upstream sequences in U3). To enhance detection of SIV-specific CTL activity, we stimulated peripheral blood mononuclear cells with autologous B-lymphoblastoid cell lines which had been infected with recombinant vaccinia viruses expressing SIV proteins and subsequently inactivated with psoralen and UV light. Animals chronically infected with SIV239⌬nef or SIV239⌬3 mounted vigorous CTL responses against the SIV Gag and Env proteins. This CTL activity was major histocompatibility class restricted and mediated by CD8 ؉ T lymphocytes. CTL responses persisted at relatively high levels for more than 6 years after infection. Limiting dilution precursor frequency assays demonstrated that the frequency of SIV-specific CTLs was as high as 234 CTL precursors per 100,000 cells. Animals acutely infected with SIV239⌬nef developed CTL activity by day 14 after infection, coincident with decreases in viral load. Animals acutely infected with SIV239⌬3 developed CTL responses within 4 weeks of infection. Thus, vaccination of juvenile or adult animals with SIV239⌬nef or SIV239⌬3 results in the induction of a vigorous CTL response which arises early in the course of infection and persists for years after a single inoculation of virus.

Inhibition of Antigen Presentation by the Glycine/Alanine Repeat Domain Is Not Conserved in Simian Homologues of Epstein-Barr Virus Nuclear Antigen 1

“…at 100 Ci per 10 6 cells. Standard 51 Cr release assays were then carried out as previously described (12,13), and the percent specific cytotoxicity was calculated as described above. The spontaneous release of target cells was Ͻ25% in all assays.…”

Vaccination with SIVmac239Δnef activates CD4+ T cells in the absence of CD4+ T‐cell loss

“…Currently, vaccinations with live attenuated SIVs are the only effective means of inducing sterile protection against lentivirus infections [8,9,33,34], and although it is unlikely a live attenuated HIV vaccine will ever be used in practice, this model has provided fundamental insights into the necessary components for protective immunity. Various attenuated SIV strains have been shown to induce potent humoral and cellular immune responses, all of which may contribute to sterilizing immunity [2,3,11,12,17,33]. Moreover, live attenuated SIVs are replication-competent, and the nef-deficient virus, SIVmac239Dnef, has been shown to infect predominantly CD4 + T cells in vivo [29].…”

Protection of macaques against AIDS with a live attenuated SHIV vaccine is of finite duration

“…However, the data from macaques showing that attenuated SIVmac239 which proved to be highly efficacious in preventing AIDS in adult macaques was still pathogenic in infant animals (Baba et al, 1995) greatly dampened enthusiasm for pursuing development of such vaccines for use in humans. Despite this, live vaccine studies in macaques are still being pursued using SIV and SHIV vaccines (Amara et al, 2005;Desrosiers, 1998;Johnson and Desrosiers, 1998;Johnson et al, 1997;Koff et al, 2006) because such vaccines have proven to be efficacious in adult animals and still safe in young animals even after considerable effort to bring out the pathogenic potential of such viruses . Such efforts have included IV inoculation of animals at birth and observation for more than six years (Smith, unpublished observation), IC inoculation and serial passage of the virus in young animals (Mackay et al, 2002) all without pathological effects.…”

“…Deletion of accessory genes from pathogenic SIV provided the first method for development of live vaccines against macaque lentiviral pathogens (Daniel et al, 1992;Johnson and Desrosiers, 1998;Wyand et al, 1999;Wyand et al, 1996). Use of this concept has been exploited for development of SIV and later, safe SHIV vaccines (Abel et al, 2003;Amara et al, 2005;Desrosiers, 1998;Hu, 2005;Joag et al, 1998b;Johnson and Desrosiers, 1998;Johnson et al, 1997;Koff et al, 2006;Silverstein et al, 2000). The process resulted in development of viruses that have attenuated replication potential and pathogenicity, thereby making them candidates for live virus vaccines against AIDS.…”

“…The process resulted in development of viruses that have attenuated replication potential and pathogenicity, thereby making them candidates for live virus vaccines against AIDS. These SHIV agents have been used to test proof of concept hypotheses about mechanisms of vaccine-induced protection, identification of immunological correlates or protection, and duration of the protection following immunization (Joag et al, 1998b;Johnson et al, 1997;Kumar et al, 2002;Wyand et al, 1999). Studies on the SHIV vaccines showed that the viruses replicated productively for a few weeks, after which they persisted in a minimally productive state for an indefinite period (Joag et al, 1998b;Kumar et al, 2002;Mackay et al, 2004;Silverstein et al, 2000).…”