Detailed notes for these documents
can be found in Chapter 7 of Principles of Molecular Virology.
Standard
Version:The 4th edition contains new
material on virus structure, virus evolution, zoonoses, bushmeat, SARS
and bioterrorism, CD-ROM with FLASH animations, virtual interactive tutorials
and experiments, self-assessment questions, useful online resources, along
with the glossary, classification of subcellular infectious agents and
history of virology. (Amazon.co.uk)
Instructors
Version:The 4th edition contains new
material on virus structure, virus evolution, zoonoses, bushmeat, SARS
and bioterrorism, CD-ROM with all the Standard Version content plus all
the figures from the book in electronic form and a PowerPoint slide set
with complete lecture notes to aid in course preparation. (Amazon.co.uk)
It is not clear how much of the pathology of AIDS is directly due to the virus and how much is caused by the immune system itself. There are numerous models which have been suggested to explain how HIV causes immune deficiency:
Direct Cell Killing:
This was the earliest mechanism suggested, based on the behaviour of laboratory
isolates of HIV. Cell fusion resulting in syncytium formation is one of the major
mechanisms of cell killing by HIV in vitro. However, different isolates of HIV
vary considerably in the extent to which they promote the fusion of infected cells.
Subsequent experiments suggested there may not be sufficient virus present in
AIDS patients to account for all the damage seen, although killing of CD4+ cells
may contribute to the overall pathogenesis of AIDS in some circumstances. Recently,
it has become clear that up to half of the CD4+ cells in the body may be infected
with HIV, so the idea of direct cell killing has been re-examined, but in light
of induction of apoptosis (see below) rather than by cell fusion. Indirect effects
of infection, e.g. disturbances in cell biochemistry and lymphokine production
may also affect the regulation of the immune system:
HIV-infected cells can induce autophagy in bystander CD4+ T lymphocytes through
contact of the Env protein with CXCR4, leading to apoptotic cell death, a mechanism
most likely contributing to immunodeficiency. HIV-1 envelope glycoproteins (Env),
expressed at the cell surface, induce apoptosis of uninfected CD4+ T cells.
Independently of HIV replication, transfected or HIV-infected cells that express
Env induced death uninfected CD4+ T lymphocytes via CXCR4. Espert
L, et al. Autophagy is involved in T cell death after binding of HIV-1 envelope
proteins to CXCR4. J Clin Invest. 2006 116: 2161-2172.
Antigenic Diversity:
This theory proposes that the continual generation of
new antigenic variants eventually swamps and overcomes the immune system,
leading to its collapse.
There is no doubt that new antigenic variants of HIV constantly arise during
the long course of AIDS because of the low fidelity of reverse transcription.
It is envisaged that there might be a 'ratchet' effect, with each new variant
contributing to the slight but irreversible decline in immune function as
described
in 'T-cell Anergy' and 'Apoptosis' below. Because of the way virus infections
are handled by the immune system, it is probable that variation of T-cell
epitopes
on target proteins recognized by CTL are more important than B-cell epitopes
which generate the antibody response to a foreign antigen. Mathematical models
have been constructed which simulate antigenic variation during the course
of
infection. When primed with known data about the state of immune system during
HIV infection, these provide an accurate depiction of the course of AIDS
(Nowak
MA, et al. Antigenic diversity thresholds and the development of AIDS. Science
254: 963-969, 1991). Recently, it has been shown that there is a simple relationship
between virus load and survival time, and that a patient can withstand only
~1,300 "viral years" of HIV (i.e. copies of the virus genome/ml x survival
time in years).
