Christopher;
I read your suggestion that CD4+8+ cells may be targets of HIV
infection. There are a number of problems with this hypothesis:
1. Very few CD4+8+ T cells reside in the periphery, especially in
adults. There are a significant number of immature double positive
thymocytes that escape into the periphery, but usually this is found only
during the period shortly after birth- a number of studies
peripheral immune system development in mice have shown this.
2. Infection of the thymus by HIV is generally considered a late stage
event in the pathophysiology of HIV-AIDS. In fact, due to the failure of
the primary immune response to adequately keep the virus in check, the
virus replicates in the lymph nodes during the so-called "latent phase"
of the disease. This often lasts for years. During this time free
virion is virtually undetectable in the peripheral blood. Following the
latent phase, virus begins to spill over into the peripheral blood and
also infects other lymphoid organs, especially the thymus. By this time,
the patient is nearing, or already undergoing, the full-blown AIDS stage of
the disease. The body seems to attempt one final assault so to speak
through a chronic immune response due to the now widespread dissemination
of the virus, again failing. This may explain AIDS
cachexia (high circulating TNF, IL-1 etc.,i.e., inflammatory cytokines)
found during this time.
3. The fact is HIV does not seem to kill the cells it infects. That is
what recent research is uncovering. Even in an evolutionary sense it does not
make sense for a virus to kill its host cell- this is obviously not
conducive to viral replication!! In fact, the most "clever" viruses
(e.g., adenovirus, human papillomavirus, Hepatitis B, EBV, small pox virus
etc.) have evolved genetic elements coding for proteins that actually
ensure cell survival by preventing apoptosis during productive
infection!! I predict that HIV
will be found to do the same, we simply haven't looked hard enough at the
problem yet. Unfortunately, virologists are not cell biologists. As
AIDS is now FINALLY being recognized as an immune problem not a viral
problem per se, and more attention (and more funding) is being paid to the
cell biology of the problem (apoptosis etc.), I'm sure answers will be
forthcoming. A recent paper published in Nature Medicine actually
found that HIV-infected T cells in lymph node follicles were
the ones NOT undergoing apoptosis. I think the record has to be set
straight on this once and for all.
More pertinent questions to ask are; how does HIV infect antigen
presenting cells (APCs), the actual orchestrators of the immune response?
What is the nature of HIV infection of dendritic cells in the lymph node
follicles? If HIV does not infect professional APCs very well during the
initial course of infection, then why not? Should a successful vaccine
entail an attenuated virion which prefentially infects APCs for Th1
triggering, and how can this be achieved?
Laszlo
Laszlo Radvanyi
Ontario Cancer Institute,
Princess Margaret Hospital
Toronto, Ontario M4X 1K9
tel: 416-924-0671 ext. 4994
fax: 416-926-6529
e-mail: radvanyi at oci.utoronto.ca
