The increasing severity of the global AIDS crisis means the need for methods of preventing or treating the disease is similarly increasing. An effective HIV vaccine is the 'Holy Grail' that researchers seek. Now, work by Kenji Okuda and co-workers shows that a surprisingly simple gene therapy approach is a promising future vaccination strategy.Human immunodeficiency viruses type 1 and 2 (HIV-1, HIV-2), retroviruses belonging to the Lentivirus genus, cause acquired immunodeficiency syndrome (AIDS).1 These viruses are, arguably, currently responsible for more human misery than any other disease: 40 million people are living with HIV-AIDS, more than 50% in the sub-Saharan African region.2People become infected with HIV when the mucosas of the mouth, rectum or vagina are exposed to infected body fluids (during sex or breast feeding) or when such fluids are injected. Subsequently, often years after the initial infection, the virus starts to destroy the CD4+ T cells that are a vital part of the body's immune system. The depleted immune system causes a raft of negative symptoms, and opens the body to other infections and cancers. Tragically, those infected invariably die.3The advent of highly active antiretroviral therapy (HAART) has improved the lot of HIV patients. HAART reduces the symptoms and secondary infections caused by AIDS, and also prolongs survival. It is, however, very far from being a cure. HAART is expensive, must be continued throughout the patient's life, has negative side-effects, and can fail due to resistance of the virus.4 The ideal solution, as it has been for so many other diseases, would be a vaccine. However, attempts to develop such a vaccine have been less than successful.5The new study, published in September's issue of Human Gene Therapy, describes a novel approach for inducing an HIV-specific immune response. The Okuda group vaccinated mice with a single oral dose of a recombinant adeno-associated virus vector expressing the env gene from HIV-1 (AAV/HIVenv vector).6 The vaccination induced a strong immune response, both locally (in the mucosa) and systemically.The Human Gene Therapy study showed that anti-HIV antibodies (IgG and IgA) were present for 3–5 months after vaccination. Importantly, this means that the oral vaccine induced humoral mucosal immunity. Demonstrable mucosal immunity is crucial when the aim is to protect individuals from pathogens like HIV that are generally acquired via mucosal surfaces.The researchers also convincingly demonstrated that the vaccine induced a strong HIV-specific cell-mediated immunity. This represents a significant improvement compared to previous vaccines administered by injection into muscle tissue that, typically, did not induce a strong cellular immune response.However, to really show a vaccine actually works, one must show it induces protective immunity. To do this, the authors challenged immunized mice with a recombinant vaccinia virus expressing HIV-1 env. Using a rectal inoculum they observed a decreased viral load (about 2 logs) in immunized animals. These results are encouraging, but, in addition to the surrogate viral challenge used by Okuda and his colleagues, they need to be repeated for HIV itself.The success of this new approach in mice is exciting because, theroretically, it could be equally successful in humans. We already know that the AAV vector used is safe and effective in humans.7 This vector is also almost certainly less pathogenic than all vectors presently adopted in animal and human trials.8 In addition, because the vaccine is a live viral preparation, it is more likely to induce a protective immune response. Now Okuda's group have shown that AAV's resistance to a range of temperatures, proteases and pH variations allows successful oral delivery of an HIV vaccine.However, we should not crack open the champagne yet. The short duration of the induced immune response in the mouse model suggests that the AAV vector mainly infects rapidly renewing cells of the intestinal lumen. Therefore, in conjunction with the AAV/HIVenv oral vaccination, we need to boost immunity in other ways. Adoptive immunotherapy with professional antigen-presenting dendritic cells or combined DNA/protein vaccinations with different gene products and schedules are two promising ways this may be achieved.General use of this approach in humans will also be hampered by the strong anti-AAV immunity induced by the initial vaccination, that curtails the positive effects of subsequent vaccinations.9 Consequently, AAV vector-based vaccines such as this one may be most effective when used in conjunction with other approaches. The way to a successful HIV vaccine is paved with difficulties and surely monkeys, and not mice, will have to be used for setting the first standard of protection before human trials. Notwithstanding, the new work by Okuda's group at least represents a promising lead in the quest for the Holy Grail of a vaccine to prevent further misery being inflicted by the plague of AIDS.

Immunotherapy: oral route to Holy Grail?

