Better protective effects in rhesus macaques by combining systemic and mucosal application of a dual component vector vaccine after rectal SHIV89.6P challenge compared to systemic vaccination alone.

In this study we investigated the efficacy of a multigenic DNA prime/modified vaccinia Ankara (MVA)boost vaccine approach, followed by mucosal challenge with highly pathogenic simian-human immunodeficiency virus (SHIV) 89.6P, using different routes for vaccine delivery. After three times of DNA priming (SIVmac239, GagPol, and SHIV 89.6P Env) one vaccine group of monkeys was immunized with MVA systemically via intramuscular (IM) and intradermal (ID) application, and in another vaccine group the MVA booster immunization comprised the IM, ID, and atraumatic oral route. Although all vaccinees became infected after intra-rectal challenge with SHIV 89.6P, substantial protection as indicated by lower peak and set point viral loads and unambiguous preservation of CD4 T cells could be achieved. As we could only transiently detect low levels of neutralizing antibodies in some vaccinees, these antibodies did not seem to add to the protection in the vaccinees. Our results indicate that both preventive multigenic DNA prime/MVA booster immunization strategies promote the control of virus replication and protect from disease progression. We also demonstrated that combining mucosal and systemic vaccination mediated better protective effects compared to systemic vaccination alone.

A simian immunodeficiency virus V3 loop mutant that does not efficiently use CCR5 or common alternative coreceptors is moderately attenuated in vivo.

Sexually transmitted HIV-1 strains utilize the chemokine receptor CCR5 for viral entry and inhibitors targeting this coreceptor offer great promise for antiretroviral therapy. They also raise the question, however, whether viral variants exhibiting altered coreceptor interactions and resistance against these antiviral agents might still be pathogenic. In the present study, we analyzed a SIVmac239 envelope (Env) mutant (239DL) containing two mutations in the V3 loop which reduced viral entry via CCR5 by 10- to 20-fold, disrupted utilization of common alternative SIV coreceptors and changed the way Env engaged CCR5. To evaluate its replicative capacity and pathogenic potential in vivo we infected six rhesus macaques with 239DL. We found that 239DL replication was only slightly attenuated early during infection. Thereafter, a D324V change, which restored efficient CCR5 usage and coincided with 239wt-like levels of viral replication, emerged in two animals. In contrast, the viral geno- and phenotype remained stable in the other four rhesus macaques. Although these animals had about 100-fold reduced viral RNA loads relative to 239wt-infected macaques, they showed pronounced CD4 T-cell depletion in the intestinal lamina propria, and one developed opportunistic infections and died with simian AIDS. Thus, changes in the V3 loop that diminished CCR5 usage and altered Env interactions with CCR5 reduced the pathogenic potential of SIVmac in rhesus macaques but did not abolish it entirely.

Readily acquired secondary infections of human and simian immunodeficiency viruses following single intravenous exposure in non-human primates.

Accumulating evidence suggests that exposed individuals may acquire multiple human immunodeficiency virus (HIV) infections more frequently than originally believed. As a result, circulating recombinant forms of HIV are emerging that are of particular concern in the AIDS epidemic and HIV vaccine development efforts. The aim of this study was to determine under what conditions secondary or superinfections of HIV or simian immunodeficiency virus (SIV) may be acquired under controlled settings in well-defined, non-human primate models. Retrospective analysis of macaques that had acquired apparent immunity upon infection with a defined attenuated SIV(mac) strain revealed that eight out of eight animals that were secondarily exposed to a new virus variant became infected with the new virus strain, but at low levels. Interestingly, similarly high frequencies of secondary infections were observed after early (4 months), as well as late (5 years), exposure following primary infection. As possible causes of susceptibility to secondary infections, perturbations in the immune system associated with exacerbated infections were then investigated prospectively. Results revealed that short-term immune-suppression therapy did not increase susceptibility to secondary infections. Taken together, data suggested that neither early- nor late-exposure immune-suppressive events following primary infection accounted for the observed high incidence of secondary infections. With HIV-1, the question of whether secondary infections with very closely related viral variants could occur in the chimpanzee model was addressed. In both animal models, secondary infections were confirmed, notably with relatively closely related SIV(mac) or HIV-1 strains, following a single exposure to the secondary virus strain. These findings reveal that secondary lentiviral infections may be acquired readily during different stages of primary infection, in contrast to co-infections, which are acquired at the moment of initial infection.