HIV and AIDS
When
in the summer of 1981 the Centers for Disease Control in the USA noticed an unusual demand for a drug used
to treat Pneumocystis pneumonia, a rare infection except in severely
immunosuppressed patients, and cases began to be increasingly reported in
homosexual men, haemophiliacs receiving certain batches of blood products and
drug users sharing needles, it became clear that a potentially terrible new
epidemic had hit mankind, more insidious than the plague, more deadly than
leprosy. The disease was baptized acquired immune deficiency syndrome (AIDS),
and has become the most widely studied infectious disease of all time.
By 1984 the cause had been traced
to a virus, now named HIV (human immunodeficiency virus), an RNA lentivirus (a
subfamily of the retroviruses) that possesses the enzyme reverse transcriptase.
This allows it to copy its RNA into DNA which is then integrated into the nucleus
of the cells it infects, principally T-helper cells and macro- phages. By
processes still not fully understood, this leads to a slow disappearance of
T-helper cells, with derangement of the whole immune system and the development
of life-threatening opportunistic infections and tumours. The origin of HIV
continues to be debated.
Attempts to link the epidemic to
contaminated polio vaccine, or even to
a political conspiracy have been totally discredited. The most likely
hypothesis is that it spread from chimpanzees at some time during the twentieth
century, perhaps due
to human consumption of infected meat. Enormous effort
has gone into trying to develop vaccines against HIV. HIV infection stimulates
strong cellular immunity and antibody responses, but these responses never seem
to be able to completely eliminate the virus, or even stop it dividing. In
part, this may be because the virus infects T-helper cells, and hence blocks
the development of full immunity. But the properties of HIV reverse transcriptase
also give it an unusual ability to vary its anti- gens, which makes protective
immunity or vaccination very difficult to attain.
Gag The gene for the core proteins p17, p24 and p15.
Like many viruses, HIV uses single
genes to make long polyproteins which are then cut up by the virus’s own enzyme
(a protease) into a number of different functional units. Drugs that block this
protease are an important class of HIV inhibitors.
Pol The gene for various enzymes, including the
all-important reverse transcriptase.
Env The gene for the envelope protein gp160, which
is cleaved during viral assembly to make gp120, the major structural protein of
the viral envelope. Interaction with the CD4 molecule found on T cells
and macrophages, and a second interaction with a chemokine receptor (usually
CCR5 or CXCR4), allows the virus to infect cells. About 1 in 10 000 Caucasian
individuals have a homozygous deletion in CCR5, and these individuals are highly
resistant to infection with HIV. Gag, pol and env genes
are found in all lentiviruses.
Tat, rev, nef, vif, vpu Genes unique to HIV, which can either enhance
or inhibit viral synthesis. Several of these molecules also antagonize cellular
defence systems. For example, nef downregulates MHC class I and hence
helps the virus escape immune detection, while vif blocks the enzyme
APOBEC which destroys the viral RNA.
Reverse transcriptase is required to make a DNA copy of the viral
RNA. This may then be integrated into the cell’s own nuclear DNA, from which
further copies of viral RNA can be made, leading to the assembly of complete
virus particles which bud from the surface to infect other cells. A key feature
of this enzyme is that it allows errors in transcription to occur (on average
there is one base pair mutation for every round of viral replication). This
feature allows the rapid evolution of new variants of virus during the course
of an infection.
Acute infection A few weeks after HIV infection some patients
develop a flu-like or glandular fever-like illness, although many remain
symptomless. This is associated with a rapid rise in the level of virus in
blood. During these weeks infected individuals rapidly develop antibody to HIV,
which is routinely used for diagnosis. A very strong cellular TC response also
develops, which decreases the amount of virus in blood (‘viral load’) to a much
lower, and sometimes undetectable, level. However, during this early phase
there is also massive destruction of CD4 cells, predominantly in gut tissue.
The mechanisms remain unclear.