Using mathematical modelling techniques, Martin Nowak
and Robert May describe ideas about how populations of viruses and populations
of immune system cells
may interact in various circumstances, and how infectious diseases spread
within patients. They explain how this approach to understanding infectious
diseases
can reveal insights into the dynamics of viral and other infections, and
the interactions between infectious agents and immune responses. This book
is intended
for researchers, postgraduates, and graduate students, biologists working
on disease ecology, evolution, and dynamics, mathematical biologists, immunologists
and virologists, and mathematicians working on biological problems. (Amazon.co.UK)
Superantigens are molecules which short-circuit the immune system, resulting
in massive activation of T-cells rather than the usual, carefully controlled
response
to foreign antigens. It is believed that they do this by binding to both the
variable
region of the β-chain of the T-cell receptor (V-β)
and to MHC II molecules, cross-linking them in a non-specific way:
This results in polyclonal T-cell activation rather than the usual situation
where only the few clones of T-cells responsive to a particular antigen presented
by the MHC II molecule are activated. The over-response of the immune system
produced results in autoimmunity, as rare clones of T-cells which recognize
self antigens are activated, and immune suppression, as the activated cells
subsequently die or are killed by other activated T-cells. It is possible
that
such superantigens might also induce apoptosis (pronounced
"apo-toe-sis", Greek: "falling leaves"),
or "programmed cell killing":
However, unlike other retroviruses (e.g. mouse mammary tumour virus (MMTV)
and the murine leukaemia virus (MLV) responsible for murine acquired immunodeficiency
syndrome (MAIDS)) no superantigen has been conclusively identified in HIV, despite
intensive investigation. Thus the practical relevance of superantigens in AIDS
is thus in doubt. However, it is possible that exposure to superantigens produced
by opportunistic infection(s) might play a role in AIDS.
T-cell anergy:
Anergy is an immunologically unresponsive state in which lymphocytes
are present but not functionally active. This is usually due to incomplete activation
signals and may be an important regulatory mechanism in the immune system, e.g.
tolerance of 'self' antigens. In AIDS, anergy could be induced due to HIV infection,
e.g. interference with cytokine expression. There is experimental in vitro evidence
that gp120-CD4 interactions result in anergy due to interference with signal
transduction.
Many AIDS patients are anergic, i.e. fail to mount a delayed-type hypersensitivity
(DTH) response to skin-test antigens. Impaired DTH responses are directly related
to decreasing CD4+ T-lymphocyte counts. However, there is no strong evidence that
this phenomenon is directly related to any aspect of HIV infection in vivo rather
than to general depletion of immune functions.
Apoptosis is believed to be a normal part of T-cell maturation, e.g. the elimination
of self-responsive clones. Like T-cell anergy, apoptosis could potentially be
induced in large numbers of uninfected cells by factors released from a much smaller
number of HIV-infected cells. In addition to clonal deletion as a normal part
of the evolution of the T-cell repertoire, apoptosis may be induced following
T-cell activation as a negative regulatory mechanism to control the strength and
duration of the immune response. This is relevant, since HIV infection of T-cells
induces an activated phenotype, e.g. surface expression of CD45 and HLA-DR markers,
which suggests that these cells may be inevitably doomed due to activation of
the apoptosis pathway. Because HIV establishes a persistent infection, it is by
no means clear that apoptosis has an entirely negative effect - induction of cell
death may well limit virus production and slow down the course of infection. The
present situation is rather confused, with several HIV proteins having been identified
as both inducers and repressors of apoptosis under various circumstances. However,
the proportion of CD4+ T cells in the later stages of apoptosis is about twofold
higher in HIV-1 infected individuals than in uninfected people.
Early in HIV infection, TH1-responsive T-cells predominate and are
effective in controlling (but not eliminating) the virus. At some point, a (relative)
loss
of the TH1 response occurs and TH2 HIV-responsive cells
predominate:
Regulation of the immune system depends on a complex network of cells, but
central to the process is the role of CD4+ T-helper (TH) cells.
Immunological theory (Clerici M, Shearer G. A TH1-TH2
switch is a critical step in the etiology of HIV infection. Immunol. Today
14: 107-111,
1993) suggests that there are
two types of these, TH1 cells which promote the cell mediated
response and TH2 cells which promote the humoral response. This
theory suggests that early in
HIV infection, TH1-responsive T-cells predominate and are effective
in controlling (but not eliminating) the virus. At some point, a (relative)
loss of the TH1 response occurs and TH2 HIV-responsive
cells predominate. It has been reported that at least some virus variants
can
inhibit the CTL response to HIV. The hypothesis
is therefore that the TH2-dominated humoral response is not effective
at maintaining HIV replication at a low level and the virus load builds up,
resulting in AIDS.
Although this is largely a theoretical proposal which has not been proved,
this thinking is shaping our understanding of the immune response to many
different
pathogens, not just HIV. However, no experimental study has demonstrated
an actual switch from the TH1 to TH2 pattern of cytokine
expression and secretion that is associated with disease progression, hence
there is no evidence for
the involvement of these mechanisms in AIDS.
