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r L—1— 1— —1— 1— 1— i_*j— 1— L . 1 . 1 1 1 / i . . . 1- 1 1 1 1 1 1 1— r—^ 0 3 6 9 12 Weeks 2 3 4 5 6 7 8 9 10 11 Years 0 3 6 9 12 Weeks 1 2 3 4 5 6 7 Years 8 9 10 11Figure 1.6- Different routes of progression of HIV
Four schematics, showing CD4^ T cell counts and viraemic levels, illustrate the different courses of dis ease progression. SoUd symbols represent CD4^ T cell counts, and symbol-less hnes to levels of plasma viraemia. (Diagram adapted from Pantaleo, G. & Fauci, LS.Annu Rev Microbiol (1996) 50,825-854).
progress rapidly and some slowly may be of fundamental importance to understanding pathogenesis.
1.4.3.1- Rapid progressors
Rapid progression is defined as having an AIDS defining diagnosis within four years of contracting the disease, and occurs in 10-15% of cases (Phair et al, 1992). Rapid progressors experience faster CD4+ T-cell loss (see Fig. 1.6), and tend to have a higher viral burden and lower levels of virus-specific CTL than average (Bollinger et al, 1996, de Rossi et al, 1991, Sheppard et al, 1993). It has been shown that age, race and gender are probably not significant factors in rate of progression, but a greater number of high risk sexual activities, and by association repeated exposure, does correlate with faster progression (Phair et al, 1992). However there is some weak evidence that older people who are infected may progress fractionally faster (Belanger et al, 1997).
Analysis of virus taken at multiple time points from an individual who was infected in an accident by T-tropic, syncytium-inducing virus and who progressed rapidly, showed that post-transmission the virus had shifted from a T-tropic to a predominantly M-tropic phenotype, before switching back again shortly before a diagnosis of AIDS was made, but at all times the virus remained SI (Schuitemaker et al, 1992a). This provides anecdotal evidence that SI phenotype, but not viral tropism, is important in rapid progression. Indeed others have shown that the presence of SI phenotype in viruses during the initial illness appears to result in rapid progression (Nielsen et al, 1993).
As well as having lower levels of CTL, rapid progressors often fail to develop a broad CTL response, and instead have a major expansion of only a single VB subset (Fauci
et al, 1996, Pantaleo et al, 1994). They may also possess enhancing antibodies, that, as opposed to neutralising the virus, render it more infective (Levy, 1993). In addition it is possible that certain human leukocyte antigens, HLA, such as HLA-DQB1 in Caucasians, may be associated with rapid progression (Achord et al, 1997).
1.4.3.2- Typical progressors
This group represents the majority, 70-80%, of HIV-l infected people. They progress to AIDS in about 8-10 years post-infection (see Fig. 1.6), and their CD4+ T-cell count decreases by an average of 70 a year (Sheppard et al, 1993). They exhibit a gradual loss of lymph node architecture, especially in the follicular dendritic cell (FDC) network, and eventual lymph node involution (Pantaleo et al, 1995). In comparison to long-term non- progressors they have a higher viral burden in both the blood and the lymph nodes, and virus can be cultured from plasma (Pantaleo e ta l, 1995).
1.4.3.3- Long-term non-progressors
and a stable CD4+ T-cell count above 500 x 10^/1 more than eight years after initial infection (see Fig. 1.6) define long-term non-progression, LTNP (Schrager et al., 1994). Approximately eight percent of those infected fall into this category (Buchbinder et al.,
1994).
In comparison to typical progressors, LTNPs have detectable but quantifiably less viral RNA in their plasma and furthermore it is not possible to culture virus from plasma nor observe infectious virus in PBMC (Cao et al., 1995, Cao et al., 1996, Pantaleo et al.,
1995). Phenotyping of virus reveals a predominantly M-tropic, NSI population that is replication proficient, with little or no T-tropic or SI virus (Cao et al., 1995, Cao et al.,
1996, Sheppard et al., 1993). Genotyping indicates that the accessory genes vpr, and
vpu are all intact and functional (Zhang et al, 1997).
Although experiments in monkeys have shown that «^/-deficient SIV infection leads to non-progression, in 90% of LTNP, nef is intact (Huang et al, 1995). Nevertheless there is much evidence that if there is no intact nef the patient will not progress, accounting for a discrete subset of LTNPs (Blaak et al, 1998, Deacon et al, 1995, Kirchhoff et al,
1995, Premkumar et al, 1996). Genotyping of patients has revealed that those heterozygous for a mutant form of CCR5, a co-receptor for HIV-cell entry, have a statistically significant greater chance of being an LTNP (Dean et al, 1996).
