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Thursday, July 3, 2014

Progress in HIV-1 Vaccine Development

Advances in HIV vaccine development have been hampered by roadblocks associated with failure to prevent infection. In recent years, a number of basic and translational science advances have shown promise in the development for an effective vaccine. In their review, Haynes and colleagues summarize these advances along with the roadblocks that still remain, as well as the most promising approaches to successful vaccine design (J Allergy Clin Immunol 2014, 134(1): 3-10). 

This year, the field of HIV-vaccine research had a major disappointment in the announcement of the lack of a vaccine efficacy seen in a DNA prime, recombinant adenovirus type 5 (rAd5) boost HIV-1 vaccine trial developed by the NIH Vaccine Research Center. The vaccine was designed to test the hypothesis that high levels of CD8+ cytotoxic T cells (CTLs) could either protect against transmission or lead to control of plasma HIV-1 viral load. The second failed trial, the Merck recombinant adenovirus type 5 trail, not only lacked vaccine efficacy, but also appeared to enhance infection in those vaccines seropositive for Ad5. Although these 2 trials were of great disappointment, they provided valuable information on the types of immune responses that are unlikely to be protective.

New advances have demonstrated a variety of promising results such as the discovery of new envelope (Env) targets of potentially protective antibodies. A recent study shows promise with the finding that CD8+ T cells are associated with control and eradication of early retrovirus infections in rhesus macaques. Another recent study shows that the development of immunogens to overcome HIV-1 T cell epitope diversity while another study identifies correlates of transmission risk in an HIV-1 efficacy trail. And finally, a recent advancement has mapped the co-evolution of HIV-1 founder Env mutants in infected individuals who develop broad neutralizing antibodies (bnAbs), thereby defining bnAb developmental pathways.

Despite these advances, the field is still years away from deployment of an effective vaccine. Moving forward in HIV-1 vaccine research requires the conversion of subdominant immune responses into dominant ones, which has yet to be accomplished by an infectious disease vaccine. HIV-1 vaccine research is breaking promising new ground in vaccinology, and success in its development will herald success for other difficult vaccines such as influenza and hepatitis C. 

Prenatal exposure to diesel exhaust induces asthma susceptibility through NK cell priming

Asthma often begins early in life and is attributed to more than just genetic factors, because the prevalence continues to rise. Epidemiological studies have indicated roles for prenatal and early childhood exposures, including exposure to diesel exhaust, however, little is known about the mechanisms involved. To elucidate this, Manners et al developed a mouse model of asthma susceptibility through prenatal exposure to diesel exhaust (J Allergy Clin Immunol 2014; 134(1): 63-72).

In this model, pregnant mice were repeatedly exposed to diesel exhaust particles (DEPs). Offspring were immunized and challenged with ovalbumin (OVA) or exposed to PBS (control) then examined for features of asthma. Compared to controls, offspring that were exposed to DEP were hypersensitive to OVA, indicated by airway hyperresponsiveness, elevated serum levels of OVA-specific IgE, and elevated levels of pulmonary and systemic T-helper type 2 (Th2) and Th17 cytokines. The authors determined that natural killer (NK) cells were the primary source of cytokine production and airway inflammation was diminished by antibody-mediated depletion of NK cells. Furthermore, asthma susceptibility was associated with increased transcription of genes known to be specifically regulated by the aryl hydrocarbon receptor (AhR) and oxidative stress.

These results coincide with previous data that suggests NK cells initiate allergic inflammation. AhR is expressed in NK cells which may provide a link between maternal exposure to diesel exhaust and asthma in offspring. Taken together, this data provides mechanistic insight into the process of prenatally-induced asthma susceptibility.