The so called  "HIV vaccine researchers" work for the wishyes american
drug companies who will have nothing to sell if a vaccine became a
reality. Or else they are driven by the 'nobel motto'.
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http://www.deccanherald.com/Content/Dec42007/snt2007120339209.asp

The elusive HIV vaccine
The amount of HIV-related research notwithstanding, a vaccine for the
dreaded virus still remains a dream. The possibility of having one in
the near future seems to be very bleak too.

"We hope to have a vaccine against AIDS ready for testing in about two
years," said Margaret Heckler, US health and human services secretary
on 23rd April 1984 while announcing the discovery by Dr Robert Gallo
of the National Cancer Institute, of virus which causes AIDS.

It is over two decades now. We have no vaccine for HIV yet and the
possibility of having one in the near future seems to be bleak!

Last month, Merck and its partners called off their ambitious T-cell
vaccine concept based HIV clinical trial after it failed to provide
convincing results. "We were all in shock and devastated," puts Dr
Peggy Johnston, a lead scientist at the National Institute of Allergy
and Infectious Diseases.

Worldwide estimation of people living with HIV is over 39.5 million,
including about 2.3 million children. Over 4.3 million people were
newly infected in 2006 alone! United Nations HIV program finds 95 per
cent of the infected people in developing countries!

The National Institute of Health spends over 500 millions each year on
HIV-related research. No vaccine search program in the past was as
intense as the one with HIV. Scientists know almost everything by now
on HIV as a result of its passionate study over the past two decades.

Yet, it looks we know very little about HIV and its infection. Blame
is partly on HIV and partly on us. We seem to invite HIV, no reason,
why? And condemn the killer molecules - GP120 of HIV and CCR5 of ours!

There are many variants in HIV and they invade human immune system in
several/ different phases. The chief form, HIV-1, initially prefers
macrophages, a type of immune cells. It binds through a molecule know
as GP120 (a viral surface glyco-protein) to the protein molecule CD4
on the macrophage surface. This interaction alters the GP120
conformation to reveal a binding site for CCR5, a key surface protein.
This triggers conformational changes in the GP41 (another viral glyco-
protein) to mediate fusion of viral and host cell membranes. Once
bound, it enters cells to reproduce. Subsequent strains produced have
GP120 molecules capable of recognising one more surface protein called
CXCR4 on T-cells, another type of immune cells along with macrophages.
Later strains of the virus may preferentially infect T-cells and
destroy them. This leads to the collapse of the immune system of the
body which is nothing but the onset of AIDS. Another form, HIV-2, can
recognise CXCR4 directly and this can quickly lead to AIDS. Hampered
immune system leaves the body defenseless and susceptible for the
attack by all other disease causing microbes and cancer.

In order to prevent HIV from taking over, antibodies (defense protein
molecules in the body) must recognise and neutralise viral particles.
Viral surface glyco-protein, a composite of three copies each of GP120
and GP41, is the only target available for antibodies. The remarkable
diversity, rearrangements, glycosylation and conformational
flexibility of this surface protein allows virus to elude body's
defense mechanisms. Additionally, HIV-1 mutates at an incredibly fast
rate leaving scientists frustrated in the attempt of finding a
vaccine.

Despite this sneakiness, virus must retain minimum identity of its
surface glyco-protein to mediate CD4 and CCR5 binding, should it need
to enter the cell. Scientists have recently identified such a
conserved region in the GP120 and shown the crystal structure of B12,
a neutralising antibody.

Unlike most other parts of the protein, which change constantly, the
newly discovered protein site appears to be stable and vulnerable to
attack, scientists wrote in one of the issues of this years Nature, a
science journal.
There is something special about HIV infection that relates to CCR5,
the protein molecule found on the surface of our own immune cells.
CCR5 (chemokine C-C motif receptor 5) and many other related cytokine
receptors such as CXCR4 are basically involved in the signaling
process. Researches learnt that cytokines (small signaling proteins
and peptides which bind to CCR5) suppress HIV infection, indicating
the involvement of CCR5 in the infection process.

Also, it was found that some people who have only one normal copy of
CCR5 gene are tolerant to HIV as the infection is achieved using over
1000 times more virus than ordinarily required! Those who altogether
lack normal copies of CCR5, but have a mutated version (CCR5 delta 32)
are just immune to HIV. How lucky are they! No one is sure why or when
such a mutation was selected.

Although it was hypothesised that CCR5 mutation was the result of a
recent plague epidemic, a latest study found the occurrence of mutated
CCR5 in Bronze Age skeletal remains from many burial sites in Europe.
Why do we need CCR5 at all when a mutated version has no significant
effect on normal functioning? CXCR4, on the other hand, is found to be
more critical as mice with cells engineered to be CXCR4-deficient died
during gestation!
CCR5 and related proteins appear to have profound implications for the
future treatment of HIV infection and AIDS. For example, if stem cells
with defective CCR5 gene could be successfully transplanted into HIV
infected individuals, they would produce immune cells that would be
naturally immune to HIV-1 infection!

"Creating an HIV vaccine is one of the great scientific challenges of
our time," puts Dr Elias Zerhouni, director of the National Institute
of Health. Can we conquer these killer molecules in any way? We shall
live with hope!
RSP Rao