ReviewAIDS in Africa: the impact of coinfections on the pathogenesis of HIV-1 infection
Introduction
The HIV-1 epidemic is having a devastating impact in sub-Saharan Africa. In 2002, it was estimated that 29.4 million people in the continent were living with HIV-1 infection and that the epidemic had claimed the lives of approximately 2.4 million Africans during that year.1 Indeed, HIV/AIDS accounts for, approximately 20% of deaths and disability-adjusted life-years lost in Africa.2 This epidemic in this region has developed on the background of a high pre-existing burden of infectious diseases, leading to potentially important disease interactions.
The natural history of HIV-1 infection is very variable; some individuals live with HIV-1 infection for over 10 years without developing significant immunosuppression, whereas, others may develop AIDS and die within one or two years. The rate of progression may be affected by many factors, relating to the infecting viral strain, host susceptibility and immune function as well as to exogenous influences such as access to healthcare and coinfections.3., 4., 5., 6. The relative importance of these factors may vary between populations in different regions of the world. This review addresses the hypothesis that frequent coinfections in HIV-1-infected individuals living in sub-Saharan Africa accelerate the progression of HIV-1 infection to AIDS, reduce survival and increase the risk of HIV-1 transmission.7., 8. In this region, the high prevalence of chronic and recurrent acute infections and relative inaccessibility to treatment for these conditions, may heighten any cofactor effect.
This review arises from the Barnett Christie Lecture delivered to the 9th Conference of the Federation of Infection Societies in November 2002. The mechanisms underlying the impact of coinfections on HIV-1 pathogenesis are reviewed and the findings of the author's own research in this field are presented.
Section snippets
Immune activation and HIV-1 replication
The HIV-1 life-cycle is intimately related to the level of activation of immune cells supporting viral replication. An increase in cellular activation in response to coinfections or immunisations may enhance viral replication by facilitating three key stages of the viral life-cycle; viral cellular entry, reverse transcription and proviral transcription.3
Viral cellular entry. HIV-1 particles typically gain entry to host cells by binding to the cell surface CD4 receptor and a chemokine
Tuberculosis and HIV-1 pathogenesis
Mycobacterium tuberculosis is a key opportunistic infection in HIV-1-infected individuals living in sub-Saharan Africa. In view of its high incidence, chronic course and associated systemic immune activation and proinflammatory cytokine drive,29., 30. TB is potentially an important cofactor in HIV-1 pathogenesis. Numerous in vitro studies have demonstrated the ability of M. tuberculosis to induce HIV-1 transcription in infected peripheral blood mononuclear cells.31., 32. In vivo, development of
Parasitic infections and HIV-1 pathogenesis
The huge burden of disease associated with parasitic infections in sub-Saharan Africa57 overlaps with the HIV-1 epidemic in this region. Despite the importance of determining the impact of these coinfections on HIV-1 pathogenesis, few studies address this issue as yet.
Coinfections and sexual transmission of HIV-1
There is a strong positive correlation between plasma HIV-1 load and risk of heterosexual HIV-1 transmission.69 Therefore, coinfections that lead to increased plasma viral load may potentially promote transmission. However, sexually transmitted infections within the genital tract itself clearly play a pivotal role in the heterosexual HIV-1 epidemic in sub-Saharan Africa.70., 71. The association with genital ulcer disease is particularly strong and it has been hypothesised that these
Epidemiological data on rate of progression to AIDS in Africa
Compelling in vitro and in vivo data have characterised the significant impact of immune activation associated with coinfections on HIV-1 replication and virus–host dynamics.3 Furthermore, high viral load is strongly associated with faster progression to AIDS.77 In view of these data, it is hypothesised that a high prevalence of coinfections leads to accelerated decline in immune function and shortened survival in HIV-1-infected individuals living in sub-Saharan Africa. To date, the rate of
Conclusions
The intimate relationship between the HIV-1 life-cycle and the activation state of the cells supporting viral replication results in a dynamic interaction between coinfections and HIV-1 pathogenesis. Systemic effects of recurrent coinfections potentially increase viral load, viral heterogeneity and CD4 cell loss leading to accelerated decline in immune function and reduced survival. These effects may be particularly important among those living in sub-Saharan Africa, although this remains
Acknowledgments
The Barnett Christie Lecture that forms the basis for this review was sponsored by the British Infection Society at the 9th Annual Conference at the Federation of Infection Societies. The author's work at the Centers for Disease Control and Prevention (CDC), Atlanta, USA was initially funded by a fellowship from the Wellcome Trust, London, UK (1997–1999) and then by a fellowship administered by the Oak Ridge Institute for Science and Education, Oak Ridge TN, USA (1999–2001). The author is
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