Part 1: The Pathogenesis of AIDS (including therapy)
Part 2: Who gets AIDS?
The Pathogenesis of AIDS
Latest statistics from WHO
The pathogenesis of AIDS is dependent on the biology of HIV, e.g:
Some of the immune abnormalities in HIV infection include:
- 'Trojan horse' mechanism - virus escapes recognition by replication inside monocytes, from where it can spread to other tissues and other hosts.
- Latency - Lentiviruses do not show true latency (unlike Herpes viruses or lambda) but do have the capacity to control the expression of their genome by means of virus-encoded trans-acting regulatory proteins (tat and rev).
- Antigenic variation - new variants continually arise. In other Lentiviruses such as CAEV, each new antigenic variant results in a flare up of disease. May also occur in HIV and contribute to decline of immune system - 'ratcheting' mechanism due to increasing virus load?
- Altered cytokine expression
- Decreased CTL and NK cell function
- Decreased humoral and proliferative response to antigens and mitogens
- Decreased MHC-II expression
- Decreased monocyte chemotaxis
- Depletion of CD4+ cells
- Impaired DTH reactions
- Polyclonal B-cell activation
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 first mechanism suggested, based on the behavior of certain laboratory isolates of HIV. Subsequent experiments suggested that there is not sufficient virus present in AIDS patients to account for all the damage seen, although killing of CD4+ cells may contribute to the overall pattern of pathogenesis seen in AIDS. Indirect effects of infection, e.g. disturbances in cell biochemistry and lymphokine production may also affect the regulation of the immune system:
However, the expression of virus antigens on the surface of infected cells leads to indirect killing by the immune system (NK/CTL/ADCC) - effectively a type of autoimmunity. Recently, this hypothesis has been resurrected as a result of more accurate quantitation of virus load and replication kinetics in infected individuals (see below).
This theory holds 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, in a similar way to CAEV infection of goats. It has not been completely established how this might lead to the collapse of the immune system, but it is envisaged that there might be a 'ratchet' effect, with each new variant contributing to the slight but irreversible decline in immune function.
N.B: Because of the way virus infections are handled by the immune system, it is probable that variation of T-cell epitopes on target proteins recognised by CTLs are at least (probably more) important than B-cell epitopes which generate the antibody response to a foreign antigen. It has recently been reported that at least some variants can inhibit the CTL response to wild-type HIV (Meier, U. et al. Cytotoxic T lymphocyte lysis inhibited by viable HIV mutants. Science 270: 1360-62, 1995).
A mathematical model has been constructed which simulates antigenic variation during the course of infection. When primed with all of the known data about the state of immune system during HIV infection, it provides a startling accurate depiction of the course of AIDS (Nowak MA, et al. Antigenic diversity thresholds and the development of AIDS. Science 254: 963-969, 1991).
Medscape Article: Genotypic Variation and Molecular Epidemiology of HIV.
The Superantigen Theory:
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 beta-chain of the T-cell receptor (V-beta) 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 recognise 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-tosis"), or 'programmed cell killing' (Cohen JJ. Apoptosis. Immunol. Today 14: 126-136, 1993):
It has been reported that in some AIDS patients, certain clones of T-cells bearing particular Vb T-cell receptor rearrangements are depleted or absent. This is precisely what would be expected if some clones of cells were being eliminated by the presence of a superantigen. However, unlike other retroviruses (e.g. mouse mammary tumour virus (MMTV) and the murine leukaemia virus (MuLV) 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 remains in some doubt. However, it is possible that exposure to superantigens produced by opportunistic infection(s) might play an important role in AIDS.
There have been several reports that HIV binding to CD4 induces an intracellular signal which may have a detrimental effect on cells. None of these have been completely convincing. However, there is a second component to the HIV receptor which is required for cell entry: chemokine receptors such as CXCR4 & CCR5. Although HIV-mediated signal transduction is not required for fusion & entry, at least some HIV isolates induce a signal when the envelope protein binds to CCR5 (Weissman et al, Nature 389: 981-985, 1997). HIV disease is characterized (in part) by persistent immune activation. Envelope-mediated signalling through binding to chemokine receptors could contribute to cellular activation. HIV replicates only in activated cells, so this activity promotes replication directly & may also assist in the spread of the virus to uninfected cells by inducing the migration of activated cells to sites of virus replication via chemotaxis. These signals may also contribute indirectly to the pathogenesis of the infection by inducing apoptosis or anergy.
Neuronal apoptosis is a feature of HIV-1 infection in the brain, contributing to dementia. gp120 from some strains of HIV binds with high affinity to CXCR4 expressed on hNT neurons. Both gp120 and the Cys-X-Cys chemokine SDF-1[alpha] can directly induce apoptosis in hNT neurons in the absence of CD4 and in a dose-dependent manner. Thus the HIV-1 envelope glycoprotein may elicit apoptotic responses through chemokine receptors.
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:
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.
N.B. This is a theoretical proposal, and has not yet been proved, but is shaping our understanding of the immune response to many different pathogens, not just HIV (Clerici M, Shearer G. A TH1-TH2 switch is a critical step in the etiology of HIV infection. Immunol. Today 14: 107-111, 1993).
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
- The average half-life of an HIV particle/infected cell in vivo is 2.1 days
- Up to 2x109 HIV particles are produced each day
- An average of 2.6x109 new CD4+ cells are produced
Thus, contrary to what has recently been thought, there is a very dynamic situation in HIV-infected subjects involving continuous infection, destruction and replacement of CD4+ cells, with billions of new cells being infected and killed each day. These data suggest a return to cellular killing (although predominantly immune-mediated rather than virus-mediated) as a direct cause of the CD4+ cell decline in AIDS. For reasons which are not yet clear, this is a (marathon) race between virus production, destruction and cellular regeneration which, after many years, most individuals loose, resulting in the absolute decline of the CD4 segment of the immune system and the development of full-blown AIDS.
The ultimate mechanism by which HIV infection causes AIDS remains unknown, but recent reports strongly implicate immune-mediated killing of virus-infected cells as the major factor in the pathogenesis of this disease. These new ideas are informing future thinking about possible therapeutic intervention in HIV-infected individuals.
Therapy of HIV Infection:
Several distinct classes of drugs are now used to treat HIV infection:
- 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).
- 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.
- 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.
© AJC 1998