Title: Give a detailed account of the pathogenesis and course of AIDS.
Undergraduate Degree Level Essay
The study of HIV / AIDS is a vast topic and the literature on the subject fills many volumes. In this essay therefore we propose to take an overview of some of the most current views and developments in the field with particular emphasis on the pathophysiology of HIV / AIDS
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In 1997 the World Health Organisation gave the assessment that since HIV / AIDS had been recognised, over 11.7 million people had died of the condition world wide and at the time of publication 30 million more were thought to be infected with 16.000 new infections occurring daily. Current predictions estimate that at the current rate of infection 55 million will have died by 2010. (Greek R et al 2002)
Perhaps the most worrying of all of these gargantuan statistics was the fact that of the 30 million infected, 27 million were thought to be unaware of their condition. Quite apart form the devastation the disease causes on a personal basis, the vast majority of those infected are young adults which has enormous implications for the social structure of their communities. (Graham B S 1998)
Pathophysiology of the condition
As we have implied earlier, the volume of work relating to the pathophysiology of HIV / AIDS is enormous, in this essay we therefore intend to “cherry-pick” a number of selected topics and discuss them in some detail.
The implications of genetics in both the acquisition of HIV and the subsequent development of AIDS is a rapidly expanding field.
The interaction between virus and host is a multifaceted and extremely complex one. From the point of infection onwards there is usually a significant HIV viraemia even though in the early stages, the patient may be completely asymptomatic. It is known that the degree of virus replication is directly related to the degree of T-cell depletion and equally correlates with progression of the disease process. It would therefore appear that HIV induces symptomatic disease process by replicating in, and subsequently destroying, CD4 and T-cells thereby weakening the immune system. (Stilianakis NI et al 1997),
.Different hosts and indeed different genotypes of hosts (see on) have differing patterns of disease expression. CD4 and T-cell levels are rapidly diminished in the early stages of the disease but are not restored by effective anti-viral therapy if given later in the disease. (Littman D R 1998)
One area of obvious interest is in those who appear to survive with HIV for a longer than average time before it progresses to AIDS. A study by Dean (M et al 1995) proved to be seminal in this area, with a prospective study of nearly 2,000 men. The authors considered the status of CCR5 genotype and its relation to the likelihood of disease progression. The paper is both long an detailed, but provides a strong evidence base for further research (Berwick D 2005).
In essence, the main findings of the paper were that most people have two normal alleles for the CCR5 gene, but 1 in 7 has one mutant allele (technically 32bp deletion), which means that they still have one normal allele (heterozygous genotype). 1 in 100 have two mutant alleles. The rates of mutation are highly racially specific ranging from 11% in Caucasians to < 1% in Asians (Finzi D et al 1998).
The significant finding in the study was that none of the 1,300 HIV +ve people in the study had the homozygous mutation, 15% of the HIV +ve had the heterozygous genotype, so the heterozygous genotype clearly does not protect against infection, but the significant difference is that the average transition time from HIV to AIDS for the homozygous man was 10 years whereas the average transition time for the heterozygous genotype was 13 years. Possibly even more significant is the fact that of the 17 people in the entry cohort who were homozygous for the mutation and in the high risk of infection group, none of them had contracted HIV. It would therefore appear that the CCR5 mutation plays some critical role early in the primary stages of HIV infection since it appears that HIV infection can be blocked if a functioning version of this receptor is not present.
During the later stages of the infection it would appear that other co-receptors (the CXCR4 has been implicated) can take over the role as the properties of the virus evolve within the host. (McMichael A 1998). On this basis some authors have suggested a classification taxonomy that differentiates HIV virus sub-types on the basis of their CCR5 receptor affinity. (Berger E A et al 1998).
It would appear that the viruses eventually evolve into the R5X4 (in this classification) type which allows them to eventually produce the full blown AIDS syndrome. The absence of one working CCR5 allele simply retards the evolutionary progress. (Chan DC et al 1998),
This is in congruity with other pathophysiological observations. For example, it is already known that the influenza virus enhances the CXCR4 dependent HIV infection. It is thought that the pathway of influenza infection activates the CD4 and T- lymphocytes which, in turn utilise the CXCR4 co-receptors on the cell. This activation would therefore appear to increase the potential number of HIV target cells in an individual which would clearly accelerate viral spreading. (AIDS RU 1998).
In the same way, syphilis is known to be an active agent in increasing CCR5 expression and is also known to be a strong predisposing factor for the overall HIV risk whereas it does not induce CXCR4 (Lafeuillade A et al 1997),
From our considerations thus far it is clear that the pathophysiology of the HIV infection revolves around the build up (replication) of the HIV virus in the CD4 and T-cells. This is not an immediate process as new T-cells are being produced (albeit from a progressively dwindling stock) of non-infected bone marrow stem cells. (Greek R et al 2002)
Why are there a number of specific AIDS-defining diseases?