Virus Load and Replication Kinetics:
Recent reports involving accurate quantitation of the amount of virus in infected patients have revealed that much more virus is present than originally thought. Using quantitative PCR methods to accurately measure the amount of virus present in HIV-infected individuals and determining how these levels change when patients are treated with compounds which inhibit virus replication, it has been shown that:
Continuous and highly productive replication of HIV occurs in all infected individuals,
although the rates of virus production vary by up to 70-fold in different individuals
It was initially reported that the average half-life of an HIV particle/infected
cell in vivo is 2.1 days. Recent report have suggested an even faster turnover
of plasma virus, corresponding to a particle half-life of 28-110 min.
Up to 109-1010 HIV particles are produced each day
An average of 2x109 new CD4+ cells are produced each day
Thus contrary to what was initially believed, there is a very dynamic situation
in HIV-infected people involving continuous infection, destruction and replacement
of CD4+ cells. Billions of new CD4+ cells are produced, infected and killed
each day. These data suggest a return to cellular killing (although predominantly
through apoptosis and immune-mediated killing rather than cell fusion) as a
direct cause of the CD4+ cell decline in AIDS.
These new ideas are informing future thinking about possible therapeutic intervention
in HIV-infected individuals. What is clear is that the presence of HIV is necessary
for the development of AIDS and that it is vital that the worldwide spread of
HIV infection is halted and reversed. Work on developing anti-HIV vaccines is
continuing but because of the complex biology of the virus, is proving to be formidably
difficult. A better understanding of the pathogenesis of AIDS and, in particular,
the role of the immune system in the early stages of the disease is vital to permit
the development of more appropriate therapies for AIDS. Highly active antiretroviral
therapy (HAART) has a dramatic effect on supressing virus production and temporarily
restores CD4 cell populations. Unfortunately, because of the long half life of
latently-infected cells, the estimated time to completely eradicate HIV from the
body is roughly 12-60 years - something which is not presently achievable due
to the failure of therapy as a result of toxicity and virus resistance.
Both HIV-1 and HIV-2 are of zoonotic origin. The closest simian relatives
of HIV-1 and HIV-2 have been found in the common chimpanzee (Pan troglodytes)
and the sooty mangabey (Cercocebus atys), respectively, and phylogenetic
evidence indicates that lentiviruses from these species have been transmitted
to humans on at least eight occasions [ref].
3D Animation of HIV Replication:
Therapy of HIV Infection:
Several distinct classes of drugs are now used in combination
to treat HIV infection,
commonly referred to as HAART, "Highly Active Antiretroviral Therapy:
Nucleoside-Analog Reverse Transcriptase Inhibitors (NRTI). These
drugs inhibit viral RNA-dependent DNA polymerase (reverse transcriptase) and
are incorporated into viral DNA (they are chain-terminating drugs).
Zidovudine (AZT = ZDV, Retrovir) first approved
in 1987
Didanosine (ddI, Videx)
Zalcitabine (ddC, Hivid)
Stavudine (d4T, Zerit)
Lamivudine (3TC, Epivir)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). In contrast
to NRTIs, NNRTIs are not incorporated into viral DNA; they inhibit HIV replication
directly by binding non-competitively to reverse transcriptase.
Nevirapine (Viramune)
Delavirdine (Rescriptor)
Protease Inhibitors. These drugs are specific for the HIV-1 protease
and competitively inhibit the enzyme, preventing the maturation of virions
capable of infecting other cells, e.g:
Saquinavir (Invirase) first approved in 1995
Ritonavir (Norvir)
Indinavir (Crixivan)
Nelfinavir (Viracept)
A number of fusion inhibitors, such as "T-20" and "T1249",
which interfere with the binding and fusion between gp120 and gp41 and
the CD4 molecule on
the host cell are currently in clinical trials. Unfortunately, these have
yet to reveal any significant clinical benefit.
Low-dose oral alpha-interferon, used quite widely for the treatment of patients
with HIV infection, does not appear to have a significant effects on the signs
and symptoms of the disease.
Standard
Version: The 4th edition contains new
material on virus structure, virus evolution, zoonoses, bushmeat, SARS
and bioterrorism, CD-ROM with FLASH animations, virtual interactive tutorials
and experiments, self-assessment questions, useful online resources, along
with the glossary, classification of subcellular infectious agents and
history of virology. (Amazon.co.uk) 
Instructors
Version: The 4th edition contains new
material on virus structure, virus evolution, zoonoses, bushmeat, SARS
and bioterrorism, CD-ROM with all the Standard Version content plus all
the figures from the book in electronic form and a PowerPoint slide set
with complete lecture notes to aid in course preparation. (Amazon.co.uk) 
