connorGGbamford

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Posts Tagged ‘antibody

HIV & Measles – double hit pathogenesis?

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ResearchBlogging.org

Despite ongoing worldwide eradication efforts, measles infection still results in significant morbidity and mortality. Although, throughout most of the developed world measles infection has been considerably reduced there still exists massive (and deadly) outbreaks in areas such as Africa and South-East Asia. Investigation of the reasons why this disparity occurs therefore  is of major medical, political and social interest.

Many factors are likely to be behind this major difference – and all of which deserve our attention if we are ever to remove measles from the human population. There exists problems in rolling out vaccines in countries with poor infrastructure such as roads and transport facilities; disruption to what is known as the vaccine ‘cold-chain’ (vaccines have to be kept cold to avoid rendering them unusable) is likely to occur; general poor health of the population in these regions and possible interference of vaccination in children with high levels of passively acquired maternal antibody.

Measles vaccination efforts in Africa may not be entirely effective

Today in PLoS Pathogens, Nilsson and Chiodi highlight in a featured opinion article, another possible source: the link between co-infection with HIV-1 and Measles infection. They point out that HIV-1 infection and replication may result in impaired immune responses in both mothers and children leaving open the possibility of measles infection (no immune system, no protection). HIV-1, as I’m sure you will all know, is a potentially deadly pandemic retrovirus – particularly a major problem in sub-Saharan Africa- which infects humans where it resides in the bodies own immune system: T cells, dendritic cells and macrophages. Viral replication results in the death of these immune cells and destruction of important lymphoid tissues resulting in an individual without key immune functions.

The authors note that children born to mothers who are HIV-1 positive or are HIV-1 positive themselves develop lower levels of anti-measles antibody upon vaccination -a big deal if we’re looking to protect these kids through vaccination. They show that memory B cells may be impaired and lower protection will result through failure to mount a B cell-generated antibody response. Immunity is a highly regulated system, if you remove one aspect-  in this case T cells – you will affect another pathway , in this case B cells. Thus there exists a major  problem with HIV-1 infected people and infection with other pathogens in the environment; HIV-1 infection significantly alters the host immune system weakening it to other invading pathogens such as measles which is endemic in these areas.

So how do we overcome this problem? Well, the authors suggest that on top of increasing vaccination coverage through catch-up programs it would be wise to administer anti-retroviral drugs  to mothers and children prior to vaccination to allow sufficient immune function; this should hopefully make a difference in combating both measles and HIV in the developing world, especially in an area where both cause so much pain. Hopefully, strategies such as this will aid treatment efforts for other pathogens rife in the developing world – targeting both HIV and the individual agents may be more effective.

Sadly, there exists another interaction between HIV and co-infection with other pathogens. Infection usually results in increased levels of immune cells in the blood and tissues yet these very cells are the target for HIV and if these cells increase, HIV replication will also. There exists a deadly interaction between multiple pathogens which must be broken.

Nilsson, A., & Chiodi, F. (2011). Measles Outbreak in Africa—Is There a Link to the HIV-1 Epidemic? PLoS Pathogens, 7 (2) DOI: 10.1371/journal.ppat.1001241

Written by Connor

February 11, 2011 at 3:05 pm

A mothers love declines – a measles vaccine problem?

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Worldwide, measles virus infection accounts for around 200,000 deaths annually; the importance of which is emphasized given the availability of a highly effective vaccine. Vaccine effectiveness, however, is a complex matter and is subject to many problems – a major one being transfer of maternal antibodies to children during early life, a form of natural passive immunity. Although these antibodies are there for a reason and do protect offspring from infections in early life, bridging the gap until they can synthesize their own antibodies, they have been shown to inhibit the activity to certain vaccines – measles vaccine is an example (see figure below).

Antibody concentrations in child following birth showing decline in attenuation (infection attenuation)

During early childhood, maternal antibody concentrations begin to wane and eventually reach such a level as to offer little protection from microbial challenge. These antibodies however are able to dampen the ability of a child to develop protective immunity following vaccination; it is this ‘window of opportunity’ that is responsible for a great number of measles virus infections and fatalities every year. The development of an effective vaccination strategy to get around this blocking effect would therefore be of great medical interest.

Recently, Kim et al (2010) publish their investigations into understanding how and why measles virus infection, in the presence of specific antibody results in the inhibition of a protective response following vaccination. Prior to this study it was unknown whether in this situation, MeV-specific B cells were being generated at all or whether they simply failed to secrete neutralizing antibody. The group used a rat model of MeV infection and simulated maternal antibody effects by passively transferring MeV specific antibodies and measuring the immunological outcomes. They demonstrated that there is a specific failure of B cells to secrete protective antibody in the presence of transferred antibody.

B cells will only secrete antibody when 3 signals are triggered:

1.     B-cell receptor/antigen interactions

2.     B – cell/ T-cell interactions

3.     Action of soluble mediators (for example: cytokines like interferon)

Kim et al hypothesized that in this model, where both signals 1 and 2 were active, inhibition of antibody secretion may be accounted for by the interference with certain soluble mediators. This idea was attractive providing the great deal of evidence showing MeV obstruction of interferon production – a pathway that normally results in the robust development of innate and adaptive immune responses. This results in two major problems involving antibody-specific inhibition of protective immune responses (maternal antibody) combined with MeV’s natural ability to inhibit the development of immunity; cases which are shared during the ‘window of opportunity’.

To this effect, the group developed a novel vaccine vector to circumvent wild-type measles interferon inhibition. Using reverse-genetics technology, they incorporated a MeV antigen gene, the haemagglutinin (HN) glycoprotein into the Newcastle Disease virus (NDV) genome as an extra gene, generating NDV-HN. NDV is an avian virus that induces high concentrations of IFNs upon infection allowing for the possibility of an effective measles vaccine in the presence of measles antibody.

The investigation confirmed the group’s predictions in that NDV-HN induced much higher levels of IFN in rat tissues when compared to MeV and that this led to development of MeV-specific neutralizing antibodies in the presence of transferred antibody. This work further verified that role that the restoration signal 3, in the form of alpha-IFN allows for B-cell secretion of antibody in in vivo and in vitro systems.

Given how medically important vaccination has been in protecting populations from often fatal and serious infectious disease and the troubles that arise when maternal antibody concentrations drop, any work developing vaccine technology to avoid these difficulties should be welcomed. Kim et al. confirmed the basis for the immunological blocks in generating MeV antibodies and began the development of a novel vector system to rationally provide protection. The results in this rat model, although not specifically applicable to the human situation, are promising in that it provides a logical framework to advance vaccine technology and prevent thousands of childhood deaths worldwide.

Kim D, Martinez-Sobrido L, Choi C, Petroff N, García-Sastre A, Niewiesk S, Carsillo T. (2011) Induction of Type I Interferon Secretion through Recombinant Newcastle Disease Virus Expressing Measles Virus Hemagglutinin Stimulates Antibody Secretion in the Presence of Maternal Antibodies. J Virol. 2011 Jan;85(1):200-7. PMID: 20962092

Written by Connor

December 17, 2010 at 10:43 pm