This is a vast area in its own right. The presence of HIV in a T-cell does not immediately destroy the cell, but alters its function. Each T cell has a number of receptor areas determined by the V region of the receptor gene, and these determine the subclass (and specificity) of the T-cell itself . Each sub-type has specific receptor sequences that allow it to recognise a broad spectrum of histocompatibility complexes. (Hecht F M et al 1998)
The HIV presence alters the expression of the V site region and thereby allows certain pathogens to be sub-optimally challenged (Connors M et al 1997). It is the nature of HIV infection that specific colonies (or sub-types) of CD4 T-cells are depleted before others are altered. This translates clinically into the situation where certain pathogens ( viz. Pneumocystis carinii, Mycobacterium avium-intracellulare, and cytomegalovirus. ) can be present, virtually unchallenged even though the T-cell population may be apparently quite active. Typically the reservoir of CD4 and CD8 lymphocytes may remain skewed despite the overall apparent adequacy of circulating T-cells. (Nosik M N et al 2002),
Alongside this altered state of immunity a number of other immune-related phenomenon can be seen including some types of autoimmunity and AIDS-related malignancies including squamous cell carcinoma of skin, testicular cancer, myeloma, Hodgkin’s disease.
Some investigators have recently demonstrated a statistically very significant relationship between a profound immunodeficiency state (with marked CD4 depletion) and the development of a non-Hodgkin’s lymphoma, presumably by a similar mechanism. (Voulgaropoulou et al. 1999)
Aggressive anti-viral therapy has been partially successful in reducing the frequency of malignancies such as Kaposi’s sarcoma and B cell lymphomas. Study of these progressive “blind spots” in the T-cell’s response mechanisms suggest that a diversity of the T-cell receptor V genes can be re-established in patients with an undetectable viraemia for longer than a six month period, which is strongly suggestive of the fact that regeneration of uninfected (or immuno-protected) naïve precursors is possible with aggressive therapy. (Connors M et al 1997),
There is an overall increase in the incidence of AIDS-related malignancies. This is not thought to be due to any new or progressive evolution of the HIV virus, but mainly due to the development of new and more effective antiretroviral therapies together with more efficient prophylaxis for opportunistic infections which is allowing the HIV / AIDS patient to survive for longer in the immunodeficient state.
We do not intend to present any detail relating to specific treatments for HIV / AIDS but will make a few general comments. A current pressing question for clinicians is “can antiretroviral therapy ever be safely stopped?” The current generations of protease inhibitors that are combined with non-nucleoside reverse transcriptase inhibitors are capable of reducing viraemia to undetectable levels. (Jordan R et al 2002),
Clinical experience suggests that as soon as treatment is stopped, viraemia tends to rapidly recur at pre-treatment levels. This strongly suggests an ability of the HIV to enter a latent phase or to remain in immunoprivilleged sites (such as the testes and central nervous system). Like most retro-viruses, the HIV has the ability to integrate its DNA into the host genome even though it may remain transcriptionally dormant and thereby avoid cellular detection and apoptosis until it enters its replication cycle (Wei X et al 1995),
It is difficult to draw specific conclusions from a presentation such as this as the overriding impression that one gets from any examination of the literature on the subject is both the speed and the diversity of the research that is currently being undertaken world-wide. There appear to be two main thrusts as far as research is concerned. One is the development of new antiretroviral and immunoactive therapeutic measures to try to combat the pathophysiology of the disease process itself, the other is the search for a vaccine which would ultimately be the “holy grail” in this particular pandemic. (Malegapuru W et al 2002)
One of the main stumbling blocks as far as vaccine development is concerned is the difficulty in targeting the antigenicity of the frequently changing immunological profile of the HIV. (Musey L et al 1997). Considerable interest has been shown in the persistently sero-negative partners of sero-positive patients who have been frequently found to have a specific ability to produce interleukin 2 from peripheral mononuclear cells together with the detectable presence of HIV specific IgA in mucosal secretions. (Mazzoli S et al 1997),
Many vaccine research projects are currently exploring the avenue of designing vaccines which have the potential to stimulate and produce HIV-specific CD8 cytotoxic T-cell responses to the HIV. Initial primate studies suggest that prevention of infection at a mucosal site (as opposed to parenteral infection) is actually possible as mucosal infection is relatively inefficient and only a small number of HIV virons are likely to be involved. (Matano T et al 1998).
Phase one clinical trials have been undertaken in this regard already but with disappointing results as the immunogenic responses that have been engendered are 5-10 times lower than those produced by HIV infection with a comparatively short half-life. (Mugerwa R D et al 2002).
There are a number of approaches with recombinant viral entities of various types which have also met with limited success Currently it would appear that vaccine candidates can manage to induce CD8 cytotoxic T lymphocyte responses with killing activity across different strains which can last a significant length of time, but they are yet unable to induce neutralising antibody with activity against typical transmitted HIV virus. (Lenzer J 2003)
AIDS RU 1998
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HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies.
Nature Med 1997; 3: 533-540
Dean M. et al 1996
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Sexual transmission of an HIV-1 variant resistant to multiple reverse-transcriptase and protease inhibitors.
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McMichael A. 1998
T cell responses and viral escape.
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17.3.06 PDG Word count 2,514
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