PALU', GIORGIO;PAROLIN, MARIA CRISTINA
2003

Abstract

The increasing severity of the global AIDS crisis means the need for methods of preventing or treating the disease is similarly increasing. An effective HIV vaccine is the 'Holy Grail' that researchers seek. Now, work by Kenji Okuda and co-workers shows that a surprisingly simple gene therapy approach is a promising future vaccination strategy.Human immunodeficiency viruses type 1 and 2 (HIV-1, HIV-2), retroviruses belonging to the Lentivirus genus, cause acquired immunodeficiency syndrome (AIDS).1 These viruses are, arguably, currently responsible for more human misery than any other disease: 40 million people are living with HIV-AIDS, more than 50% in the sub-Saharan African region.2People become infected with HIV when the mucosas of the mouth, rectum or vagina are exposed to infected body fluids (during sex or breast feeding) or when such fluids are injected. Subsequently, often years after the initial infection, the virus starts to destroy the CD4+ T cells that are a vital part of the body's immune system. The depleted immune system causes a raft of negative symptoms, and opens the body to other infections and cancers. Tragically, those infected invariably die.3The advent of highly active antiretroviral therapy (HAART) has improved the lot of HIV patients. HAART reduces the symptoms and secondary infections caused by AIDS, and also prolongs survival. It is, however, very far from being a cure. HAART is expensive, must be continued throughout the patient's life, has negative side-effects, and can fail due to resistance of the virus.4 The ideal solution, as it has been for so many other diseases, would be a vaccine. However, attempts to develop such a vaccine have been less than successful.5The new study, published in September's issue of Human Gene Therapy, describes a novel approach for inducing an HIV-specific immune response. The Okuda group vaccinated mice with a single oral dose of a recombinant adeno-associated virus vector expressing the env gene from HIV-1 (AAV/HIVenv vector).6 The vaccination induced a strong immune response, both locally (in the mucosa) and systemically.The Human Gene Therapy study showed that anti-HIV antibodies (IgG and IgA) were present for 3–5 months after vaccination. Importantly, this means that the oral vaccine induced humoral mucosal immunity. Demonstrable mucosal immunity is crucial when the aim is to protect individuals from pathogens like HIV that are generally acquired via mucosal surfaces.The researchers also convincingly demonstrated that the vaccine induced a strong HIV-specific cell-mediated immunity. This represents a significant improvement compared to previous vaccines administered by injection into muscle tissue that, typically, did not induce a strong cellular immune response.However, to really show a vaccine actually works, one must show it induces protective immunity. To do this, the authors challenged immunized mice with a recombinant vaccinia virus expressing HIV-1 env. Using a rectal inoculum they observed a decreased viral load (about 2 logs) in immunized animals. These results are encouraging, but, in addition to the surrogate viral challenge used by Okuda and his colleagues, they need to be repeated for HIV itself.The success of this new approach in mice is exciting because, theroretically, it could be equally successful in humans. We already know that the AAV vector used is safe and effective in humans.7 This vector is also almost certainly less pathogenic than all vectors presently adopted in animal and human trials.8 In addition, because the vaccine is a live viral preparation, it is more likely to induce a protective immune response. Now Okuda's group have shown that AAV's resistance to a range of temperatures, proteases and pH variations allows successful oral delivery of an HIV vaccine.However, we should not crack open the champagne yet. The short duration of the induced immune response in the mouse model suggests that the AAV vector mainly infects rapidly renewing cells of the intestinal lumen. Therefore, in conjunction with the AAV/HIVenv oral vaccination, we need to boost immunity in other ways. Adoptive immunotherapy with professional antigen-presenting dendritic cells or combined DNA/protein vaccinations with different gene products and schedules are two promising ways this may be achieved.General use of this approach in humans will also be hampered by the strong anti-AAV immunity induced by the initial vaccination, that curtails the positive effects of subsequent vaccinations.9 Consequently, AAV vector-based vaccines such as this one may be most effective when used in conjunction with other approaches. The way to a successful HIV vaccine is paved with difficulties and surely monkeys, and not mice, will have to be used for setting the first standard of protection before human trials. Notwithstanding, the new work by Okuda's group at least represents a promising lead in the quest for the Holy Grail of a vaccine to prevent further misery being inflicted by the plague of AIDS.
2003
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2465414
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact