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.
HIV I and II, the AIDS viruses, closely related to the simian (monkey) virus SIV and more distantly to retroviruses such as HTLV I and II, which are rare causes of T-cell leukaemias. Their genome consists of double-stranded RNA. HIV II causes a much slower and less aggressive disease, and is predominantly found in Africa.
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.