HIV This Week

Lemiale F, Korokhov N. Lentiviral vectors for HIV disease prevention and treatment. Vaccine. 2009; 27:3443-3449.

HIV has posed major challenges to the scientific community, both in terms of treatment and prevention. Current drug regimens, while efficacious, are expensive, inaccessible to major parts of the world, induce major side effects, and cannot prevent escape mutants due to lack of compliance and drug fatigue. In the vaccine field, recent setbacks related to the interruption and cancellation of major advanced clinical trials using adenoviral vectors have highlighted the need for new and innovative strategies. Unique features of HIV-based lentiviral vectors (LVs) and the current progress in the LV-based platform development make them an attractive alternative for the further LV-based HIV vaccine development. In preclinical studies, they have demonstrated a high degree of immunogenicity, while overcoming pitfalls faced by other viral vectors. These findings, combined with recent progress in large scale lentiviral vectors production/purification, make this strategy worth considering for further vaccine development.

Editors’ note: In making the case for further study of lentiviral vectors, this article provides a description of the evolution of HIV vaccine strategies. These aim to overcome the challenges of HIV-1 sequence diversity, latency, high rates of mutation and recombination, and infection by HIV of critical immune cells. Among the current approaches are strategies using protein-based formulations to induce neutralising antibodies and vector systems to induce cellular immunity – we will likely need both for an effective HIV vaccine.

Wang L, Cheng C, Ko SY, Kong WP, Kanekiyo M, Einfeld D, Schwartz RM, King CR, Gall JG, Nabel GJ. Delivery of adenovirus HIV vaccine vectors to the intestine induces enhanced mucosal cellular immunity. J Virol. 2009;83:7166-75.

Effective vaccines for human immunodeficiency virus-1 (HIV-1) will likely need to stimulate protective immunity in the intestinal mucosa, where HIV-1 infection causes severe CD4(+) T cell depletion . While replication-competent adenoviral vectors (rAd) can stimulate Ad-specific mucosal immunity after replication, oral delivery of replication-defective rAd vectors encoding specific immunogens has proven challenging. In this study, Wang and colleagues have systematically identified barriers to effective gut delivery of rAd vectors and identify sites and strategies to induce potent cellular and humoral immunity. Vector-mediated gene transfer by rAd5 was susceptible to low pH buffer, gastric and pancreatic proteases, and extracellular mucins. Using ex vivo organ explants, they found that transduction with rAd5 was highest in the ileum and colon compared to other intestinal segments. Transgene expression was 100-fold higher after direct surgical introduction into the ileum than observed with oral gavage, with rAd5 showing greater potency than rAd35 or rAd41 vectors. A single immunization of rAd5 encoding HIV-1 gp140B to the ileum stimulated potent CD8(+) T cell responses in the intestinal and systemic compartments, and these responses were further enhanced by intramuscular rAd5 boosting. These studies suggest that induction of primary immune responses by rAd5 gut immunization elicits potent antigen-specific mucosal responses after subsequent systemic boosting.

Editors’ note: This study is one of a series of studies aimed at determining whether different adenovirus vectors with alternative routes of administration can enhance mucosal immunity. Because the gastrointestinal tract is the predominant site of CD4 T-cell loss during the first weeks of HIV infection, these researchers hypothesized that targeted delivery of vaccines to the gut could stimulate mucosal responses that would inhibit uncontrolled viral replication and protect gut-associated lymphoid tissue (GALT). Immune responses induced by a single injection into the small bowel of a recombinant adenovirus encoding gp140B, followed by an intramuscular boost, produced strong cellular immune responses in mice. Whether this will have clinical utility in the future is anyone’s guess (a small bowel injection to prevent HIV seems quite a stretch), but it is a good model for learning more about how mucosal immune responses contribute to protection against HIV.