Single-dose bNAb cocktail or abbreviated ART post-exposure regimens achieve tight SHIV control without adaptive immunity

Shapiro, Mariya B.; Cheever, Tracy; Malherbe, Delphine C.; Pandey, Shilpi; Reed, Jason S.; Yang, Eun Sung; Wang, Keyun; Pegu, Amarendra; Chen, Xuejun; Siess, Don C.; Burke, David; Henderson, Heidi; Lewinsohn, Rebecca; Fischer, Miranda; Stanton, Jeffrey J.; Axthelm, Michael K.; Kahl, Christoph; Park, Byung; Lewis, Anne D.; Sacha, Jonah B.; Mascola, John R.; Hessell, Ann J.; Haigwood, Nancy L.

doi:10.1038/s41467-019-13972-y

Cited by 45 publications

(48 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We obtained this type of outcome with our previous adenovirus-based vaccine ( 12 ), where the cell-associated viral loads were significantly lower in SAd7+Protein vaccinated macaques compared to control animals. In related studies in primates, we showed that bNAbs can limit viral seeding when present within 24 to 30 h of exposure to Tier 2 SHIV SF162P3 ( 28 , 45 ) and that it is possible to reduce the levels of tissue viral DNA in macaques exposed to Tier 1 SHIV in the presence of a single human monoclonal antibody directed to V1V2 ( 46 ). In the current experiment, both regimens significantly lowered viral DNA copies in lymphoid and gut tissues tested.…”

Section: Discussionmentioning

confidence: 92%

Modified Adenovirus Prime-Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge

et al. 2021

Self Cite

View full text Add to dashboard Cite

Designing immunogens and improving delivery methods eliciting protective immunity is a paramount goal of HIV vaccine development. A comparative vaccine challenge study was performed in rhesus macaques using clade C HIV Envelope (Env) and SIV Gag antigens. One group was vaccinated using co-immunization with DNA Gag and Env expression plasmids cloned from a single timepoint and trimeric Env gp140 glycoprotein from one of these clones (DNA+Protein). The other group was a prime-boost regimen composed of two replicating simian (SAd7) adenovirus-vectored vaccines expressing Gag and one Env clone from the same timepoint as the DNA+Protein group paired with the same Env gp140 trimer (SAd7+Protein). The env genes were isolated from a single pre-peak neutralization timepoint approximately 1 year post infection in CAP257, an individual with a high degree of neutralization breadth. Both DNA+Protein and SAd7+Protein vaccine strategies elicited significant Env-specific T cell responses, lesser Gag-specific responses, and moderate frequencies of Env-specific TFH cells. Both vaccine modalities readily elicited systemic and mucosal Env-specific IgG but not IgA. There was a higher frequency and magnitude of ADCC activity in the SAd7+Protein than the DNA+Protein arm. All macaques developed moderate Tier 1 heterologous neutralizing antibodies, while neutralization of Tier 1B or Tier 2 viruses was sporadic and found primarily in macaques in the SAd7+Protein group. Neither vaccine approach provided significant protection from viral acquisition against repeated titered mucosal challenges with a heterologous Tier 2 clade C SHIV. However, lymphoid and gut tissues collected at necropsy showed that animals in both vaccine groups each had significantly lower copies of viral DNA in individual tissues compared to levels in controls. In the SAd7+Protein-vaccinated macaques, total and peak PBMC viral DNA were significantly lower compared with controls. Taken together, this heterologous Tier 2 SHIV challenge study shows that combination vaccination with SAd7+Protein was superior to combination DNA+Protein in reducing viral seeding in tissues in the absence of protection from infection, thus emphasizing the priming role of replication-competent SAd7 vector. Despite the absence of correlates of protection, because antibody responses were significantly higher in this vaccine group, we hypothesize that vaccine-elicited antibodies contribute to limiting tissue viral seeding.

show abstract

Section: Discussionmentioning

confidence: 92%

Modified Adenovirus Prime-Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Stimulating effectors using vaccines has been shown to suppress viral replication and lower the set-point viremia [ 47 , 48 ], but several additional design challenges must be overcome, including the need to stimulate effectors early enough and, interestingly, prevent effector exhaustion due to the vaccine [ 49 ], for the successful deployment of T cell vaccines [ 50 ]. Further, such strategies may not work in children, where bNAbs may elicit control without effector responses, possibly due to the inadequately developed immune system [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