CD4+ T-cell counts remain high in LTNPs. However they are lower than those in the general population (Buchbinder et al, 1994, Lifson et al, 1991). CD8^ T-cell counts are raised and a high number of Gag-, Pol-, and Env-specific CTL are detectable (Bollinger
et al, 1996, Buchbinder et al, 1994, Lifson et al, 1991). NK activity is lower than in the general population, and indeed less than that of progressors (Lifson etal, 1991). In contrast to progressors their lymph node architecture and FDC network remain intact and lymph nodes have a lower viral burden (Pantaleo et al, 1995).
In comparison to typical progressors titres of antibody are higher (Pantaleo et al,
1995), and the range of neutralising antibody broader (Pilgrim et al, 1997). These lack enhancing ability and neutralise laboratory strains of HIV-l such as HIV-IIIB poorly (Lifson
et al, 1991). In addition to higher antibody titres, levels of non-cytolytic, soluble CD8^ T- cell-mediated anti-HIV-1 activity are greater, rendering PBMC less susceptible to infection (Bollinger et al, 1996, Cao et al, 1995). Analysis of RANTES and M IP -la levels show that although RANTES is raised and M IP -la is reduced in comparison to healthy controls, they are not significantly different to those of progressors. This intimates that not only are these chemokines not the “soluble CD8+ T-cell factor”, but also that they do not play a significant role in disease progression (Krowka et al, 1997, Zanussi et al, 1996).
While LTNPs are outwardly normal, they do have significant immune system abnormalities compared to uninfected individuals. Also most virological and immunological markers are similar to those found early in progression in typical progressors, suggesting that all will eventually get AIDS without treatment (Sheppard et al, 1993). Furthermore
alm ost all (90%) after ten years of disease show some signs, either virological, immunological, or both, of disease progression (Lefrere e ta l, 1997). This intefs, with the exception of those infected with ne/-deficient virus, that LTNPs are the tail end of a continuous group.
1.4.3.4- Long-term survivors
In the majority of infected individuals when CD4+ T-cell counts drop below approximately 200 x lOVlitre the immune system can no longer cope with opportunistic infections, resulting in AIDS and death within two to three years. Long-term survivors decline at a similar rate to typical progressors (see Fig. 1.6), but on reaching a low CD4+ T- cell count do not suffer from any AIDS-defining illnesses and do not progress any further, remaining in this state for more than five years (Schrager etal, 1994). This group represents a tiny proportion of cases and of those, patients are predominantly of African race (Apolonio
et a l, 1995), Absence of SI variants of HIV-l and p24 antigenaemia, and a high PHA- induced T-cell activity are good predictors of long-term survival (Keet et al, 1994a).
1.4.4-AIDS
As the CD4 cell count drops and the immune system becomes ever more impaired, the infected individual becomes susceptible to opportunistic infections and neoplasms. These fall into two categories, based on the US Centres for Disease Control and Prevention definitions (1987, 1992), those that are AIDS defining and those that are not.
Conditions that do not define AIDS are termed AIDS-related complexes (ARC) and include substantial unexplained weight loss, diarrhoea, or fever, oral hairy leukoplakia, oral candidiasis, listeriosis and pelvic inflammatory disease.
AIDS itself is defined as the presence of one or more of a list of life-threatening opportunistic illnesses ( 1987), or a CD4+ T cell count of less than 200/mm^ ( 1992) although this criterion is not used in the UK. AIDS-defining infections include bronchial candidiasis, cryptococcosis, CMV-based illnesses, tuberculosis, toxoplasmosis, and PCP. Opportunistic neoplasms include Kaposi’s sarcoma and non-Hodgkin’s lymphoma. In addition there are conditions of unknown aetiology such as HIV encephalopathy, and HIV wasting syndrome.
The exact point at which a person is defined as having AIDS varies. As the US definition suggests, it is commonly associated with a CD4+ T cell count below 200/mml However Kaposi’s sarcoma can occur at CD4 counts of above 500 (Rozenbaum et al,
1990), and people can remain well with counts below 50 (Schrager et al, 1994). What causes the immune system to switch from being able to cope to being unable to cope is not clear.