- Mondays basic science sessions of the 12th World AIDS Conference
highlighted major information on immune recovery following the use of highly active
anti-HIV therapy, which typically includes three drugs including a potent protease
inhibitor. Additionally, new advances in understanding the viruss interaction with
cells shed light on new targets to inhibit HIV replication and possibly transmission.
- In the course of HIV disease, many cell populations decrease over time. These
include CD4+ cells, CD8+ cells (which initially increase and subsequently decrease
throughout the course of disease), B cells and many other important immune system cells.
In addition to a decrease in cell numbers, there are also profound defects in immune
functions. CD8+ cells, which are important for directly destroying HIV infected cells and
also produce factors which can inhibit HIV replication, do not appear to maintain anti-HIV
activity, despite initial increases in CD8+ cell number. Moreover, the ability of the
immune system to respond to a large number of infections becomes increasingly restricted.
The environments necessary for new cell development and maturation (such as the bone
marrow and thymus) might also be impaired as a consequence of HIV infection, making the
prospect of immune restoration a challenge.
- Presentations from the recent conference largely confirmed previous observations
that treatment with aggressive anti-HIV therapy (e.g. triple-drug protease inhibitor
containing regimens) appears to improve many immunologic abnormalities associated with HIV
infection. Nevertheless, improvements are noted in almost every area including an increase
in cell number and functional responses, these improvements are not the same as those
observed in healthy, HIV-uninfected people, however. The following are highlights of new
information presented at the conference on Monday:
- Restoration of functional immune responses to common infections has been observed
following anti-HIV therapy. Immune responses against HIV, however, appear to only be
maintained in people treated very early (e.g. days to weeks following infection by HIV),
but do not recover as a consequence of anti-HIV therapy in people treated at other stages
of HIV disease.
- People who initiate therapy at other stages of HIV disease demonstrate
improvements in certain types of anti-HIV immune responses (e.g. HIV-specific CTL) if they
are able to maintain suppression of virus for an extended period of time (e.g. greater
than 2 years).
- Exciting preliminary observations come from a group which imaged the thymus of
HIV-infected children before and after anti-HIV therapy. In one representative case, the
thymus before therapy was barely visible (0.07 cm3 in area). One year after
starting therapy, the size of the thymus increased 100 fold (19.8 cm3 in area).
This was a child who was quite advanced in disease with an AIDS diagnosis (CDC Class III).
This increase was also associated with an increase in the proportion of naïve T cells
perhaps new cells being generated from the thymus. This news is encouraging
suggesting that this important immune environment, critical for new T cells with diverse
abilities to mature, is able to function to some degree. More research is necessary in
both adults and children to better understand this preliminary observation.
- A large portion of Mondays presentation highlighted new information on
fairly recent and important discoveries on the role of cell proteins, called chemokine
receptors, and immune chemicals, called chemokines, in the process of HIV infection of
immune cells. Initially two proteins, CXCR4 and CCR5, were identified as critical
co-receptors necessary for HIV to attach to in order to infect an immune cell. What that
means is that in addition to the CD4+ protein on T-cells, HIV must also attach to a second
protein in order to gain entry into a cell. CCR5 was identified as the second receptor
important for the most commonly sexually transmitted strain of HIV (the NSI virus). CXCR4
was identified as the second protein important for enabling a more aggressive form of HIV
(the SI virus) to infect a cell. This virus is more predominant among people in
advanced-stage disease. Chemokines, natural products of many cells can bind to the second
receptors, rendering the co-receptor inaccessible to the virus and thus inhibiting
infection of immune cells. The conference highlighted the following advances in this
important area of discovery:
- Viruses from people who are long-term non-progressors (e.g. do not show symptoms
of HIV disease progression after infection for 10+ years) appear to restrictively use the
CCR5 protein in order to infect immune cells.
- Viruses from people who follow a more traditional course of HIV disease
progression will sometimes restrictively use CCR5, but not in all cases. This means that
factors associated with disease progression and non-progression are not solely explained
by the restricted use of certain co-receptors by the virus.
- The majority of people who progress very rapidly to disease appear to have
viruses which use many different co-receptors in order to infect immune cells.
- This information, taken together, supports the need for further research on the
role of co-receptor utilisation and disease progression in order to shed light on what
processes are at work which conserves the use of certain receptors by the virus. Moreover,
this information provides the basis for new directions in novel therapies for HIV disease.
- A number of new therapeutic approaches, which interfere with HIVs ability
to access a co-receptor, are being evaluated in test tubes and animals. These include a
class of drugs called biclyclams. AOP Rantes, a drug which resembles a chemokine, is also
being researched.
- While it is encouraging that new therapeutic approaches are being evaluated,
there are concerns that inhibiting one pathway (e.g. CCR5) may drive the virus to start
using another pathway (e.g. CXCR4), and may have detrimental effects on the disease.
Other notable new developments included:
- Infected human immune cells were put in the vagina of a mouse (SCID-hu PBL) and
productive infection was established in human white cells that had been put in the mouse.
This model may be very useful for understanding transmission and testing HIV prevention
approaches.
- One showed that cells releasing HIV that is protease deficient can transmit virus
that is infectious by cell-to-cell contact.
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