Pathogenesis and Course of AIDS

Pathogenesis and Course of AIDS Title: Give a detailed account of the pathogenesis and course of AIDS. Undergraduate Degree Level Essay 2,500 words   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 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 â€Å"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 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, Hodgkins 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-Hodgkins 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 Kaposis sarcoma and B cell lymphomas. Study of these progressive â€Å"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) naà ¯ve 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. Treatment 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 â€Å"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 â€Å"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) References AIDS RU 1998 AIDS research updates. Science 1998; 280: 1856-1894 Berger E A et al 1998 Nature 391:240, 1998 Berwick D 2005 Broadening the view of evidence-based medicine Qual. Saf. Health Care, Oct 2005; 14: 315 316. Chan DC, Kim PS. 1998 HIV entry and its inhibition. Cell 1998; 93: 681-684 Connors M, Kovacs J, Krevat S, Gea-Banacloche JC, Sneller MC, Flanigan M, et al. 1997 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 Science 273:1857, 1996 Finzi D, Siliciano RF. 1998 Viral dynamics in HIV-1 infection. Cell 1998; 93: 665-671 Graham B S 1998 Science, medicine, and the future: Infection with HIV-1 BMJ, Nov 1998; 317: 1297 1301 Greek R, Pandora Pound, and Nancy L Haigwood 2002 Animal studies and HIV research BMJ, Jan 2002; 324: 236 ; Hecht FM, Grant RM, Petropoulos CJ, Dillon B, Chesney MA, Tian H, et al. 1998 Sexual transmission of an HIV-1 variant resistant to multiple reverse-transcriptase and protease inhibitors. N Engl J Med 1998; 339: 307-311 Jordan R, Lisa Gold, Carole Cummins, and Chris Hyde 2002 Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral combination therapy BMJ, Mar 2002; 324: 757 ; Lafeuillade A, Poggi C, Tamalet C, Profizi N. 1997 Human immunodeficiency virus type 1 dynamics in different lymphoid tissue compartments. J Infect Dis 1997; 175: 804-806. Lenzer J 2003 Claim that smallpox vaccine protects against HIV is premature, say critics BMJ, Sep 2003; 327: 699 ; Littman D R 1998 Chemokine receptors: keys to AIDS pathogenesis? Cell 1998 May 29;93(5):677-80. Malegapuru W, Makgoba, Nandipha Solomon, and Timothy Johan Paul Tucker 2002 Science, medicine, and the future: The search for an HIV vaccine BMJ, Jan 2002; 324: 211 213 ; Matano T, Shibata R, Siemon C, Connors M, Lane HC, Martin MA. 1998 Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 1998; 72: 164-169 Mazzoli S, Trabattoni D, Lo Caputo S, Piconi S, Ble C, Meacci F, et al.1997 HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals. Nature Med 1997; 3: 1250-1257 McMichael A. 1998 T cell responses and viral escape. Cell 1998; 93: 673-676 Mugerwa R D, Pontiano Kaleebu, Peter Mugyenyi, Edward Katongole-Mbidde, David L Hom, Rose Byaruhanga, Robert A Salata, and Jerrold J Ellner 2002 First trial of the HIV-1 vaccine in Africa: Ugandan experience BMJ, Jan 2002; 324: 226 229 ; Musey L, Hughes J, Schacker T, Shea T, Corey L, McElrath MJ. 1997 Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. N Engl J Med 1997; 337: 1267-1274 Nosik M N, Matsevich G R 2002 HIV-1 chemokine receptors and their role in the pathogenesis of AIDS Vopr Virusol. 2002 Jan-Feb;47(1):4-8. Stilianakis NI, Dietz K, and Schenzle D, 1997, Analysis of a model for the pathogenesis of AIDS Mathematical Biosciences, 145, 27-46 Voulgaropoulou et al. 1999 Distinct Human Immunodeficiency Virus Strains in the Bone Marrow Are Associated with the Development of Thrombocytopenia, J Virol 1999 Apr;73(4):3497-504 Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, et al.1995 Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995; 373: 117-122 ############################################################# 17.3.06 PDG Word count 2,514