Protection against Mucosal SIV_smChallenge in Macaques Infected with a Chimeric SIV that Expresses HIV Type 1 Envelope

Abstract

In a monkey model we used a chimeric SIV expressing the HIV-1 envelope gene (SHIV-4) as a live attenuated vaccine and a virulent SIVsm as a mucosal challenge. Four cynomolgus monkeys were inoculated intravenously with SHIV-4. Virus was repeatedly isolated from blood mononuclear cells of all four animals for 2 to 7 months after the inoculation of SHIV. All monkeys developed neutralizing antibodies to HIV-1 and high antibody titers to HIV-1 envelope glycoproteins. In contrast, no neutralizing antibodies to SIVsm were detected and cross-reacting antibodies to SIV envelope glycoproteins were demonstrable in low titers. Nine to 12 months after the SHIV inoculation the four monkeys and six naive control monkeys were challenged intrarectally with 10 monkey infectious doses of macaque cell-grown SIVsm. After a follow-up period of 1 year, two of four SHIV-infected monkeys were completely protected against SIVsm infection as shown by repeated negative virus isolations and negative polymerase chain reaction for SIV envelope DNA. One naive monkey that received blood from the two protected monkeys showed no signs of infection. The remaining two SHIV-infected monkeys showed an initial infection on challenge with SIVsm, but viral replication was thereafter suppressed. Cytotoxic T lymphocytes to SIV Nef and RT were demonstrable in one of four SHIV-infected monkeys before SIVsm challenge, but this monkey was not protected against SIV infection. All six control animals yielded virus repeatedly after SIVsm challenge and three of them showed declining CD4 cell counts. Thus, infection with SHIV expressing HIV-1 envelope could induce cross-protection against mucosal SIVsm challenge.

Both Mucosal and Systemic Routes of Immunization with the Live, Attenuated NYVAC/Simian Immunodeficiency Virus SIVgpeRecombinant Vaccine Result in Gag-Specific CD8+T-Cell Responses in Mucosal Tissues of Macaques

“…However, it should be noted that systemic immunization with recombinant vaccinia virus vac-gp160 protected three of four macaques against intrarectal challenge with SIV mne virus 47 (39) or, in another model, cats against feline immunodeficiency virus (38). Similarly, such protection has been achieved with live attenuated virus (41,42) and whole killed virus (10). Finally, in the case of the NYVAC/SIV gpe vaccine, intramuscular immunization was previously shown to be able to protect 50% of the macaques that were challenged intrarectally with SIV mac251 from high viremia ( (7) and an even higher number of macaques when a DNA prime/NYVAC/SIV gpe boost was used (18a).…”

The importance of local mucosal HIV-specific CD8(+) cytotoxic T lymphocytes for resistance to mucosal viral transmission in mice and enhancement of resistance by local administration of IL-12.

“…Conversely, while other studies have shown the induction of CTL in the mucosa, they have not established that these cells have a role in protection (9)(10)(11)(12). Yet, other studies have shown the induction by vaccines of protective immunity in the mucosa but, in the face of multiple immune responses including neutralizing antibodies, have not been able to sort out which responses are responsible for protection (3)(4)(5)(6)(7)(8). Thus, studies have either looked at immune responses or looked at protection, but it has been hard to prove that a particular immune response is the one mediating protection.…”

“…Previous studies demonstrating protection against mucosal challenge with virus have generally not determined the immune mechanism of protection (2)(3)(4)(5)(6)(7)(8). Other studies have demonstrated induction of cytotoxic T lymphocytes (CTL) in the mucosa but have not shown a role for these in protection (9)(10)(11)(12).…”

Polyvalent Envelope Glycoprotein Vaccine Elicits a Broader Neutralizing Antibody Response but Is Unable To Provide Sterilizing Protection against Heterologous Simian/Human Immunodeficiency Virus Infection in Pigtailed Macaques

“…For example, the clearance of HIV-1 from plasma during the primary infection occurs prior to the appearance of NAbs in newly infected individuals (37). Furthermore, in many studies, vaccinated macaques are able to efficiently control a virus challenge in the absence of detectable NAb, particularly those animals immunized with live, attenuated-virus vaccines (2,16,45,51). Nonetheless, passive immunization experiments have demonstrated the protective effects of NAbs against subsequent challenges with primate lentiviruses (17,20,30,32,33,42,44,47,48).…”