Asymptomatic period Virus levels remain low for variable periods
between a few months and more than 20 years. During this period infected
individuals show few symptoms, although the number of CD4+ T cells falls
gradually. Despite this apparent ‘latency’, virus is in fact replicating
rapidly and continuously, mainly within lymph nodes, and there is an enormous
turnover of CD4+ T cells, as infected cells die and are replaced. There may be
a stage of progressive generalized lymphadenopathy (PGL).
Symptomatic period Patients develop a variety of symptoms, including
recurrent Candida infections, night sweats, oral hairy leukoplakia and
peripheral neuropathy (AIDS-related complex; ARC).
AIDS The full pattern includes the above plus severe
life-threatening opportunistic infections and/or tumours. In some patients
cerebral symptoms predominate. Almost every HIV-infected patient eventually
progresses to AIDS. In 2009 there were estimated to be 33 million individuals
infected with HIV worldwide, and over 2 million deaths from the disease,
although the numbers of infected people appear to have reached a plateau. The
vast majority of infected individuals are
in sub-Saharan Africa, but there
are expanding epidemics in many countries in the Far East. There are an
estimated 1.5 million infected people in North America, 600 000–800 000 in
western Europe and around 86 000 in the UK (many of them undiagnosed).
Kaposi’s sarcoma A disseminated skin tumour thought to originate
from the endothelium of lymphatics. It is caused by human herpes virus-8
(HHV-8, also known as KSHV), although it is still not clear why it is more
common in AIDS than in other immunodeficient conditions.
T cells are the most strikingly affected cells, the
numbers of CD4+ (helper) T cells falling steadily as AIDS progresses, which
leads to a failure of all types of T-dependent immunity. Although only 1% or
less of T cells are actually infected, the virus preferentially targets memory
cells.
MAC Macrophages
and the related
antigen-presenting cells, brain microglia, etc. are probably a main
reservoir of HIV and are usually the initial cell type to become infected.
Transmission is still mainly by intercourse (heterosexual as
well as homosexual), although in some areas infected blood from drug needles is
more common. HIV can also be transmitted from mother to child at birth
(vertical transmission) giving rise to neonatal AIDS. Not every exposure to HIV
leads to infection, but as few as 10 virus particles are thought to be able to
do so.
Pathology HIV is not a lytic virus, and calculations
suggest that uninfected as well as infected T cells die. Many mechanisms have
been proposed (including autoimmunity) but none is generally accepted.
Immunity The major antibody responses to HIV are against
p24, p41 and gp120. Some antibody against gp120 is neutralizing but is
very specific to the immunizing strain of virus. A strong CD8 T response
against HIV-infected cells persists throughout the asymptomatic phase of HIV
infection, suggesting that these cells are the major effector mechanism keeping
HIV replication in check. Several innate mechanisms that may have a role in
limiting lentivirus replication have been described (the molecules involved are
often referred to as restriction factors). An RNA/DNA-modifying enzyme related
to the one believed to be involved in somatic hypermutation (see Fig. 13) can
provide protection by causing lethal mutations in viral nucleic acids. A
cellular protein called TRIM5 acts at the stage of viral uncoating, while a
membrane protein called tetherin inhibits the ability of newly formed virus to
bud off from the cell surface. But HIV appears to have evolved ways of escaping
all of them!
Therapy Early drugs used for treatment against HIV were
inhibitors of viral reverse transcriptase, such as zidovudine (AZT). Treatment
with a single drug provides only very short-term benefit as the virus mutates
so fast that resistant strains soon emerge. However, the development of new families
of drugs, e.g. against the HIV-specific protease, allowed the introduction of
multidrug therapy, known as HAART (highly active antiretroviral therapy).
Patients are treated with three, four or even more different antivirals
simultaneously. These regimens have seen some spectacular successes in the
clinic, leading to disappearance of AIDS-associated infections, and
undetectable levels of virus for several years. However, this approach never
results in permanent elimination of virus, and resistant strains eventually
emerge. In any case the cost is prohibitive in most of the countries where HIV
is common. Thus, the requirement for an effective HIV vaccine remains acute,
and several trials aimed especially at stimulating a strong cellular response
are under way.