2020

View full text Add to dashboard Cite

Antiretroviral therapy (ART) for HIV-1 infection is lifelong. Stopping therapy typically leads to the reignition of infection and progressive disease. In a major breakthrough, recent studies have shown that early initiation of ART can lead to sustained post-treatment control of viremia, raising hopes of long-term HIV-1 remission. ART, however, elicits post-treatment control in a small fraction of individuals treated. Strikingly, passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 early in infection was found recently to elicit longterm control in a majority of SHIV-infected macaques, suggesting that HIV-1 remission may be more widely achievable. The mechanisms underlying the control elicited by bNAb therapy, however, remain unclear. Untreated infection typically leads to progressive disease. We hypothesized that viremic control represents an alternative but rarely realized outcome of the infection and that early bNAb therapy triggers a dynamical switch to this outcome. To test this hypothesis, we constructed a model of viral dynamics with bNAb therapy and applied it to analyse clinical data. The model fit quantitatively the complex longitudinal viral load data from macaques that achieved lasting control. The model predicted, consistently with our hypothesis, that the underlying system exhibited bistability, indicating two potential outcomes of infection. The first had high viremia, weak cytotoxic effector responses, and high effector exhaustion, marking progressive disease. The second had low viremia, strong effector responses, and low effector exhaustion, indicating lasting viremic control. Further, model predictions suggest that early bNAb therapy elicited lasting control via pleiotropic effects. bNAb therapy lowers viremia, which would also limit immune exhaustion. Simultaneously, it can improve effector stimulation via cross-presentation. Consequently, viremia may resurge post-therapy, but would encounter a primed effector population and eventually get controlled. ART suppresses viremia but does not enhance effector stimulation, explaining its limited ability to elicit post-treatment control relative to bNAb therapy.

show abstract

“…As in the previous study, all animals that received the bNAb therapy were free of viremia in both the plasma and tissue measurements 6 months after treatment. A later study showed that in infant macaques, treatment with the same combination of bNAbs at 30 h post SHIV-SF162P3 challenge, but not at 48 h, was sufficient for keeping the animals from becoming infected (Shapiro et al, 2020). These studies show that bNAb therapy could be used for treating early infections if the treatment is started within a very early window of exposure.…”

Section: Learning From Passive Infusion Efficacy Studies Preclinical mentioning

confidence: 88%

Promise and Progress of an HIV-1 Cure by Adeno-Associated Virus Vector Delivery of Anti-HIV-1 Biologics

Gardner

2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Despite the success of antiretroviral therapy (ART) at suppressing HIV-1 infection, a cure that eradicates all HIV-1-infected cells has been elusive. The latent viral reservoir remains intact in tissue compartments that are not readily targeted by the host immune response that could accelerate the rate of reservoir decline during ART. However, over the past decade, numerous broadly neutralizing antibodies (bNAbs) have been discovered and characterized. These bNAbs have also given rise to engineered antibody-like inhibitors that are just as or more potent than bNAbs themselves. The question remains whether bNAbs and HIV-1 inhibitors will be the effective "kill" to a shock-and-kill approach to eliminate the viral reservoir. Additional research over the past few years has sought to develop recombinant adeno-associated virus (rAAV) vectors to circumvent the need for continual administration of bNAbs and maintain persistent expression in a host. This review discusses the advancements made in using rAAV vectors for the delivery of HIV-1 bNAbs and inhibitors and the future of this technology in HIV-1 cure research. Numerous groups have demonstrated with great efficacy that rAAV vectors can successfully express protective concentrations of bNAbs and HIV-1 inhibitors. Yet, therapeutic concentrations, especially in non-human primate (NHP) models, are not routinely achieved. As new studies have been reported, more challenges have been identified for utilizing rAAV vectors, specifically how the host immune response limits the attainable concentrations of bNAbs and inhibitors. The next few years should provide improvements to rAAV vector delivery that will ultimately show whether they can be used for expressing bNAbs and HIV-1 inhibitors to eliminate the HIV-1 viral reservoir.

show abstract

Single-dose bNAb cocktail or abbreviated ART post-exposure regimens achieve tight SHIV control without adaptive immunity

Cited by 45 publications

References 56 publications

Modified Adenovirus Prime-Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge

Modified Adenovirus Prime-Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

Promise and Progress of an HIV-1 Cure by Adeno-Associated Virus Vector Delivery of Anti-HIV-1 Biologics

Contact Info

Product

Resources

About